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 Table of Contents  
ORIGINAL ARTICLE
Year : 2021  |  Volume : 34  |  Issue : 1  |  Page : 340-346

Relation of serum tumor necrosis factor-α level with disease severity in spastic cerebral palsy


1 Department of Physical Medicine, Rheumatology and Rehabilitation, Faculty of Medicine, Menoufia University, Shebin El Kom, Egypt
2 Department of Pediatrics and Neonatology, Faculty of Medicine, Menoufia University, Shebin El Kom, Egypt
3 Department of Medical Biochemistry, Faculty of Medicine, Menoufia University, Shebin El Kom, Egypt

Date of Submission25-May-2019
Date of Decision26-Jun-2019
Date of Acceptance04-Jul-2019
Date of Web Publication27-Mar-2021

Correspondence Address:
Jehan D Fayed
Gamal Abd El-Nasr St., Shebin El Kom 32511, Menofia
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/mmj.mmj_178_19

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  Abstract 


Objective
To detect the relation between serum tumor necrosis factor-α (sTNF-α) level and disease severity in children with lower limb spastic cerebral palsy (CP).
Background
Glial cells are activated following a primary insult to the immature brain, secreting chemical mediators such as tumor necrosis factor-α, leading to secondary white matter injury, causing CP.
Patients and methods
A randomized controlled clinical trial was conducted, including 80 ambulatory children with lower limb spastic CP and 80 healthy age-matched and sex-matched children as control group. At baseline, patients with CP were assessed using Modified Modified Ashworth Scale, bilateral adductor tone score, passive range of motion of lower limb joints, and outcome measures, such as Edinburgh Visual Gait Scale, Gross Motor Functional Measure-88, and Caregiver Priorities and Child Health Index of Life with Disabilities. Interventions were botulinum toxin-A injection, sTNF-α measurement, and rehabilitation. Follow-up after 2, 6, and 12 weeks had the same assessment as baseline, except for sTNF-α, and outcome measures were done at baseline and week 12. The control group had sTNF-α measured.
Results
Modified Modified Ashworth Scale, ankle dorsiflexion, popliteal angle, and outcome measures significantly improved after intervention (P > 0.001). Baseline sTNF-α was significantly higher in patients with CP (P > 0.001), positively correlated with CP severity (P = 0.01), and significantly improved after treatment (P > 0.001). Age and weight negatively correlated with baseline sTNF-α. Outcome measures significantly correlated with sTNF-α after intervention.
Conclusion
Baseline sTNF-α in spastic CP was higher than controls and positively correlated with disease severity. It significantly improved after rehabilitation and significantly correlated with improvement in all outcome measures.

Keywords: botulinum toxin, cerebral palsy, rehabilitation, spasticity, tumor necrosis factor


How to cite this article:
Soliman SG, Labeeb AA, Esaily HA, Abd El-Naby SA, Tayel SI, Abd Allah EA, Fayed JD. Relation of serum tumor necrosis factor-α level with disease severity in spastic cerebral palsy. Menoufia Med J 2021;34:340-6

How to cite this URL:
Soliman SG, Labeeb AA, Esaily HA, Abd El-Naby SA, Tayel SI, Abd Allah EA, Fayed JD. Relation of serum tumor necrosis factor-α level with disease severity in spastic cerebral palsy. Menoufia Med J [serial online] 2021 [cited 2021 May 8];34:340-6. Available from: http://www.mmj.eg.net/text.asp?2021/34/1/340/312007




  Introduction Top


An insult to the immature brain can cause a persistent movement disorder known as cerebral palsy (CP) [1]. Most children with CP will have spasticity as the main motor disorder. Spasticity can be treated with oral medication, phenol, selective dorsal rhizotomy, and baclofen injection intrathecally. Botulinum toxin serotype A (BTX-A) is used as a selective treatment option for localized spasticity [2]. Etiology is multifactorial, but infections or ischemia–hypoxia are the most probable causes [3]. Following this primary insult to the nervous tissue, glial cells are activated secreting various chemical mediators of tissue necrosis leading to secondary white matter (WM) injury termed periventricular leukomalacia (PVL). Of these mediators are inflammatory cytokines like tumor necrosis factor-α (TNF-α), interferon-γ, interleukin-1β (IL-1β), and superoxide radicals [4]. Although the exact immune responses involved in CP remain unclear, abnormal inflammatory responses may continue to guide the reconstruction of postnatal cerebral function [5]. The aim of this study was to determine the relation between serum tumor necrosis factor-α (sTNF-α) level with disease severity in children with lower limb spastic CP and its predictive value for response to rehabilitation protocols including BTX-A injection.


  Patients and methods Top


In this randomized controlled clinical trial, 80 randomly selected children having spastic CP of the lower limbs (diplegia and hemiplegia) were included. They were selected from the Pediatrics Outpatient Clinic and the Physical Medicine, Rheumatology and Rehabilitation Outpatient Clinic at Menofia University Hospitals in the period from October 2015 to July 2017. They were selected using the ideal bowl method, where the names of all children with CP fulfilling the inclusion and exclusion criteria attending our outpatient clinic were put on a list, and each was assigned a serial number. Then an equal number of cards were prepared, of the same size and color; the serial number of each patient was written on a card, and then all cards were folded and put in a prepared bowl. The cards were then mixed thoroughly, and the first 80 consecutive cards drawn from the bowl were included in this study. Moreover, 80 randomly selected healthy children with matched age and sex were enrolled in the study as a control group. They were selected using the ideal bowl method as well. The study was approved by the Faculty of Medicine (Menofia University), Ethics Committee, and parents of all patients and controls gave a written informed consent. The inclusion criteria were children aged between 2 and 16 years, clinical diagnosis of spastic CP of the lower limbs by pediatric neurologist, and ambulatory children with Gross Motor Function Classification System (GMFCS) levels I, II, III, and IV [6]. Exclusion criteria in this study were as follows: nonambulatory children with spastic CP with GMFCS level V, presence of muscle contracture in the lower limb based on needle EMG of suspicious muscles or hip dislocation, previous orthopedic surgery, history of antispasticity medication in the past 2 months, BTX injection in the past year, history of epilepsy or fever in the past 2 months, and history of autoimmune disease, endocrine disorders, metabolic disorders, or other diseases that can elevate TNF-α. All patients were subjected to the following: demographic data recording (age, sex, and residence), clinical assessment, and intervention. At baseline (week 0), medical history (disease duration, spasticity distribution, drug history, and developmental milestone achievement); clinical examination, including classification of CP severity using GMFCS [6], muscle tone examination using Modified Modified Ashworth scale (MMAS) [7], tone in the adductor muscles scored using bilateral adductor tone score [8], passive range of motion (PROM) of lower limb joints, mainly, hip extension, popliteal angle, and ankle dorsiflexion using goniometer; and functional outcome measures were recorded. Three functional outcome measures were used in this study: (a) a two-dimensional visual gait analysis involved the children walking barefoot at a steady pace along a 10-meter track while recording sagittal and frontal plane videos. The video recordings were captured using three Canon Vixia HF R42 digital cameras (Canon USA Inc., Melville, New York, USA). One camera was placed in the sagittal plane 5 meters lateral to the midpoint of the walkway, at the level of the hips of the patient adjusted according to each patient's height. Two cameras were placed in the frontal plane on a tripod at a distance of 2.5 meters in front of the midpoint of the walkway, one at the level of the hips of the patient, and the second placed at the level of the ankle. The video recording was analyzed using Kinovea software (version 0.8.15; Kinovea Open Source Project, http://www.kinovea.org) and scored using Edinburgh Visual Gait Scale (EVGS) [9] to define gait quality. (b) The quality of life was assessed using Caregiver Priorities and Child Health Index of Life with Disabilities (CPCHILD) Questionnaire [10], and (c) the Gross Motor Functional Measure-88 (GMFM-88) was used to assess gross motor function [11]. Interventions at baseline were as follows: (a) sTNF-α level was measured by collecting 3-ml venous blood samples in pyrogen-free tubes. The samples were allowed to clot for 30 min before the centrifugation at 6000g (gravity at the earth's surface) for 5 min. The serum is then separated and stored at temperature of −80°C. The serum samples were processed using Human Tumor necrosis factor, ELISA kit (catalog no. E0133h, ElAab; ARP American Research Products Inc. Waltham, Massachusetts, Unites States of America), and sTNF-α levels were measured by ELISA (BMS223/4, Bender MedSystems GmbH, Vienna, Austria) using Magellan software (For Infinite F50 Standard Software, version 6.6; Tecan, GmbH, Vienna, Austria). (b) BTX-A injections were diluted at a rate of 100 U of Botox (Allergan, Irvine, California, USA) in 1–2 ml of normal saline, administered under local anesthetic with a minimum dose of 0.5 U Botox/kg body weight and to a maximum dose of 2–6 U Botox/kg body weight per muscle. Needle placement into each muscle was done using electromyographic guidance [12]. Muscle selection for injection was based on clinical assessment of each patient. (c) Rehabilitation began 1 week after the multilevel Botox injections, 3–5 times a week for 12 weeks, from a physiotherapist. Treatment included traditional physiotherapy (stretching of planter flexors, hamstring, and adductors and strengthening exercises of planter dorsiflexors, knee extensors, and hip abductors), functional stretching exercise, strengthening of core muscles (abdominal and back muscles), and gait re-education (balance exercise and walking between parallel bars). A home program was given to the children consisting of proper positioning, stretching exercises for spastic muscles, and strengthening exercises for weak muscles. When needed, children also received orthotic management in the form of ankle–foot orthosis or knee–ankle–foot orthosis. Follow-up at week 2 and week 6 included MMAS, bilateral adductor tone score, and PROM. Follow-up at week 12 measured MMAS, bilateral adductor tone score, PROM, functional outcome measures (EVGS, CPCHILD, and GMFM-88), and sTNF-α. The control group had demographic data recording (age, sex, and residence); medical history taking, to ensure the control group was healthy; and sTNF-α measurement.

Statistical analysis

Results were collected, tabulated, and statistically analyzed by IBM personal computer and statistical package for social sciences (SPSS) version 22 (IBM Corp., Armonk, New York, USA). Descriptive statistics used were percentage, mean, and SD. Analytic statistics used were χ2-test, Student t-test, Mann–Whitney, analysis of variance test, Kruskal–Wallis test, paired t-test, Wilcoxon signed-rank test, Pearson correlation coefficient. P value of less than 0.05 was considered statistically significant.


  Results Top


This randomized controlled clinical trial included 80 patients with spastic CP, comprising 46 (58%) males and 34 (42%) females. Their age ranged from 2.5 to 11 years old. The control group included 80 apparently healthy children, comprising 48 (60%) males and 32 (40%) females. Their age ranged from 3 to 10 years old. Of the patients with CP, 67 (83.3%) were diplegic and 13 (16.7%) were hemiplegic. GMFCS level III (58%) was the most common type of spastic CP followed by level I (24%), level II (9%), and level IV (9%) [Table 1].
Table 1: Demographic data of patients with cerebral palsy and controls

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MMAS was highly significantly decreased (P > 0.001) after intervention starting at 2 weeks. The adductor muscle tone steadily decreased after intervention, but this decrease was only statistically significant at 12 weeks after intervention (P = 0.396). Ankle dorsiflexion ROM and popliteal angle were highly significantly increased starting at 2 weeks after intervention (P > 0.001). The hip extension and abduction ROM increased after intervention but was not statistically significant (P = 0.054 and 0.108, respectively; [Figure 1]).
Figure 1: The spasticity scores and passive range of motion in lower limb joints before and after interventions in patients with cerebral palsy.

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Baseline TNF-α was significantly higher in patients with CP than controls (P > 0.001) and significantly improved after intervention (P > 0.001; [Table 2]).
Table 2: Comparison of serum tumor necrosis factor-α levels at baseline between patients with cerebral palsy and controls and between baseline and after intervention in patients with cerebral palsy

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All outcome measures showed highly significant improvement after interventions in patients with CP (P > 0.001). The EVGS showed significant improvement at 12 weeks after intervention, with mean reduction of 6.2 points. The gross motor function significantly improved by 3.8% at 12 weeks after intervention, and the CPCHILD was significantly reduced by 6.4% at 12 weeks after intervention. All levels of GMFCS showed significant improvement in outcome measures. The GMFM-88 showed the greatest improvement at GMFCS level II of 7.8 (P > 0.001), whereas CPCHILD showed the greatest improvement at GMFCS level III of 7.2 (P > 0.001). Baseline TNF-α significantly positively correlated with severity of CP according to GMFCS (P = 0.01; [Table 3]).
Table 3: Relation between functional outcome measures, tumor necrosis factor-α level, and Gross Motor Function Classification System before and after intervention in patients with cerebral palsy

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TNF-α level negatively correlated with GMFM-88 and CPCHILD scores before and after intervention. On the contrary, it positively correlated with EVGS after intervention [Table 4].
Table 4: Correlations between tumor necrosis factor-α levels and outcome measures before and after intervention in patients with cerebral palsy

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The patient's age and weight negatively correlated with baseline TNF-α (P > 0.001; [Figure 2]).
Figure 2: Correlation between baseline serum tumor necrosis factor-α level and age in patients with cerebral palsy.

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  Discussion Top


The prevalence of CP is 2–2.5/1000 live births and its incidence may be increasing secondary to improved neonatal ICUs and improved survival of low-birth-weight infants [13]. Most children with CP will have spasticity as the main motor disorder, which is a major challenge for rehabilitation [2]. The principal neuropathology seen in CP is a form of WM injury known as PVL [3]. Following this primary insult to the nervous tissue, glial cells are activated secreting various chemical mediators of tissue necrosis leading to secondary PVL. Immunohistochemical explorations for possible immunoinflammatory mechanisms revealed in-situ expression of two major proinflammatory cytokines (mainly, TNF-α and to a lesser extent IL-1β) whose levels in PVL were much higher than control brains [4]. This study was designed to determine the relation between sTNF-α level and disease severity in children with lower limb spastic CP and its predictive value for response to rehabilitation protocols including BTX-A injection. Our work showed improvement in spasticity starting 2 weeks after intervention. Two studies found similar improvement at their first follow-up after 4 weeks of intervention [14],[15], so improvement could have occurred earlier and was not recorded. In this study, the adductor muscle significantly decreased only at week 12 after intervention. Several studies had the same results [16],[17],[18]. The PROM for ankle dorsiflexion and popliteal angle significantly increased starting 2 weeks after intervention. Gonnade et al. [17] also found significant improvement at 6 and 12 weeks after intervention. On the contrary, Matsuda et al. [19] found a nonsignificant improvement probably owing to smaller sample size. The hip extension ROM improved after intervention but was not statistically significant. However, El-Etribi et al. [15] found significant increase starting 4 weeks after treatment. The ileo-psoas muscle was not injected with BTX in our study owing to lack of facilities, as it requires complete sedation of the child and an operating room. Spastic hip flexors were only treated with stretching and hip extensor strengthening. Hip abduction steadily increased after intervention in our study, but was not statistically significant. In agreement, Matsuda et al. [19] had a nonsignificant increase starting at 4 weeks; this may be owing to a small sample size of nine children in their study. On the contrary, Gonnade et al. [17] found statistically significant improvement at 6 and 12 weeks after intervention. In this study, baseline TNF-α level was significantly higher in cases than controls, which indicates an underlying immunological abnormality; this comes in agreement with Wu and Li [20]. Full-term babies diagnosed with hypoxic ischemic encephalopathy showed high blood levels of IL-1b, IL-6, and TNF-α [21]. In this study, kinematic parameters of gait analysis in patients with CP improved at 12 weeks after intervention. However, Scholtes et al. [14] found significant improvement at 6 weeks. Such improvement was not detected earlier in our study because gait analysis was performed at baseline and 12 weeks after intervention. Another study by Matsuda et al. [19] showed improvement after 4 weeks following intervention using the Physician Rating Scale. The gross motor function significantly improved by 3.8% at 12 weeks after intervention. In agreement, Hong et al. [22] found significant improvement of 4.7% at 8 weeks after intervention. Matsuda et al. [19] also found significant improvement of only 1% starting 8 weeks after intervention, most probably owing to their use of shorter version of GMFM-66. In contrast, Mall et al. [18] found no improvement after 12 weeks of intervention, as they limited BTX-A injection to the adductors and medial hamstring muscles, whereas in our study, all spastic muscles requiring BTX-A were treated. The quality of life in patients with CP improved at 12 weeks after intervention. Similarly, Copeland et al. [23] found significant improvement at 4 and 16 weeks after treatment using the Canadian Occupational Performance Measure. To our knowledge, there was no other study that used CPCHILD with BTX-A injection. Our work showed that gait kinematic parameters significantly improved in all levels of CP severity (GMFCS), indicating that EVGS is a sensitive assessment tool for changes in gait kinematics in all severity levels of CP. Gross motor function showed the greatest improvement in level II CP (7.8) followed by level III (3.9), level I (2.4), and finally, level IV (2.3). This comes in agreement with Hong et al. [22] who found greatest improvement in level II (8.9). However, this was followed by level I (5.8), level III (4.4), level IV (3.5), and lastly, level V (2.3). This shows that lower level of CP severity (I–II) is associated with better response to treatment. In our study, level III showed more improvement than level I, as it represented 58.8% of our sample, whereas level I was only 23.8%, which biased our results. The quality of life measured by CPCHILD significantly improved in all levels of CP severity; the greatest improvement was in level III. The CPCHILD was developed primarily to measure the health status and well-being of children with severe CP; therefore, it is sensitive to changes in levels III and IV [24]. TNF-α level highly significantly improved after intervention. This comes in agreement with Wu and Li [20] who found significant improvement in TNF-α level after rehabilitation. Regular exercise induces suppression of proinflammatory cytokines and upregulation of anti-inflammatory cytokines in various tissues of the body, including brain [25]. Platelet-rich plasma used by Alcaraz et al. [26] to treat CP showed improvement in cognitive and motor functions. On the contrary, Bae et al. [27] used allogeneic umbilical cord blood transplantation in treatment of CP and found significant reduction of proinflammatory cytokines. In this study, there was positive correlation between baseline TNF-α levels and severity of CP. However, Wu and Li [20] reported no association in the entire sample, but TNF-α level significantly correlated with CP severity in spastic quadriplegia and spastic diplegia. This finding supports the hypothesis that circulating levels of TNF-α can reflect the severity of motor dysfunction in some types of spastic CP. Our work showed there was a negative correlation between TNF-α level with gross motor function before and after intervention. This comes in agreement with Wu and Li [20]. There was a significant negative correlation between TNF-α and quality of life before and after intervention. On the contrary, there was a significant positive correlation between TNF-α with EVGS after intervention. To date, no other study showed the relation between TNF-α and outcome measures in children with CP. Exercise helps in promoting cell proliferation and neurogenesis [25]. The baseline TNF-α negatively correlated with age and weight. This comes in accordance with Wu and Li [20], who reported higher TNF-α in children 1–3 years old than 4–12 years old. This observation suggests that the inflammatory response may decrease with age, whereas the symptoms of CP do not necessarily improve [28]. This can be explained by the association of postnatal inflammatory illnesses such as bronchopulmonary dysplasia and sepsis and high risk for WM damage and adverse neurological outcome [29]. Therefore, persistent postnatal response might be a continuation of fetal inflammatory response. This study is not without limitations. The follow-up period was too short; therefore, long-term follow-up of a larger sample is needed to confirm the ability of TNF-α to act as a marker of disease severity. In addition, even though a correlation between TNF-α levels and rehabilitation protocols was detected, a full panel of inflammatory mediators needs to be evaluated for potential correlation with disease type, severity, and response to rehabilitation. In addition, further studies on the effect of anti-inflammatory therapies and anti-TNF-α in infants with CP on disease severity are needed as it may reduce CP symptoms.


  Conclusion Top


TNF-α levels in patients with spastic CP were higher than controls, and the younger the patient with CP, the significantly higher the TNF-α level. In addition, TNF-α level in children with spastic CP positively correlated with disease severity. Lastly, pretreatment levels of TNF-α significantly improved after rehabilitation and significantly correlated with improvement in all outcome measures.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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