|Ahead of print publication
The role of inflammation in children with specific learning disorders
Busra Oz, Berkan Ardiç
Department of Child and Adolescent Psychiatry, Düzce University Faculty of Medicine, Düzce, Turkey
|Date of Submission||23-Jul-2022|
|Date of Decision||30-Jul-2022|
|Date of Acceptance||02-Aug-2022|
|Date of Web Publication||07-Nov-2022|
Department of Child and Adolescent Psychiatry, Düzce University Faculty of Medicine, Düzce
Source of Support: None, Conflict of Interest: None
Background: Specific learning disorder (SLD) is a common neurodevelopmental disorder in childhood with a delay in reading, writing, and/or mathematics. The etiology of SLD is not known exactly. Aim: In our study, we aimed to evaluate the effect of inflammation in the etiology of SLD. Materials and Methods: In our study, patients aged 7–14 years who applied to the child psychiatry outpatient clinic between November 2019 and November 2020 were retrospectively screened. The hemoglobin (Hb), red cell distribution width (RDW), platelet (PLT), plateletcrit (PCT), platelet distribution width (PDW), and white blood cell (WBC) values of the children were recorded. Neutrophil/lymphocyte ratio (NLR) and PLR values were calculated. Comparisons were carried out on different variables using SPSS version 22. Results: There was no significant difference in terms of age and gender in the SLD and control groups. When blood parameters were evaluated, there was no significant difference between the groups in terms of Hb, RDW, PCT, PDW, and WBC values. The PLT count was significantly higher in the patient group than in the control group (P = 0.049). There was no significant difference between the groups in terms of TLR and NLR values. Conclusion: The results of our study showed that Hb, RDW, PCT, PDW, WBC, NLR, and TLR values were similar in SLD and healthy control groups. This does not support the hypothesis that an increased inflammatory response may be responsible for the etiology of SLD. Considering the heterogeneity in the clinical symptoms and etiopathogenesis of SLD, more extensive studies are needed in this area.
Keywords: Inflammation, lymphocyte, neutrophil, specific learning disorder
| Introduction|| |
Learning disorders are among the most frequently diagnosed developmental disorders in childhood. Specific learning disorder (SLD) is characterized by a persistent failure in learning and academic skills (reading, writing, and/or math) in children and adolescents. Epidemiological studies report that deficiencies in reading are seen between 4% and 9% and deficiencies in mathematics between 3% and 7%. Although SLD is a common psychiatric disorder in childhood, its etiology is not fully known. Suggested mechanisms include neuronal damage and degeneration, increased oxidative stress, decreased neurotrophic support, glial activation, alterations in neurotransmitter metabolism, and blood–brain barrier disruption. Therefore, the potential role of inflammation in neurodevelopmental disorders is being further investigated. In recent studies, it has been investigated that the immune response and inflammation may have an effect on the etiology of many psychiatric disorders such as attention deficit hyperactivity disorder (ADHD), psychosis, bipolar disorder, major depression, and anxiety disorders.,,, Evaluation of serum inflammatory markers gives mixed results due to high heterogeneity. However, there is evidence that increased inflammation during early development may be a risk factor for SLD.,
The immune system is effective on neurogenesis, differentiation, neuronal migration, synapse formation, and plasticity. It has been reported that the immune system is important for cognitive functions such as learning, perception, attention, and memory, as well as for healthy brain development. Considering these situations, imbalances in the immune system may play a role in the formation of neurodevelopmental disorders by causing changes in brain development, structural, and cognitive functions.
The hematologic system is a crucial organ for human immune defense and plays a central role in the inflammatory process and sepsis. Inflammation is a basic biological and physiological function that protects the body. Leukocytes, endothelium, platelets (PLTs), and many components perform the activation of the immune system. Inflammatory cells are the main elements of this function and include circulating leukocytes (neutrophils, monocytes, and lymphocytes) in addition to fixed tissue macrophages, dendritic cells, mast cells, and eosinophils. An increase in the inflammatory response triggered by the effects of environmental factors in the early stages of development may cause structural and/or functional changes in brain development and cause neurodevelopmental disorders such as SLD and ADHD.
Determining the levels of inflammatory markers requires complex procedures and these procedures are costly. This situation limits the conduct of research. However, neutrophil/lymphocyte ratio (NLR) and thrombocyte/lymphocyte ratio (TLR) are simple and inexpensive markers that show the level of systemic inflammatory response. Therefore, it is cheap and easy to use., Leukocytes play a central role in inflammation. NLR is a simple, affordable, sensitive, and reliable method representing inflammation and stress parameters used all over the world. It shows the ratio of the number of neutrophils to the number of lymphocytes. Neutrophils are an active nonspecific inflammatory mediator that initiates the first line of defense and exhibits phagocytic and apoptotic effects through the secretion of various inflammatory mediators. In contrast, lymphocytes represent the regulatory or protective component of the immune system. NLR may be more informative than other commonly used markers such as interleukin-6, tumor necrosis factor-α, or CRP., PLTs accumulate in areas of inflammation such as leukocytes and progenitor cells in proinflammatory as well as anti-inflammatory processes. The thrombocyte-to-lymphocyte ratio (TLR) is calculated as the ratio of thrombocyte count to lymphocyte count and is a commonly used simple marker that appears to be associated with cardiovascular diseases, malignancies, chronic diseases, and infections.,
There are few studies examining the relationship between psychiatric symptoms and inflammation in children and adolescents. There is only one study in the literature examining the relationship between SLD and inflammation. As a result of this study, neutrophil, lymphocyte counts, and NLR levels were high, and PLT count and TLR levels were normal in children with SLD. The aim of this study was to investigate whether there is a relationship between the etiology of SLD and inflammation by using hemoglobin (Hb), red cell distribution width (RDW), plateletcrit (PCT), platelet distribution width (PDW), white blood cell (WBC), NLR, and TLR values, which are convenient and easy options for routine use.
| Materials and Methods|| |
The files of children between the ages of 7 and 14 years who applied to the Duzce University Faculty of Medicine Pediatric Psychiatry outpatient clinic between November 2019 and November 2020 and who had examinations in the system were retrospectively analyzed. In our study, children whose psychiatric examination and family-teacher forms were evaluated and who were diagnosed with SLD according to DSM-5 diagnostic criteria were examined. Seventy children with Wechsler Intelligence Scale-Revised Form for Children (WISC-R) intelligence test scores above 80 and without any accompanying psychiatric neurological or chronic medical disease were included. For the control group, children and adolescents who came to the general pediatric outpatient clinic for routine checkup were referred to us for psychiatric evaluation. Sixty-nine age- and gender-matched healthy children without any psychiatric, neurological, or chronic disease were included as the control group. The results of the complete blood count (CBC) in the system of the children included in the study were taken. Hb, RDW, PCT, PDW, WBC, NLR, and TLR values were recorded. Patients and their parents were verbally informed about the study's design, and written informed consent forms in accordance with the Declaration of Helsinki were obtained.
Wechsler Intelligence Scale For Children-Revised Form
WISC-R is an intelligence test developed by Wechsler applied to children aged 6–16 years. It was adapted into Turkish by Uluç et al. The WISC-R test has one general intelligence score and two basic subscores (verbal and performance). In the Turkish validity and reliability study of the WISC-R, the semireliability of the tests was 0.97 for the verbal section, 0.93 for the performance section, and 0.97 for the total section.
Ethical aspect of research
The necessary permission was obtained from Düzce University Non-Interventional Health Research Ethics Committee on 18.10.2021 with the decision numbered 2021/207 to conduct the study.
Distribution of data was analyzed with Shapiro–Wilk test and homogeneity of variance Levene test, group comparisons were made with Independent samples t-test or Mann–Whitney U test and One-Way ANOVA or Kruskal–Wallis test depending on the number of groups. Pearson's Chi-square test was used in the analysis of categorical variables, and correlation analyzes were performed with Pearson's and Spearman's correlation analysis. Descriptive statistics were given as mean ± standard deviation or median, interquartile range and minimum–maximum values for numerical variables, and numbers and percentages for categorical variables. Statistical analyzes were made with the SPSS v.22 program (IBM Corp. Released 2013. IBM SPSS Statistics for Windows, Version 22.0. Armonk, NY: IBM Corp.) was used to perform statistical analysis, and the significance level was taken into account as 0.05.
| Results|| |
In our study, the files of the patients who applied to the Duzce University Faculty of Medicine Pediatric Psychiatry outpatient clinic and who were diagnosed with SLD were reviewed retrospectively. Hb, RDW, PCT, PDW, WBC, NLR, and TLR values were recorded in 70 patients and 69 healthy children who, despite having normal cognitive capacity, had significant retardation in reading, writing, and/or mathematics compared to their peers.
The mean age of the children in the SLD group was 9.93 ± 1.88 years, while the mean age of the children in the control group was 10.22 ± 2.22 years. In the SLD group, there were 27 (38.6%) girls and 43 (61.4%) boys; there were 23 (33.3%) girls and 46 (66.7%) boys in the control group. No significant difference was found in terms of age and gender in children in the SLD and control groups (P = 0.409 and P = 0.520, respectively). When blood parameters were evaluated, there was no significant difference between the groups in terms of Hb, RDW, PCT, PDW, and WBC values. The PLT count was significantly higher in the SLD group than in the control group (P = 0.049). There was no significant difference between the groups in terms of TLR and NLR ratios (P = 0.409 and P = 0.202, respectively). The general characteristics and biochemical values of the groups are shown in [Table 1].
|Table 1: Comparison of complete blood count variables, neutrophil-to-lymphocyte ratio, and thrombocyte-to-lymphocyte ratio values in specific learning disorder and healthy control groups|
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When the sex and blood parameters were evaluated in the SLD group, no significant difference was found in terms of Hb, RDW, PLT, PCT, PDW, WBC, and NLR. TLR value was significantly lower in girls (P = 0.031) [Table 2].
|Table 2: Comparison of gender and complete blood count variables, neutrophil-to-lymphocyte ratio, and thrombocyte-to-lymphocyte ratio values in the specific learning disorder group|
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Patients with SLD were evaluated in terms of SLD types. It was determined that 12 (17.1%) of the patients had dyslexia (reading disorder) alone, 4 (5.7%) had dysgraphia (written expression disorder) alone, 5 (7.1%) had dyscalculia alone (mathematics disorder), 17 (24.2%) had dyslexia + dysgraphia, 9 (12.8%) had dyslexia + dyscalculia, 5 (7.1%) had dyscalculia + dysgraphia, and 18 (25.7%) had dyslexia + dyscalculia + dysgraphia. The relationship between SLD types and inflammation parameters was evaluated. There was no statistically significant correlation between Hb, RDW, PCT, PDW, WBC, NLR, and TLR values and SLD types. The results are shown in [Table 3].
|Table 3: The relationship between specific learning disorder types and complete blood count variables, neutrophil-to-lymphocyte ratio, and thrombocyte-to-lymphocyte ratio values|
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| Discussion|| |
Our study is one of the rare studies evaluating the importance of inflammation in the etiology of SLD. In our study, Hb, RDW, PCT, PDW, WBC, NLR, and TLR values were similar to healthy children in children diagnosed with SLD. PLT counts were higher in the SLD group. TLR value was significantly lower in girls in the SLD group. As a result of our study, no significant relationship was found between SLD types and inflammation parameters.
As far as we know, there is only one study investigating NLR and TLR as inflammatory markers in children with SLD. Thirty-one children with SLD and 33 healthy children were included in this study conducted in Turkey. As a result of the study, neutrophil and lymphocyte counts and NLR value were higher in the patient group than in the control group. It was evaluated that the PLT counts and TLR value were similar in the two groups. However, in their regression analysis, the independent variables of NLR value, age, and gender did not have a significant effect on SLD. However, in our study, no significant difference was found between the two groups in terms of Hb, RDW, PCT, PDW, WBC, NLR, and TLO levels. The thrombocyte count was higher in the SLD group. Our results do not support this study, which is the only one in the literature. In this study in the literature, the relationship between SLD types and inflammation parameters was not evaluated. In our study, we examined whether there was a relationship between SLD types and Hb, RDW, PCT, PDW, WBC, NLR, and TLR values, but no significant relationship was found. Our results could not be compared with any other study as no other study investigating SLD and inflammation was found. Our study is the only one to examine the relationship between SLD types and inflammation parameters, so it is valuable.
Oxidative and immune mechanisms may contribute to SLD through neuronal damage and abnormal neurotransmitter regulation, but conclusive evidence of their contribution to this disorder has yet to be published. Inflammation can be demonstrated by elevated leukocyte levels and subtypes in CBC analyses. Neutrophils are the primary lines of defense of the innate immune system and participate in phagocytosis and apoptosis by increasing inflammatory mediators. Lymphocytes contribute to the regulatory and protective aspects of immunity. The simple NLR method represents an affordable, very sensitive, and reliable inflammation parameter that is widely used in many medical fields such as emergency medicine and intensive care, oncology, surgery, cardiology, neurology, infectious diseases, and psychiatry. It has been reported that high NLR is associated with an increase in CRP and cytokines. For this reason, NLR is widely used because it indicates systemic inflammation. PLTs have some functions such as transport, metabolism, and release of various neurotransmitters between neurons. Therefore, PLTs are used as a diagnostic biomarker and research model in various psychiatric disorders.
In the literature, studies investigating the role of inflammation in neuropsychiatric disorders including SLD and supporting this idea are increasing rapidly.,, NLR has also been investigated in adolescents with ADHD, depressive disorder, obsessive–compulsive disorder, nonaffective psychoses, and bipolar disorder.,,,
In a previous study evaluating the cytokine levels of the cerebrospinal fluid, both cell-mediated and humoral immunity disorders were found in ADHD patients. In their study, Özyurt and Binici showed that there is a positive correlation between the severity of depression and NLR and TLR in patient groups. In a study conducted with patients with autism spectrum disorder, the NLR value was higher than that in the healthy group. In another study, higher NLR levels were reported in adolescents with comorbid obsessive–compulsive disorder and anxiety disorder compared to the group with only obsessive–compulsive disorder and the healthy control group. In another study conducted in patients with mood disorders, NLR and monocyte/lymphocyte ratios were high, but the TLR level was similar. In our study, however, no significant relationship was found in terms of TLR and NLR values in patients with SLD. TLR level was higher in boys than girls in the SLD group. However, it was thought that this result did not have an important role in the pathogenesis of SLD.
Neutrophils increase inflammatory cytokines during inflammation. These cytokines can cause cellular dysfunction and immune disorders in many organs, including the brain. NLR may be high in some neuropsychiatric disorders besides physical diseases. The high rate of NLR in some psychiatric disorders shows the relationship between neuropsychiatric diseases and the immune system better., The role of chronic inflammation in SLD has not been fully demonstrated. In the only study conducted to show the relationship between SLD, which is one of the neuropsychiatric disorders, and the immune system, the NLR rate in SLD patients was high. There is no other study in the literature investigating the relationship between SLD and NLR ratio. According to our results, the mean NLR rate in the SLD group was 0.542. Although there was no significant difference between the SLD group and the control group in terms of NLR rate, the NLR rate was higher in the SLD group.
In the literature, there are studies on the relationship between ADHD and inflammation, which is one of the most common neurodevelopmental disorders accompanying SLD. In a study, TLR and NLR values were similar between ADHD and control groups. In another study, 82 children with ADHD were compared with 70 healthy controls, reporting significantly higher NLR, TLR, MLR, and neutrophil counts in the ADHD group than healthy controls. While the NLR and TLR values were higher than the control group in some studies, they were similar in some studies. In our study, TLR and NLR values were similar between the two groups.
The limitations of our study are that it was conducted in a single center, the number of samples was small, and the retrospective screening of the patients. Analyzes should be repeated in different units and centers and should include more patients.
| Conclusion|| |
No significant correlation was found between SLD and inflammation markers NLR and TLR values in our study. This research is a cross-sectional study. Therefore, no causal relationship was found. Evaluation of CRP level, cytokines, and lymphocyte subtypes may also be effective in evaluating the relationship between SLD and inflammation. Studies showing that polymorphisms in genes related to inflammatory pathways play a role in SLD may also be important.
We thank all the children and parents who participated in this study.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Franklin AM, Giacheti CM, Silva NC, Campos LM, Pinato L. Correlation between sleep profile and behavior in individuals with specific learning disorder. Codas 2018;30:e20170104.
Moll K, Kunze S, Neuhoff N, Bruder J, Schulte-Körne G. Specific learning disorder: prevalence and gender differences. PLoS One 2014;9:e103537.
Bilaç Ö, Tahıllıoğlu HA, Önder A, Kavurma C. Özgül öğrenme güçlüğünde enflamasyonun rolünün değerlendirilmesi. Turk J Child Adolesc Ment Health 2021;28:60-4.
Leffa DT, Torres ILS, Rohde LA. A review on the role of ınflammation in attention-deficit/hyperactivity disorder. Neuroimmunomodulation 2018;25:328-33.
Karageorgiou V, Milas GP, Michopoulos I. Neutrophil-to-lymphocyte ratio in schizophrenia: A systematic review and meta-analysis. Schizophr Res 2019;206:4-12.
Asherson P, Buitelaar J, Faraone SV, Rohde LA. Adult attention-deficit hyperactivity disorder: key conceptual issues. Lancet Psychiatry 2016;3:568-78.
Binici NC, Kutlu A. Is ADHD an inflammation-related disorder?. Anatolian Journal of Psychiatry 2019;20:313-21.
Kalelioglu T, Akkus M, Karamustafalioglu N, Genc A, Genc ES, Cansiz A, et al.
Neutrophil-lymphocyte and platelet-lymphocyte ratios as inflammation markers for bipolar disorder. Psychiatry Res 2015;228:925-7.
Bilbo SD, Schwarz JM. The immune system and developmental programming of brain and behavior. Front Neuroendocrinol 2012;33:267-86.
Anand D, Colpo GD, Zeni G, Zeni CP, Teixeira AL. Attention-deficit/hyperactivity disorder and ınflammation: What does current knowledge tell us? A systematic review. Front Psychiatry 2017;8:228.
Zahorec R. Neutrophil-to-lymphocyte ratio. Sixteen-year-long history since publication of our article in Bratislava Medical Journal. Bratisl Lek Listy 2017;118:321-3.
Balta S, Ozturk C. The platelet-lymphocyte ratio: A simple, inexpensive and rapid prognostic marker for cardiovascular events. Platelets 2015;26:680-1.
Avcil S. Evaluation of the neutrophil/lymphocyte ratio, platelet/lymphocyte ratio, and mean platelet volume as inflammatory markers in children with attention-deficit hyperactivity disorder. Psychiatry Clin Neurosci 2018;72:522-30.
Azab B, Bhatt VR, Phookan J, Murukutla S, Kohn N, Terjanian T, et al.
Usefulness of the neutrophil-to-lymphocyte ratio in predicting short- and long-term mortality in breast cancer patients. Ann Surg Oncol 2012;19:217-24.
Duksal F, Alaygut D, Güven AS, Ekici M, Oflaz MB, Tuncer R, et al.
Neutrophil-lymphocyte ratio in children with familial Mediterranean fever: Original article. Eur J Rheumatol 2015;2:20-3.
Topal E, Celiksoy MH, Catal F, Karakoç HT, Karadağ A, Sancak R. The platelet parameters as ınflammatory markers in preschool children with atopic eczema. Clin Lab 2015;61:493-6.
Nuñez A, Benavente I, Blanco D, Boix H, Cabañas F, Chaffanel M, et al
. Oxidative stress in perinatal asphyxia and hypoxic-ischaemic encephalopathy. An Pediatr (Engl Ed) 2018;88:228.e1-9.
Wechsler D. WISC-R Manual for the Wechsler Intelligence Scale for Children-Revised. New York: Psychological Corporation; 1974.
Uluç S, Öktem F, Erden G, Gençöz T, Sezgin N. Wechsler Intelligence Scale for Children IV: A new era for Turkey in the assessment of intelligence in a clinical context. Turkish Psychology Articles 2011;14:49.
Savaşır I, Şahin N. Wechsler Children's Intelligence Scale (WISC-R) Handbook. Ankara: Turkish Psychological Association Publications; 1995.
Verlaet AA, Breynaert A, Ceulemans B, De Bruyne T, Fransen E, Pieters L, et al.
Oxidative stress and immune aberrancies in attention-deficit/hyperactivity disorder (ADHD): A case-control comparison. Eur Child Adolesc Psychiatry 2019;28:719-29.
Mayadas TN, Cullere X, Lowell CA. The multifaceted functions of neutrophils. Annu Rev Pathol 2014;9:181-218.
Ehrlich D, Humpel C. Platelets in psychiatric disorders. World J Psychiatry 2012;2:91-4.
Mitchell RH, Goldstein BI. Inflammation in children and adolescents with neuropsychiatric disorders: A systematic review. J Am Acad Child Adolesc Psychiatry 2014;53:274-96.
Cevher Binici N, Alşen Güney S, İnal Emiroğlu FN. Neutrophil-lymphocyte and platelet-lymphocyte ratios among adolescents with bipolar disorder: A preliminary study. Psychiatry Res 2018;269:178-82.
Bustan Y, Drapisz A, Ben Dor DH, Avrahami M, Schwartz-Lifshitz M, Weizman A, et al.
Elevated neutrophil to lymphocyte ratio in non-affective psychotic adolescent inpatients: Evidence for early association between inflammation and psychosis. Psychiatry Res 2018;262:149-53.
Özyurt G, Binici NC. Increased neutrophil-lymphocyte ratios in depressive adolescents is correlated with the severity of depression. Psychiatry Res 2018;268:426-31.
Mittleman BB, Castellanos FX, Jacobsen LK, Rapoport JL, Swedo SE, Shearer GM. Cerebrospinal fluid cytokines in pediatric neuropsychiatric disease. J Immunol 1997;159:2994-9.
Tural Hesapcioglu S, Kasak M, Cıtak Kurt AN, Ceylan MF. High monocyte level and low lymphocyte to monocyte ratio in autism spectrum disorders. Int J Dev Disabil 2017;65:73-81.
Özyurt G, Binici NC. The neutrophil-lymphocyte ratio and platelet-lymphocyte ratio in adolescent obsessive-compulsive disorder: Does comorbid anxiety disorder affect inflammatory response? Psychiatry Res 2019;272:311-5.
[Table 1], [Table 2], [Table 3]