Vitamin D deficiency in obsessive-compulsive disorder patients with pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections: a case control study.
Obsessive-compulsive disorder (OCD) is characterized by the presence of obsessions (persistent and intrusive thoughts, ideas, impulses, or images that result in anxiety) and/or compulsions (repetitive or ritualistic behaviors or mental acts that reduce or prevent anxiety in response to the obsessive thought) that cause distress, interfere with age-appropriate functioning, and are time consuming. In addition, it is a severe neuropsychiatric disorder with a strong genetic component and may involve the autoimmune processes. Support for this hypothesis comes from the identification of a subgroup of children, described by the term pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS), with the onset of OCD symptoms following streptococcal infections (1).
However, the mechanisms underlying PANDAS and autoimmunity have not been fully understood yet. The most commonly accused factors are recurrent infections, genetic tendency, or possible psychosocial stress, although controversial studies have reported a pathogenic link between neuropsychiatric exacerbation and streptococcal infection (2,3). Other microorganisms may be linked to neuropsychiatric exacerbation; therefore, the description of PANDAS may change to pediatric acute-onset neuropsychiatric syndrome (PANS) (1). Recently there has been no consensus on the etiology or definition of PANDAS (3).
The active form of vitamin D plays a major regulatory role in the immune system, while vitamin D3 enhances macrophage functions (4). The former also regulates tyrosine hydroxylase, which is the rate-limiting enzyme necessary for the production of dopamine, epinephrine, and norepinephrine. Insufficient levels of vitamin D inhibit tyrosine hydroxylase, which may lead to disturbances of these neurotransmitters and a wide range of emotional and behavioral problems (5). Currently according to pediatricians, vitamin D insufficiency is defined as serum 25-hydroxyvitamin D (25-(OH) D) levels of <10 ng/mL; vitamin D deficiency is defined as 25-(OH) D levels of <30 ng/mL, and sufficient levels of vitamin D are equal to 30 ng/mL (6).
The major role of vitamin D in the immune system is the modulation of innate immunity and autoimmunity Therefore, insufficient vitamin D levels are thought to be linked to a higher susceptibility for infectious and autoimmune diseases (7).
Considering the immune modulator role of vitamin D, several autoimmune mechanisms may account for the clinical aspects of PANDAS. To date, no clinical study has described an association between pediatric OCD and vitamin D deficiency The aim of this study is to clarify the possible association between OCDs that are triggered by group A beta-hemolytic streptococci and vitamin D deficiency
Thirty-three OCD patients with PANDAS and twenty healthy controls were enrolled in the study All OCD patients were followed-up for 3 years to ensure the reliability of the differential diagnosis of OCD subgroups. The patients were chosen from those treated at University School of Medicine, Child and Adolescent Psychiatry Outpatient Department. The controls, none of whom had a chronic disorder were recruited from a primary health care clinic. The diagnostic criteria for PANDAS proposed by Swedo et al. were as follows: 1) presence of a tic disorder or OCD, 2) prepubertal age (usually between 3-12 years) at onset, 3) abrupt symptom onset or episodic course of symptom severity 4) temporal association between symptom exacerbation and streptococcal infection, and 5) presence of neurologic abnormalities during the periods of symptom exacerbation (1).
Serum 25-(OH) D, calcium, phosphorus, alkaline phosphatase (ALP), and parathormone levels in both groups were compared. Serum 25(OH) D levels less than 15 ng/mL were classified as indicating deficiency All blood specimens were collected during the interval between June and September 2012. Informed consent was obtained from all patients and their parents. The study was approved by Medical Ethics Committee of School of Medicine, Cukurova University
A socio-demographic questionnaire recording information on age, gender and onset age of illness was used. Psychiatric diagnoses were made according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) criteria (8), and the Turkish version of the Schedule for Affective Disorders and Schizophrenia for School-Aged Children-Present and Lifetime Version (K-SADS-PL) (9,10). The children's Yale-Brown Obsessive Compulsive Scale (CYBOCS) was used to assess the severity of obsessive-compulsive symptoms (11).
Statistical analysis was performed using the Statistical Package for the Social Sciences 13.0 for Windows (SPSS Inc; Chicago, IL, USA). Pearson's chi-square and Fisher's exact tests were used for comparing categorical variables (patients and control groups, age, and vitamin D status according to serum levels). The Mann-Whitney U test was used to compare the mean values of vitamin D levels between both groups and other continuous variables as well. Correlations between bone metabolic markers (Ca, P, ALP, PTH, and vitamin D) and YBOCS scores were evaluated by Pearson's correlation coefficient.
Of the 33 PANDAS OCD patients, 14 (42.4%) were female and 19 (57.6%) were male. Of the 20 control patients, 4 (20%) were female and 16 (80%) were male. The mean age in the OCD group was 9.5 [+ or -] 2.5 years and that in the control group was 11.7 [+ or -] 5.2 years.
There was no significant difference between the patient and control groups for serum 25-(OH) D levels although the controls had higher levels of 25-(OH) D than patients (21.54 [+ or -] 10.23 vs. 17.39 [+ or -] 9.48; p>0.05). Vitamin D deficiency (levels<15 ng/mL) was significantly more frequent in the patient group than in the control group (48.5% vs. 20.0%; p=0.038; Table 1). The patients had higher serum levels of ALP and lower serum levels of phosphorus than controls (Table 2). The most common comorbid condition in the patient group was ADHD. Moreover, OCD patients with vitamin D deficiency had higher rates of comorbid ADHD than those without vitamin D deficiency (87.5% vs. 52.6%; p=0.027). The serum levels of vitamin D, PTH, ALP calcium, calcitonin, and parathormone were compared between the ADHD comorbid OCD group and pure OCD group. There was no relationship between two groups for bone metabolic markers (vitamin D, PTH, ALP calcium, calcitonin, and parathormone) and YBOCS sub scores (p=0.1 60, 0.062, 0.21 9, 0.378, 0.548, and 0.161, respectively).
Although there was no significance, the levels of vitamin D and PTH were lower in the ADHD comorbid OCD group than in the control group (p=0.073 and 0.061, respectively).
The serum levels of ALP and phosphorus were lower in the ADHD comorbid OCD group when than in the control group. (p=0.002 and 0.013, respectively).
No correlation was found between the serum vitamin D level and other variables. However, serum phosphorus levels were negatively correlated with age, ALP, and ASO levels and were positively correlated with the YBOCS total score, sub-scores, and global severity score. Similarly serum PTH levels were positively correlated with the YBOCS total score, sub-scores, and global severity score, while they were negatively correlated with ASO titers. In addition, serum PTH levels were positively correlated with the YBOCS total score, compulsion score, obsession score, and global severity score and were negatively correlated with ASO titers (Table 3).
The comparison of vitamin D levels for ADHD comorbidity has been presented in Table 4.
There was no association between the levels of calcium and calcitonin between the two groups (p>0.05; Table 5).
Vitamin D deficiency does not only result in low bone mass, but it may also lead to neuropsychiatric disorders (12,13). Recently the possible etiological role of vitamin D has become increasingly defined among patients with sleep disorders and seasonal affective disorders (14,15). To our knowledge, this is the first study investigating the association between immune-related pediatric OCD and vitamin D metabolism. Based on the present findings, we conclude that the serum levels of bone metabolic turnover markers, including 25-(OH) D3, phosphorus, calcium, and PTH, may be associated with serum ASO titers, age of onset, and clinical severity in PANDAS-related OCD cases. The vitamin D status may be associated with increasing oxidative stress due to recurrent infectious attacks in PANDAS patients.
In particular, the serum levels of phosphorus and PTH may be useful in predicting the autoimmune process in PANDAS-related OCD by identifying the increased osteoclastic activity PTH and phosphorus levels that have been found to be positively correlated with OCD severity and obsession-compulsion sub-scores in the patient group reveal a relationship with the osteoclastic activity in PANDAS-related OCD. Similarly increased osteoclastic bone activity is correlated with depression severity in adults (16). In addition, elevated PTH levels and increased osteoclastic activity may be related to increased levels of pro-inflammatory cytokines in psychiatric patients (17). The results showing no difference between serum levels of vitamin D among patients the controls may be explained by endemic vitamin D deficiency To mention a certain deficiency of vitamin D, there is also a need for other bone metabolism parameters. However, the cutaneous production of vitamin D is known to be influenced by season and latitude (18). Therefore, the seasonal effect should be considered when screening the serum levels of vitamin D in patients. Vitamin D deficiency due to demographic characteristics is very common in our society
The finding that OCD patients with vitamin D deficiency had higher rates of comorbid ADHD than those without vitamin D deficiency was consistent with the findings of Goksugur et al. (19). All bone metabolic markers were compared between the ADHD comorbid OCD group and OCD group to eliminate any association between vitamin D deficiency and ADHD, However compared with the pure OCD group, there was no significant relationship between metabolic markers and YBOCS sub-scores in the ADHD comorbid OCD group,
Poststreptococica ADHD cases were reported in the PANDAS subgroup (20), In OCD patients with PANDAS, the symptoms of ADHD may differ from those in pure ADHD patients, Vitamin D deficiency may be related to the heterogeneous nature of pediatric OCD with PANDAS,
Consequently these bone markers seem to be partially related to the symptom profile for PANDAS-related OCD, probably by underlying autoimmune inflammatory processes, Supplements or vitamin D monotherapy may be useful for reducing psychiatric symptoms in patients with PANDAS OCDs, Further prospective, randomized, and controlled longitudinal studies are needed to define a clear association between vitamin D-related bone metabolism and pediatric OCD,
This study is presented in 15th International Congress of ESCAP European Society of Child and Adolescent Psychiatry, 6-10 July, 2013, Dublin, Ireland.
Conflict of Interest: No conflict of interest was declared by the authors,
Financial Disclosure: The authors declared that this study has received no financial support,
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Gonca CELIK , Didem TAS , Aysegul TAHIROGLU , Ayse AVCI , Bilgin YUKSEL , Perihan CAM 
 Department of Child and Adolescent Psychiatry, Cukurova University, School of Medicine, Adana, Turkey
 Department of Rheumatology Immunology, Cukurova University School of Medicine, Adana, Turkey
 Department of Pediatric Endocrinology, Cukurova University School of Medicine, Adana, Turkey
Correspondence Address: Gonca Celik, Cukurova Universitesi Tip Fakultesi, Cocuk Ergen Ruh Sagligi ve Hastaliklari Anabilim Dali, Adana, Turkiye E-mail: email@example.com
Received: 22.04.2014 Accepted: 03.12.2014
Table 1. Comparison of the vitamin D status between patients and controls Vitamin D status OCD with Control p PANDAS patients Sufficient (>20 ng/mL) 15 (45.5%) 8 (40%) 0.003 Insufficient (15-20 ng/mL) 7 (21.2%) 12 (60%) Deficiency (<15 ng/mL) 11 (33.3) 0 OCD: Obsessive-Compulsive Disorder; PANDAS: Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections Table 2. Comparison of bone metabolism markers for both groups Bone metabolism PANDAS OCD Control group markers 25-hydroxyvitamin D 17.39 [+ or -] 9.48 21.54 [+ or -] 10.23 PTH 34.77 [+ or -] 17.50 32.03 [+ or -] 21.73 ALP 179.35 [+ or -] 67.50 1 14.33 [+ or -] 60.08 Calcitonin 0.42 [+ or -] 0.1 1 0.53 [+ or -] 0.21 Calcium 9.58 [+ or -] 0.40 9.61 [+ or -] 0.42 Phosphorus 4.2 [+ or -] 0.85 4.8 [+ or -] 0.66 Bone metabolism p markers 25-hydroxyvitamin D 0.180 PTH 0.667 ALP 0.004 Calcitonin 0.161 Calcium 0.542 Phosphorus 0.018 PANDAS: Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections; OCD: Obsessive-Compulsive Disorder; PTH: Parathormone; ALP: Alkaline Phosphatase Table 3. Correlations between bone metabolic markers and YBOCS 25-(OH) D Age Onset PTH CS -0.18 0.25 0.34 0.64 OS -0.06 0.18 0.05 0.54 TS -0.16 0.14 0.13 0.63 Insight -0.05 -0.37 0.04 0.43 Avoidance -0.37 -0.27 0.03 0.58 Indecision -0.28 -0.18 0.1 1 0.69 Responsibility 0.03 -0.13 -0.1 1 0.28 Slowing -0.28 -0.14 -0.12 0.54 Skepticism -0.17 -0.17 -0.24 0.12 Severity -0.12 -0.04 0.24 0.63 ASO 0.01 0.01 0.12 -0.45 CRP 0.03 0.05 0.28 0.03 Calcium Calcitonin Phosphorus ALP CS 0.17 -0.19 0.21 0.01 OS 0.18 -0.33 0.34 0.31 TS 0.18 -0.27 0.28 0.16 Insight 0.15 -0.00 0.67 -0.37 Avoidance 0.36 -0.36 0.37 0.05 Indecision 0.18 -0.41 0.42 0.16 Responsibility 0.29 -0.24 0.27 -0.05 Slowing 0.14 -0.22 0.20 -0.02 Skepticism 0.27 -0.22 0.01 0.04 Severity 0.23 -0.23 0.31 0.15 ASO -0.58 0.53 -0.43 0.00 CRP -0.53 0.75 -0.02 0.00 Spearman Correlation test. CS: YBOCS-Compulsion Sub-score; OS: YBOCS-Obsession Sub-score; TS: YBOCS-Total Score; ASO: Antistreptolysin Serum Titers; CRP: C-reactive protein; 25-(OH) D: 25-hydroxyvitamin D; PTH: parathormone; ALP: alkaline phosphatase Table 4. Comparison of vitamin D levels for ADHD comorbidity Serum OCD n (%) OCD comorbid p vitamin D levels ADHD n (%) Sufficient 7 (29.2) 10 (90.9) 0.003 Insufficient 6 (25) 1 (9.1) Deficient 11 (45.8) -- <25 15 (62.5) 2 (18.2) 0.015 >25 9 (37.5) 9 (81.8) ADHD: Attention Deficit Hyperactivity Disorder and OCD: Obsessive-Compulsive Disorder Table 5. Comparison between OCD patients with PANDAS based on ADHD comorbidity OCD OCD comorbid ADHD Vitamin D 16.6 [+ or -] 9.9 19.3 [+ or -] 8.2 PTH 37.1 [+ or -] 18.6 28.0 [+ or -] 12.5 ALP 197.1 [+ or -] 69.4 137.8 [+ or -] 42.7 Calcium 9.5 [+ or -] 0.4 9.6 [+ or -] 0.1 Calcitonin 0.4 [+ or -] 0.1 0.4 [+ or -] 0.1 Phosphorus 4.9 [+ or -] 0.6 4.5 [+ or -] 0.7 Control [P.sup.1] Vitamin D 21.5 [+ or -] 10.2 0.160 PTH 32.0 [+ or -] 21.7 0.062 ALP 114.3 [+ or -] 60.0 0.219 Calcium 9.6 [+ or -] 0.4 0.378 Calcitonin 0.5 [+ or -] 0.2 0.548 Phosphorus 4.2 [+ or -] 0.8 0.161 [P.sup.2] [P.sup.3] Vitamin D 0.073 0.887 PTH 0.061 0.941 ALP 0.002 0.285 Calcium 0.550 0.735 Calcitonin 0.148 0.613 Phosphorus 0.013 0.316 [P.sup.1] (ADHD comorbid OCD and OCD), [P.sup.2] (ADHD comorbid OCD and control), and [P.sup.3] (OCD and control), PANDAS: Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections; OCD: Obsessive-Compulsive Disorder; PTH: parathormone; and ALP: alkaline phosphatase
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|Title Annotation:||Research Article|
|Author:||Celik, Gonca; Tas, Didem; Tahiroglu, Aysegul; Avci, Ayse; Yuksel, Bilgin; Cam, Perihan|
|Publication:||Archives of Neuropsychiatry|
|Date:||Mar 1, 2016|
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