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Introduction

Acute transverse myelitis (ATM) is a myelopathy characterized by acute or subacute movement, sensory, and autonomic neurospinal dysfunction, with one to four new cases per million people per year (1). The pathological and physiological mechanisms of ATM have not yet been elucidated, but it may be caused by ascending and descending spinal tracts of specific levels of bone marrow (2). Symptoms and signs of motor, sensory and autonomic nerve dysfunction in ATM patients may occur simultaneously, mainly depending on the level of the spinal cord involved (3). One-third of patients with ATM can fully recover, another third have moderate residual neurological deficits, and the remaining third show clinically severe residual neurological deficits. ATM patients with poor prognosis have spinal shock and high disability (4-6).

Currently, the first-line therapy for clinical treatment of ATM is glucocorticoid treatment, such as dexamethasone and methylprednisolone. Traditional dexamethasone treatment has slower onset, longer treatment time and more adverse reactions, often leaving serious neurological dysfunction (7,8). However, methylprednisolone can produce non-specific immunosuppressive responses to the nerve center, play a role in anti-inflammatory and anti-edema, improve the blood circulation of nerves, and reduce spinal cord inflammation (9). γ-globulin is an IgG obtained from thousands of human plasma, which can rapidly supplement antibodies in patients, inhibit the mononuclear phagocytic system, and it has good efficacy in both autoimmune and inflammatory diseases (10). At present, the pathogenesis of ATM has not been clearly clarified, and immune dysfunction may be one of its pathogenesis (11). Although there have been many studies on the application of glucocorticoids and γ-globulin in ATM (12-14), there are few studies on effects of γ-globulin combined with dexamethasone and methylprednisolone, respectively, on immune function and quality of life.

In this study, γ-globulin was combined with dexamethasone or methylprednisolone to treat patients with ATM. Clinical efficacy of the two treatment schemes and their effects on immune function and quality of life were compared.

Patients and methods

General data

A retrospective analysis of medical records from 136 ATM patients admitted to the hospital from July 2014 to September 2017 was performed. Patients treated with dexamethasone combined with γ-globulin were enrolled in group A (66 cases), and those treated with methylprednisolone combined with γ-globulin were included in group B (70 cases). In group A, there were 40 males and 26 females, aged 24 to 49 years, with a mean age of 34.7±5.9; in group B, there were 39 males and 31 females, aged 23 to 50 years, with a mean age of 35.9±6.4. All patients were informed and signed an informed consent. This study was approved by the Ethics Committee of Linzi District People's Hospital (Zibo, China).

Inclusion and exclusion criteria

Inclusion criteria were as follows: patients complied with the diagnostic criteria of ATM in the International Collaboration Group of Acute Myelitis (TMCWG) (15); the protein of the lumbar puncture cerebrospinal fluid increased, and the diagnosis was confirmed by imaging MRI; patients bilaterally asymmetric, with symmetric nervous system signs and symptoms; the level of muscular strength of double lower limbs of people was from 0 to 3, with sensory plane barriers and sphincter dysfunction; patients with complete clinical data; patients with drug contraindications in this treatment, and anti-inflammatory, immunosuppressive drugs used in the past month. Exclusion criteria were as follows: Patients with myelitis caused by vascular, metabolic, radioactive and oppressive factors; patients with other neurological deficits, peripheral nerve damage, central nervous system diseases, severe liver and kidney dysfunction, severe infections, malignant tumors, systemic immune diseases, cardiovascular and cerebrovascular disease, hypertension, diabetes and inflammation; patients with cognitive dysfunction and mental illness.

Treatment methods

Altogether 0.3-0.5 mg/(kg•day) of dexamethasone (Shandong Chenxin Pharmaceutical Co., Ltd., batch no. H37021969) was given by intravenous drip to patients in group A; at the same time, 200-400 mg/(kg•day) of γ-globulin (Beijing Tiantan Biological Products Co., Ltd., batch no. S20023026) was given by intravenous drip; after continuous use for five to seven days, prednisone tablets (Zhejiang Xianyi Pharmaceutical Co., Ltd., batch no. H33021207) were administered orally once a day, with an oral dose of 60 mg and a reduction of 5 mg per three days. Patients in group B were given high-dose methylprednisolone (Belgium PFIZER SA, batch no. H20130302) 1,000 mg mixed with 500 ml of 10% glucose injection combined with intravenous drip; 200-400 mg/(kg•day) of γ-globulin was given by intravenous drip at the same time, and then changed to take prednisone tablets orally. The usage and dosage were consistent with those in group A. During the treatment, antacids, antibiotics, and neurotrophins were normally used, and other immunosuppressants were prohibited. Both groups were treated for four weeks.

Efficacy evaluation and observation indicators

Indicators of spinal cord function were observed, including time of sensory recovery, self-walking, improving muscle strength at two levels and urination recovery. Efficacy of patients was assessed four weeks after treatment. Efficacy of the two groups was evaluated according to the recovery of sensory disturbance, dyskinesia, and autonomic nerve dysfunction, as shown in Table I. Quality of life of patients after admission and at two months was assessed in conjunction with the Quality of Life Scale (SF-36) developed by the American Institute of Medicine (16). The assessment included general health (GH), physical function (PF), role physical (RP), body pain (BP), social function (SF), role emotional (RE), Mental Health (MH) and vitality (VT) eight dimensions, and each dimension was divided into 100 points; the higher the score, the better the quality of life.

Table I Criteria of clinical efficacy.

Table I

Criteria of clinical efficacy.

Efficacy	Sensory disturbance	Dyskinesia	Autonomic nerve dysfunction
Recovery	Back to normal	Normal walking ability	Normal excretion function
Significantly	Subtle abnormalities	Able to walk by holding	Basically normal excretion
effective		on to something	function with subtle barriers
Effective	Some abnormalities	Unable to walk, but muscle function has improved	Unable to relieve oneself, but bladder function has improved
Ineffective	Clinical symptoms and signs were not changed or even deteriorated

[i] Total effective rate = (Recovery + significantly effective + effective)/all cases x100%.

Detection of T-lymphocyte subsets

Ratios of CD3+, CD4+ and CD8+ as well as CD4+/CD8+ in peripheral blood were measured by Attune NxT flow cytometry (Shanghai Thermo Fisher Technology Co., Ltd.) on admission and after treatment. In total, 100 µl of anticoagulated blood was placed in the TruCOUNT tube, and then 20 µl of fluorescein isothiocyanate (FITC) fluorescently labeled monoclonal antibody CD3-PC5, CD4-PE and CD8-ECD (Shanghai Kemin Biotechnology Co., Ltd., item no. 6607010, DXT-130-109-451, 737659) were added to the tube. Then mixed evenly, and placed at room temperature for 20 min; 500 µl of hemolysin was added to lyse the cells, and the solution was placed at room temperature for 15 min; 500 µl PBS buffer solution was added; mixed well, and then placed at room temperature for 10 min. Samples were tested on a flow cytometer, and data of CD3+, CD4+, CD8+ and CD4+/CD8+ were read.

Statistical analysis

SPSS 22.0 (Beijing Boao Yijie Technology Co., Ltd.) was used for the statistical analysis of the data; GraphPad 7 was used to draw the illustrations; normal distribution data were represented as mean ± standard deviation (SD); independent sample t-test was used for comparison between groups, and paired t-test was used for comparison of the same group before and after treatment; the counting data were represented by [n(%)] and those between groups were tested by the Chi-square. When the theoretical frequency in the Chi-square test was less than five, continuous correction Chi-square test was adopted. P<0.05 was considered statistically significant.

Results

General data of the two groups

There was no significant difference in general clinical data including sex, body mass index (BMI), course of disease, age, history of upper respiratory tract, history of drinking, history of smoking, location of spinal lesions, cerebrospinal fluid pressure, protein level of cerebrospinal fluid, quadriplegia, paraplegia, or place of residence between group A and B (P>0.05) (Table II).

Table II General data of group A and group B [n (%), mean ± SD].

Table II

General data of group A and group B [n (%), mean ± SD].

Category	Group A (n=66)	Group B (n=70)	t/χ2 value	P-value
Sex			0.334	0.563
Male	40 (60.61)	39 (55.71)
Female	26 (39.39)	31 (44.29)
BMI (kg/m2)	22.75±2.68	22.57±2.76	0.386	0.700
Course of disease (days)	6.6±1.3	6.4±1.2	0.933	0.352
Age (years)	34.7±5.9	35.9±6.4	1.135	0.258
History of upper respiratory tract			0.053	0.818
Yes	27 (40.91)	30 (42.86)
No	39 (59.09)	40 (57.14)
History of drinking			0.293	0.588
Yes	29 (43.94)	34 (48.57)
No	37 (56.06)	36 (51.43)
History of smoking			0.576	0.448
Yes	25 (37.88)	31 (44.29)
No	41 (62.12)	39 (55.71)
Location of spinal lesions			0.724	0.867
Limited to the cervical spine	13 (19.70)	14 (20.00)
Limited to the chest spine	35 (53.03)	40 (57.14)
Union of chest and neck	14 (21.21)	11 (15.72)
Lumbar spinal cord involved	4 (6.06)	5 (7.14)
Cerebrospinal fluid pressure (mmH2O)	157.39±46.58	162.37±49.75	0.602	0.548
Protein level of cerebrospinal fluid (g/l)	0.41±0.22	0.43±0.24	0.506	0.614
Quadriplegia			0.033	0.855
Yes	17 (25.76)	19 (27.14)
No	49 (74.24)	51 (72.86)
Paraplegia			0.319	0.572
Yes	39 (59.09)	38 (54.29)
No	27 (40.91)	32 (45.71)
Place of residence			0.102	0.749
City	46 (69.70)	47 (67.14)
Country	20 (30.30)	23 (32.86)

Spinal cord function indicators after treatment in the two groups

Time of sensory recovery, self-walking, improving muscle strength at two levels and urination recovery after treatment were significantly shorter in group B than those in group A (P<0.001) (Table III).

Table III Comparison of spinal cord function indicators after treatment in group A and group B (mean ± SD, days).

Table III

Comparison of spinal cord function indicators after treatment in group A and group B (mean ± SD, days).

Indicators	Group A (n=66)	Group B (n=70)	t value	P-value
Sensory recovery time	8.61±3.52	5.94±2.28	5.280	<0.001
Self-walking time	21.73±8.75	17.32±5.39	3.561	<0.001
Time of improving muscle strength at two levels	13.49±4.68	9.45±3.52	5.710	<0.001
Urination recovery time	11.36±3.74	7.97±2.86	5.958	<0.001

Effects of treatment in the two groups

After treatment, there were 14 cases (21.21%) recovered, 31 cases (46.97%) significantly effective, 10 cases (15.15%) effective, 11 cases (16.67%) ineffective in group A, and the effective rate was 83.33%; there were 21 cases (30.00%) recovered, 30 cases (42.86%) significantly effective, 15 cases (21.43%) effective, and 4 cases (5.71%) ineffective in group B, and the effective rate was 94.29%. Effective rates of treatment in group B were significantly higher than those in group A (P<0.05). More details were shown in Table IV.

Table IV Comparison of effective rates between group A and group B [n (%)].

Table IV

Comparison of effective rates between group A and group B [n (%)].

Groups	n	Recovery	Significantly effective	Effective	Ineffective	Effective rate (%)
Group A	66	14 (21.21)	31 (46.97)	10 (15.15)	11 (16.67)	83.33
Group B	70	21 (30.00)	30 (42.86)	15 (21.43)	4 (5.71)	94.29
χ2 value	-	1.373	0.232	0.892	4.153	4.153
P-value	-	0.241	0.630	0.345	0.042	0.042

Incidence rates of adverse reactions in the two groups

During treatment, there were six cases with nausea and vomiting (9.09%), three cases with rash (4.55%), four cases with bellyache (6.06%), five cases with elevated blood glucose (7.58%) in group A, and the incidence rate of adverse reactions was 27.27%. During treatment, there were four cases (5.71%) with nausea and vomiting, one case (1.43%) with bellyache, four cases (5.71%) with elevated blood glucose in group B, and the incidence rate of adverse reactions were 12.86%. Incidence rate of adverse reactions in group B was significantly lower than that in group A (P<0.05) (Table V).

Table V Incidence rate of adverse reactions in group A and group B [n (%)].

Table V

Incidence rate of adverse reactions in group A and group B [n (%)].

Groups	n	Nausea and vomiting	Rash	Bellyache	Elevated blood glucose	Incidence rate (%)
Group A	66	6 (9.09)	3 (4.55)	4 (6.06)	5 (7.58)	27.27
Group B	70	4 (5.71)	0 (0.00)	1 (1.43)	4 (5.71)	12.86
χ2 value	-	0.569	1.488	0.958	0.190	4.437
P-value	-	0.451	0.223	0.328	0.662	0.035

Results of T-lymphocyte subsets in peripheral blood in the two groups

There were no significant differences in ratios of CD3+, CD4+ and CD8+ cells or CD4+/CD8+ in peripheral blood between group A and group B before or after treatment (P>0.05); ratios of CD3+, CD4+ and CD8+ cells and CD4+/CD8+ in peripheral blood between group A and group B after treatment were significantly higher than those before treatment (P<0.05) (Fig. 1).

Figure 1 Comparison of T-lymphocyte subsets in peripheral blood before and after treatment in group A and group B. (A) Comparison of ratios of CD3+ cells in peripheral blood before and after treatment in group A and group B; (B) comparison of ratios of CD4+ cells in peripheral blood before and after treatment in group A and group B; (C) ratios of CD8+ cells in peripheral blood before and after treatment in group A and group B were compared; (D) ratios of CD4+/CD8+ in peripheral blood before and after treatment in group A and group B were compared; (E) flow cytometry of CD3+ ratio in peripheral blood; (F) flow cytometry of CD4+ ratio in peripheral blood; (G) flow cytometry of CD8+ ratio in peripheral blood. *P<0.05; **P<0.01; ***P<0.001.

Comparison of results of quality of life before and after treatment in the two groups

There were no significant differences in scores of GH, PF, RP, BP, SF, RE, MH and VT between group A and group B before treatment (P>0.05); scores of GH, PF, RP, BP, SF, RE, MH and VT in group A and group B after treatment were significantly higher than those before treatment (P<0.05); scores of GH, PF, RP, RE and MH in group B after treatment were significantly higher than those in group A (P<0.05) (Fig. 2).

Figure 2 Comparison of results of quality of life before and after treatment in group A and group B. (A) Comparison of GH scores before and after treatment between group A and group B; (B) comparison of PF scores before and after treatment between group A and group B; (C) comparison of RP scores before and after treatment between group A and group B; (D) comparison of BP scores before and after treatment between group A and group B; (E) comparison of SF scores before and after treatment between group A and group B; (F) comparison of RE scores before and after treatment between group A and group B; (G) comparison of MH scores before and after treatment between group A and group B; (H) comparison of VT scores before and after treatment between group A and group B. *P<0.05; **P<0.01; ***P<0.001.

Discussion

The onset and progress of ATM are relatively rapid. If it is not treated in time, functional disorders in sensory, motor and autonomic nerves may occur, and even death in severe cases (17,18). In our study, the combination of γ-globulin and methylprednisolone in the treatment of ATM has better clinical symptoms, which can effectively improve the clinical symptoms of patients with fewer adverse reactions, and improve their immune function and quality of life.

Clinically, γ-globulin is mostly used for the treatment of infectious diseases, and can deliver antibodies to patients, so that they can achieve immune protection from low immunity or no immunity, and promote their recovery (19). Dexamethasone is a commonly used glucocorticoid therapy drug for ATM, with anti-allergic and anti-toxic effects. However, its onset time is relatively slow, and some patients may suffer from dizziness, limb movement disorder, mental retardation and other complications (20). Methylprednisolone is a synthetic glucocorticoid, which can promote the synthesis of a variety of enzyme proteins, thus playing an anti-inflammatory and immunosuppressive role and promoting the recovery of nerve function (21). In recent years, there have been many studies on the application of methylprednisolone used in ATM patients. Defresne et al (22) reported that effects of high-dose methylprednisolone were better than not using hormone or low-dose methylprednisolone in the treatment of children with severe ATM; time of bladder function recovery, walking and muscle strength of children was significantly improved. Kovacs et al (23) verified that methylprednisolone combined with cyclophosphamide in the treatment of ATM patients was significantly better than cyclophosphamide alone. In this study, time of recovery, self-walking, improving muscle strength at two levels and urination recovery of group B was significantly shorter than that of group A, and effective rates of group B were significantly higher than those of group A. Thus indicating that γ-globulin combined with methylprednisolone was effective in the treatment of ATM, which could promote the recovery of spinal cord function with fewer adverse reactions. Further research found that the incidence rate of adverse reactions in group B was significantly lower than that in group A, indicating that there were fewer adverse reactions in combination of the two. Although some adverse reactions occurred during the treatment, all patients recovered completely without special treatment, so this is in line with expectations. Pavlou et al (24) confirmed that a patient with ATM was treated with high-dose methylprednisolone, and the condition was not effectively controlled. There were still aggravated limb paralysis and respiratory muscles paralysis, followed by intravenous γ-globulin. Patients' neurological function began to recover with no apparent complications, which was similar to our study. Changes in T-lymphocyte subsets reflect the status of immune system function, and they are classified into CD3+, CD4+ and CD8+ cells according to their functions and surface markers (25), in which CD3+ is positively correlated with T-lymphocyte immune function, while the increase and decrease of ratios of CD4+ and CD8+ can cause the ratios to become imbalanced, which leads to abnormal immune function (26). The present study showed that ratios of CD3+, CD4+, CD8+ and CD4+/CD8+ in peripheral blood of group A and group B were significantly higher than those before treatment, but there were no significant differences between the groups. γ-globulin combined with dexamethasone and methylprednisolone, respectively, can improve the immune status of patients and improve their immunity. Larroche et al (27) reported that γ-globulin was an important drug for the treatment of various autoimmune and neurological diseases, and one of its mechanisms was to immunomodulate patients. It may be that γ-globulin exerts enhancing immunity (28), while glucocorticoid drugs can alleviate the damage of peroxide to spinal cord tissue (29). Combination of these two drugs can eliminate the abnormal immune function of ATM patients, reduce the damage of immune responses to spinal cord, thereby promoting the recovery of spinal cord function. Gelfand (30) reported that γ-globulin could be used as clinical immunomodulatory therapy to treat a variety of immune diseases, such as Guillain-Barré syndrome, myasthenia gravis, Kawasaki disease, and in kidney transplant. However, γ-globulin is a mixed blood product, which is relatively expensive. Therefore, the application of γ-globulin may be accompanied by cost-effectiveness considerations. Finally, SF-36 was adopted to assess patients' quality of life. The results revealed that scores of GH, PF, RP, BP, SF, RE, MH and VT in group A and group B after treatment were significantly higher than those before treatment, and scores of GH, PF, RP, RE and MH after treatment in group B were significantly higher than those in group A, which indicated that γ-globulin combined with methylprednisolone also had a certain improvement effect on patients' quality of life. This may be because the γ-globulin combined with methylprednisolone has better efficacy and can improve the clinical symptoms and signs of patients, thereby improving their quality of life.

This study confirmed the clinical efficacy of γ-globulin combined with methylprednisolone in the treatment of ATM.However, the long-term quality of life of ATM patients was not observed and the influencing factors of the efficacy remain to be analyzed.

In conclusion, γ-globulin combined with methylprednisolone in the treatment of ATM patients has definite clinical efficacy and fewer adverse reactions, which can improve their immune function and quality of life.

Acknowledgements

Not applicable.

Funding

No funding was received.

Availability of data and materials

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Authors' contributions

PW conceived the study and wrote the manuscript. SZ analyzed and interpreted the patient general data. HLv and GQ performed flow cytometry. XZ, HLi and LZ were responsible for the analysis of the observation indicators. All authors read and approved the final version of the manuscript.

Ethics approval and consent to participate

The study was approved by the Ethics Committee of Linzi District People's Hospital (Zibo, China). Patients who participated in this study had complete clinical data. Signed informed consents were obtained from the patients and/or guardians.

Patient consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

References