Cross-Sectional Evaluation of Plasma Vitamin D Levels in a Large Cohort of Italian Patients with Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections

Abstract

Background:

Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS) are immune-mediated diseases characterized by obsessive-compulsive symptoms and/or tics triggered by group A Streptococcus infections. Despite the well-known action of 25-hydroxyvitamin D [25(OH)D] on different conditions driven by systemic inflammation, there are no data about the 25(OH)D status in patients with PANDAS.

Aims:

To evaluate plasma 25(OH)D levels in a large cohort of children and adolescents with PANDAS and comparing the results with healthy controls.

Methods:

We have evaluated plasma 25(OH)D levels in 179 Italian patients with PANDAS (49 females, 130 males, mean age at diagnosis: 101.4 ± 30.1 months) and in an age-, gender-, and body mass index-matched control group of 224 healthy subjects.

Results:

Patients with PANDAS have shown more frequently reduced 25(OH)D levels (<30 ng/mL) in comparison with controls (94.6% vs. 82.5%, p = 0.0007). Patients with PANDAS had also lower levels of 25(OH)D than controls (20.4 ± 6.9 ng/mL vs. 24.8 ± 7.3 ng/mL, p < 0.0001). This difference was observed during both winter (13.7 ± 3.25 ng/mL vs. 21.4 ± 5.9 ng/mL, p < 0.0001) and summer (21.8 ± 6.5 ng/mL vs. 32.5 ± 8.7 ng/mL, p < 0.0001). Notably, serum 25(OH)D levels correlated with both number of streptococcal (strep) infections before diagnosis of PANDAS (p < 0.005) and with infection recurrence (p < 0.005).

Conclusions:

PANDAS patients have reduced 25(OH)D levels, which appear related to streptococcal infections and the probability of recurrence. Further long-term studies with higher number of patients are needed to investigate and confirm this relationship.

Introduction

The term “pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections” (PANDAS) was coined in 1998 to describe a clinically homogeneous subcohort of children with obsessive-compulsive disorder (OCD) or tics (Swedo et al. 1998): this group was characterized by abrupt onset of neuropsychiatric symptoms and clear exacerbations (Exacs) of neurological symptoms after infections by group A β-hemolytic Streptococcus (GABHS) (Swedo et al. 1998).

GABHS is a common human pathogen causing a wide variety of diseases involving skin, joints, heart, kidney, and brain (Carelli and Pallanti 2014). In particular, a variety of psychiatric and movement disorders are thought to be precipitated by GABHS infections in genetically susceptible subjects (Swedo et al. 1989; Kiessling et al. 1993; Dale et al. 2004). Indeed, these patients may develop antibodies cross-reacting with human brain tissues (Allen et al. 1995), as autoimmune sequelae of a GABHS infection. In these cases, the onset of symptoms typically occurs several weeks to months after the resolution of either GABHS pharyngitis or asymptomatic GABHS infections (Williams and Swedo 2015). The mechanisms underlying PANDAS and autoimmunity have not yet been fully understood. Moreover, to address the conflicts regarding diagnosis of PANDAS, a workshop in 2010 developed a criterion to define a syndrome called “pediatric acute-onset neuropsychiatric syndrome” (or PANS), as other microorganisms have been pathogenetically linked to the development of neuropsychiatric disorders (Swedo et al. 2012; Murphy et al. 2014; Swedo et al. 2015).

The exact prevalence of PANDAS in the pediatric population and the percentages of all childhood-onset OCDs or tics remain unknown (Williams and Swedo 2015; Swedo et al. 2015). In addition to OCDs, PANDAS patients might also present attention-deficit/hyperactivity disorder (ADHD)-like symptoms, emotional lability, anxiety, depression, behavioral regression, or personality changes (Swedo et al. 1998). Preliminary data have shown that these patients might produce autoantibodies against basal ganglia (antibasal ganglia antibodies), though at lower concentrations compared with Sydenham's chorea (SC) (Kiessling et al. 1993; Swedo 1994; Hallett et al. 2000; Pavone et al. 2004), although other authors have obtained negative findings (Singer et al. 2005; Morer et al. 2008). In addition, antibodies against dopamine D₂ receptor may be pathologically relevant to the onset of movement disorders in both SC and PANDAS, as dopaminergic networks may be implicated in their pathogenesis (Cox et al. 2013; Williams and Swedo 2015).

It is well established that one of the most relevant extraskeletal roles of vitamin D is the modulation of both innate and adaptive immunity (Szymczak and Pawliczak 2016). In fact, insufficient vitamin D levels are thought to be linked with a higher susceptibility to infectious and autoimmune diseases (Bach 2002). Interestingly, vitamin D regulates tyrosine hydroxylase, a rate-limiting enzyme necessary for the production of dopamine, epinephrine, and norepinephrine (Cui et al. 2015). Therefore, insufficient plasma levels of vitamin D can inhibit tyrosine hydroxylase, which might lead to imbalance of these neurotransmitters and produce a wide range of emotional and behavioral problems (Sanchez et al. 2009). Additional data have also shown that vitamin D deficiency may lead to neuropsychiatric disorders (Cannell 2008; McGrath et al. 2010), sleep disturbances, seasonal affective disorders (Stumpf and Privette 1989; McCarty 2010), and different levels of cognitive impairment (Balion et al. 2012; Annweiler et al. 2011, 2013).

Little data are available about 25-hydroxyvitamin D [25(OH)D] levels in patients with PANDAS, as there is only one report in the medical literature regarding 33 patients (Çelik et al. 2016).

The main aim of our study was to evaluate 25(OH)D levels in a large cohort of Italian children and adolescents with PANDAS in comparison with a control healthy group.

Patients and Methods

One hundred seventy-nine Caucasian patients (49 females, 130 males; mean age at diagnosis 101.4 ± 30.1 months, age range 30.0–174.0 months) who strictly fulfilled the diagnostic criteria for PANDAS (Swedo et al. 1998; Swedo and Grant 2005; Esposito et al. 2014) were recruited from May 2010 to May 2016 by the Department of Internal Medicine, Rheumatology Section, Transition Clinic, University of Florence, Florence, Italy. Ethical approval was granted by the Ethics Committee of the Careggi Hospital, and a written informed consent was obtained from parents of patients after a full explanation of the nature of this study.

Case definition and study protocol

PANDAS diagnosis was performed according to the “Working Criteria for Diagnosis of PANDAS,” identifying a unique subgroup of patients with abrupt onset of neuropsychiatric symptoms (Swedo et al. 1998; Swedo and Grant 2005) in combination with the Kiddie-Sads-Present and Lifetime Version (KSAD-S-PL) and Children Yale-Brown Obsessive Compulsive Scale (CY-BOCS). All participants presented with a history of two “spikes” in OCDs and/or tics, each associated with previous pharyngitis and laboratory confirmation of a previous streptococcal (strep) infection (e.g., positive rapid strep test, positive strep culture, and/or elevation in the antistreptolysin O [ASOT] and/or anti-DNAse B titer) (Bernstein et al. 2010).

In addition, all patients were evaluated by completing a structured diagnostic interview at the time of the first examination. The age of symptom onset, occurring in all patients in pre- or early puberty, was also determined retrospectively.

After the first evaluation, monthly to 3-monthly follow-up assessments were conducted in all patients. In defining Exac status, we used the following parameters: an Exac was identified when the clinical expert determined that the subject experienced a significant worsening of tics or OCD that lasted for at least 5 days, and was not related to a change in prescribed medications (Kurlan et al. 2008). On the contrary, nonexacerbation (non-Exac) subjects were not free from tics or OCD symptoms, but rather maintained a stable clinical status. However, in defining the number of recurrences of colonization/infection by GABHS, we considered a positive culture plus at least one titer elevation of ASOT and/or anti-DNAse B upper limit of normal value. In the absence of GABHS in the throat, two titer elevations were required as evidence of a recent infection. However, data on the history of infections or recent antibiotic treatments were also collected (Shet and Kaplan 2002).

Exclusion criteria were a previous diagnosis of autism, rheumatic fever, mental retardation, schizophrenia-spectrum disorder, or chronic degenerative neurological diseases. Additional exclusion criteria were a recent history of traveling to warmer or sunnier areas before starting the study, use of vitamin D supplements within the past 6 months, or a positive history of primary hyperparathyroidism and other skeletal diseases, malabsorption disorders, or renal diseases.

Control group

Two hundred twenty-four age- and gender-matched healthy Italian children and adolescents of Caucasian origin (174 males, 50 females; mean age 100.1 ± 29.5 months, age range 32.0–176.0 months) were recruited as controls. These patients had no lifetime personal history or any first-degree relative affected with movement disorders, OCDs, PANDAS, SC, Tourette's disorder, ADHD, and no infectious disorders at the time of our evaluation. In particular, controls had no history of a recently documented streptococcal infection. Results regarding part of this group of children and adolescents have been previously published (Stagi et al. 2014).

Vitamin D status

Serum 25(OH)D levels were stratified according to the following rank: ≤10, 11–20, 21–30, and >30 ng/mL, respectively, defined as severe vitamin D deficiency, deficiency, insufficiency, and sufficiency according to previously established guidelines for bone health (in the absence of a consensus regarding appropriate levels for endocrine and extraendocrine health) (Stagi et al. 2014).

To evaluate seasonal variations, we have considered two periods of the year: the periods from November to May (winter) and from June to October (summer), also because the exposure to sun and UVB radiation is negligible between November and April (Webb et al. 1990).

Analytical evaluation

In all subjects, we evaluated serum concentrations of free-T₃, free-T₄, thyrotropin [TSH], ASOT, and anti-DNAse B titers, antithyroperoxidase autoantibodies [TPOA], antithyroglobulin autoantibodies [TgA], serum IgA, antigliadin antibodies [AGA, both IgG and IgA], antiendomysial antibodies [EmA], antitissue transglutaminase antibodies [tTGA], antinuclear antibodies, complete blood cell count, erythrocyte sedimentation rate, C-reactive protein, a comprehensive metabolic panel, including urinalysis, and plasma 25(OH)D levels.

In addition, as for clinical practice, clinical and demographic data were collected, including pubertal staging, weight, height, and body mass index (BMI), time dedicated to outdoor physical activity, vitamin D intake, sunlight exposure, and use of sunscreen.

All serum samples were coded and stored. In the PANDAS group, serum samples were collected during acute Exacs of their disease, typically in association with a confirmed streptococcal pharyngeal infection.

Laboratory personnel were blinded. ASOT titers were measured using the Dade Behring BN II nephelometer (www.dadebehring.com). Anti-DNAse B titers were measured by the commercially available kit (Streptonase-B; Wampole Laboratories, NJ) according to manufacturer's instructions. ASOT titer >200 IU/mL and anti-DNAse B titer >300 IU/mL were considered to indicate a recent infection (Spaun et al. 1961; Martino et al. 2011).

Statistical evaluation

Statistical analyses were performed by using SPSSX (SPSSX, Inc., Chicago, IL). To compare differences, we used the Student's t-test and the chi-squared test and Fisher's exact test depending on the distribution of the analyzed variable. Summaries of the continuous variables are given as mean ± standard deviations (or median and range, depending on whether the data were normally distributed). The Pearson correlation analysis was used to evaluate the significance of correlation factors with the 25(OH)D levels. We used multiple stepwise regression to determine the variables that might correlate with 25(OH)D levels independently such as age (months), gender, weight, height, BMI, time dedicated to outdoor physical activity, vitamin D intake, sunlight exposure, use of sunscreen, number of recurrences of GABHS infection, Exac or remission status, CY-BOCS score, ASOT value, anti-DNAse B titer value, and type of medications taken. Statistical tests were two tailed and considered to be significant when p was <0.05.

Results

The basic features of our study cohort and controls are summarized in Table 1. Data about demographic and general medical features, physical activity, and dietary intake of vitamin D, sunlight exposure, and use of sunscreen did not show any significant difference and are not shown. Two patients affected with celiac disease and Hashimoto's thyroiditis with final hypothyroidism, previously reported (Stagi et al. 2014), were excluded from this study.

Table 1.

Vitamin D Levels and Antistreptococcal Antibody Titers in the PANDAS Cohort and Healthy Controls

	PANDAS	Controls	p
Subjects	179	224	—
Gender, M:F	130:49	174:50	—
Age, months	101.4 ± 30.1	100.1 ± 29.5	—
Exacerbation/remission status	91/88	—	—
Total CY-BOCS score	21.98 ± 7.80	—	—
↑ ASOT, %	67.59	9.82	<0.0001
ASOT, IU/mL	684.87 ± 347. 56	135.71 ± 64.33	<0.0001
↑ Anti-DNAse B titer, %	63.68	8.19	<0.0001
Anti-DNAse B, IU/mL	762.17 ± 432.48	121.23 ± 67.89	<0.0001
25(OH)D levels <30 ng/mL, %	94.8	82.5	0.0007
25(OH)D levels, ng/mL	20.4 ± 6.9	24.8 ± 7.3	<0.0001
During winter	13.7 ± 3.25	21.4 ± 5.9	<0.0001
During summer	22.8 ± 6.5	32.5 ± 8.7	<0.0001

ASOT, antistreptolysin O; CY-BOCS, Children's Yale-Brown Obsessive-Compulsive Scale; 25(OH)D, 25-hydroxyvitamin D (mean values in the cohort and in controls); PANDAS, pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections.

Out of the 179 patients with PANDAS recruited, 91 (50.8%) were considered in a period of Exac at the time of the study, and 88 (49.2%) were in a remission phase. However, in 126 out of 179 patients (70.4%), we identified the recurrence of GABHS infection through positive strep culture and elevated titers of ASOT or anti-DNAse B, whereas we identified the recurrence of GABHS infection in 53 patients (29.6%) through elevation of both titers. Of these, 32 patients had history of recurrent GABHS infections in 1 month (17.9%) and 69 (38.5%) in the 3 months before onset of the study.

Among our cohort of subjects with diagnosis of PANDAS, 37 (20.7%) were taking psychotropic medications at the time of the study. Of these, 21 were taking only one medication (11.7%), and 16 were taking two medications (9.0%); in particular, 15 subjects were taking serotonergic agonists, including sertraline, fluvoxamine, and fluoxetine; 13 were taking dopamine antagonists, including haloperidol, risperidone, and fluphenazine; 9 were taking tricyclic antidepressants, namely clomipramine and imipramine.

As expected, ASOT titers were raised in 67.59% of PANDAS patients (mean: 684.87 ± 347.56 IU/mL), whereas anti-DNAse B titer was raised in 63.68% of PANDAS patients (mean: 762.17 ±432.48 IU/mL).

Patients with PANDAS more frequently showed reduced 25(OH)D levels (<30 ng/mL) in comparison with controls (94.8% vs. 82.5%; p = 0.0007). Of these, 14 of 179 (7.8%) patients had severe deficiency of 25(OH)D (vs. 14.3% of controls, p = 0.08), 88 of 179 (49.2%) showed deficient levels (vs. 38.2% of controls, p = 0.02), 68 of 179 (38.0%) showed insufficient levels (vs. 30.0% of controls, p = 0.08), and 9 of 179 (5.0%) showed sufficient 25(OH)D levels (vs. 17.5% of controls, p = 0.0001).

On average, PANDAS patients had lower levels of 25(OH)D than controls (20.4 ± 6.9 ng/mL vs. 24.8 ± 7.3 ng/mL, p < 0.0001). This difference between patients and controls was found during both winter (13.7 ± 3.25 ng/mL vs. 21.4 ± 5.9 ng/mL, p < 0.0001) and summer (22.8 ± 6.5 ng/mL vs. 32.5 ± 8.7 ng/mL, p < 0.0001).

We did not find any significant difference between ASOT and anti-DNAse B titers in patients with vitamin D deficiency (mean: 568.65 ± 324.77 IU/mL and 790.32 ± 577.45 IU/mL, respectively), vitamin D insufficiency (mean: 682.42 ± 388.29 IU/mL and 775.13 ± 384.02 IU/mL, respectively), and vitamin D sufficiency (mean: 492.33 ± 203.05 IU/mL and 565.68 ± 379.63 IU/mL, respectively).

However, we found significant differences for 25(OH)D levels regarding patients in a period of Exac (19.2 ± 3.9 ng/mL) in comparison with patients in a phase of remission (21.4 ± 5.6 ng/mL, p < 0.005), and in patients with history of recurrent GABHS infections in the past 3 months (18.4 ± 4.2 ng/mL) in comparison with patients with no history of a recent GABHS infection (22.1 ± 5.3 ng/mL, p < 0.005).

In addition, Pearson correlation analysis showed that plasma levels of 25(OH)D were negatively correlated with the number of streptococcal infections before diagnosis of PANDAS (r = −0.56, p < 0.005), the number of recurrences of streptococcal infections (r = −0.61, p < 0.005), and the CY-BOCS score (r = −0.67, p < 0.001). The multiple regression analysis did not identify significant predictors of a lower 25(OH)D value.

Discussion

Our study revealed that patients with PANDAS frequently present with a reduced level of vitamin D in comparison with healthy controls: the reduction of 25(OH)D levels has been observed both in winter and—remarkably—in summer. Interestingly, 25(OH)D was negatively related to the number of streptococcal infections before diagnosis, the number of recurrences rate of PANDAS, and the CY-BOCS score. Therefore, our data seem to suggest that decreased levels of vitamin D might have a potential relationship with the pathogenesis and clinical course of PANDAS.

Interestingly, our study confirms previous data suggesting a higher prevalence of hypovitaminosis D in the general population (Stagi et al. 2014), and even more so in PANDAS patients as well (Table 1). Our study shows that PANDAS patients are deficient in 25(OH)D levels more frequently than control subjects, and are significantly lower in 25(OH)D levels than controls (Table 1). Accordingly, the concept that environmental exposure might trigger the development of autoimmunity in a genetically susceptible individual (Majka and Holers 2003), vitamin D deficiency may act as an environmental trigger for the induction of autoimmune phenomena (Kriegel et al. 2011). Thus, a decrease in normal levels of vitamin D may alter immune responses and be a risk factor in PANDAS.

Recently published data have hypothesized that vitamin D deficiency may facilitate the development of neuropsychiatric disorders (Cannell 2008; McGrath et al. 2010), and particularly of sleep disorders, seasonal affective disorders (Stumpf and Privette 1989; McCarty 2010), and also immune-related pediatric OCDs (Çelik et al. 2016).

Celik et al. (2016) reported that 25(OH)D levels were related to serum ASOT titers, age of onset, and also clinical severity.

Our study, performed in a very large cohort of Caucasian patients with PANDAS, partially confirms these data, raising some points for discussion. For example, vitamin D status may be associated with increasing oxidative stress due to recurrent infections in PANDAS, possibly reflecting an increased production of proinflammatory cytokines (Van West and Maes 1999). If so, vitamin D deficiency might represent a trigger for the development of heterogeneous movement disorders with an inflammatory pathogenesis. However, additional longitudinal studies in a cohort of PANDAS patients are necessary for a better elucidation of the pathogenesis of vitamin D deficiency in PANDAS.

It is important to emphasize that hypovitaminosis of vitamin D might be a significant risk factor for the development of flares in patients with periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome. Indeed, vitamin D supplementation seems to reduce the typical febrile episodes of these conditions and their duration, supporting the role of vitamin D as an immune-regulatory factor in PFAPA syndrome, an acquired autoinflammatory disorder of uncertain origin (Rigante 2010; Stagi et al. 2014). Moreover, vitamin D is important for a proper immune response against bacterial and viral infections (Kroner Jde et al. 2015), and many data indicate that a relatively high plasma level of vitamin D facilitates an adequate antibody response to different infections and vaccinations (Peelen et al. 2013).

Other data seem to suggest a relationship between GABHS infections and vitamin D. For instance, a study involving 44 cases with recurrent GABHS tonsillopharyngitis and 50 controls showed that subjects with recurrent strep infections had significantly reduced 25(OH)D levels compared with controls, and that a plasma 25(OH)D level <20 ng/mL was associated with the risk of recurrent GABHS tonsillopharyngitis, suggesting a potential link between vitamin D deficiency and recurrence of GABHS infections (Nseir et al. 2012). Another study evaluating 84 children with recurrent tonsillitis and 71 healthy children disclosed a significantly lower plasma 25(OH)D level in the affected group, without significant differences in vitamin D receptor gene polymorphisms between the groups (Yildiz et al. 2012).

Conclusion

Our PANDAS patients showed reduced 25(OH)D values, which are related to streptococcal infections and their possibility of recurrence. Reduced plasma levels of 25(OH)D may be a contributive factor to the pathogenesis of PANDAS, although further prospective randomized and controlled longitudinal studies are required to finally clarify the association between vitamin D-related immune processes and PANDAS or PANS.

Clinical Significance

Our results suggest that optimizing vitamin D levels may be potentially useful in reducing neuropsychiatric symptoms in patients with PANDAS, as well as helping to prevent the development of recurrent streptococcal infections.

Footnotes

Acknowledgment

We profoundly thank Prof. M. Cunningham for her editorial assistance in the English revision of our work.

Authors' Contributions

S.S. carried out the endocrinological evaluations, conceived the study, participated in its coordination, and wrote the article. G.L. carried out the rheumatological evaluations and participated in the acquisition of patients' data. D.R. participated in the interpretation of data, evaluated critically the concept of the study, and wrote the article. M.M.-C. carried out the rheumatological evaluation. F.F. carried out the rheumatological evaluations, conceived the study, and participated in its design. All authors read and approved the final version of this article.

Disclosures

No competing financial interests exist.

References

Allen

, Leonard

, Swedo

: Case study: A new infection-triggered, autoimmune subtype of pediatric OCD and Tourette's syndrome. J Am Acad Child Adolesc Psychiatry, 34:307–311, 1995.

Annweiler

, Llewellyn

, Beauchet

: Low serum vitamin D concentrations in Alzheimer's disease: A systematic review and meta-analysis. J Alzheimers Dis, 33:659–674, 2013.

Annweiler

, Rolland

, Schott

, Blain

, Vellas

, Beauchet

: Serum vitamin D deficiency as a predictor of incident non-Alzheimer dementias: A 7-year longitudinal study. Dement Geriatr Cogn Disord, 32:273–278, 2011.

Bach

: The effect of infections on susceptibility to autoimmune and allergic diseases. N Engl J Med, 347:911–920, 2002.

Balion

, Griffith

, Strifler

, Henderson

, Patterson

, Heckman

, Llewellyn

, Raina

: Vitamin D, cognition, and dementia: A systematic review and meta-analysis. Neurology, 79:1397–1405, 2012.

Bernstein

, Victor

, Pipal

, Williams

: Comparison of clinical characteristics of pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections and childhood obsessive-compulsive disorder. J Child Adolesc Psychopharmacol, 20:333–340, 2010.

Cannell

: Autism and vitamin D. Med Hypotheses, 70:750–759, 2008.

Carelli

, Pallanti

: Streptococcal infections of skin and PANDAS. Dermatol Ther, 27:28–30, 2014.

Çelik

, Taş

, Tahiroğlu

, Avci

, Yüksel

, Çam

: Vitamin D deficiency in obsessive-compulsive disorder patients with pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections: A case control study. Arch Neuropsychiatr, 53:31–34, 2016.

10.

Cox

, Sharma

, Leckman

, Zuccolo

, Kovoor

, Swedo

, Cunningham

: Brain human monoclonal autoantibody from Sydenham chorea targets dopaminergic neurons in transgenic mice and signals dopamine D2 receptor: Implications in human disease. J Immunol, 191:5524–5541, 2013.

11.

Cui

, Pertile

, Liu

, Eyles

: Vitamin D regulates tyrosine hydroxylase expression: N-cadherin a possible mediator. Neuroscience, 304:90–100, 2015.

12.

Dale

, Heyman

, Surtees

, Church

, Giovannoni

, Goodman

, Neville

: Dyskinesias and associated psychiatric disorders following streptococcal infections. Arch Dis Child, 89:604–610, 2004.

13.

Esposito

, Bianchini

, Baggi

, Fattizzo

, Rigante

: Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections: An overview. Eur J Clin Microbiol Infect Dis, 33:2105–2109, 2014.

14.

Hallett

, Harling-Berg

, Knopf

, Stopa

, Kiessling

: Anti-striatal antibodies in Tourette syndrome cause neuronal dysfunction. J Neuroimmunol, 111:195–202, 2000.

15.

Kiessling

, Marcotte

, Culpepper

: Antineuronal antibodies in movement disorders. Pediatrics, 92:39–43, 1993.

16.

Kriegel

, Manson

, Costenbader

: Does vitamin D affect risk of developing autoimmune disease?: A systematic review. Semin Arthritis Rheum, 40:512–531, 2011.

17.

Kroner Jde

, Sommer

, Fabri

: Vitamin D every day to keep the infection away?. Nutrients, 7:4170–4188, 2015.

18.

Kurlan

, Johnson

, Kaplan

; Tourette Syndrome Study Group: Streptococcal infection and exacerbations of childhood tics and obsessive-compulsive symptoms: A prospective blinded cohort study. Pediatrics, 121:1188–1197, 2008.

19.

Majka

, Holers

: Can we accurately predict the development of rheumatoid arthritis in the preclinical phase?. Arthritis Rheum, 48:2701–2705, 2003.

20.

Martino

, Chiarotti

, Buttiglione

, Cardona

, Creti

, Nardocci

, Orefici

, Veneselli

, Rizzo

; Italian Tourette Syndrome Study Group: The relationship between group A streptococcal infections and Tourette syndrome: A study on a large service-based cohort. Dev Med Child Neurol, 53:951–957, 2011.

21.

McCarty

: Resolution of hypersomnia following identification and treatment of vitamin d deficiency. J Clin Sleep Med, 6:605–608, 2010.

22.

McGrath

, Burne

, Féron

, Mackay-Sim

, Eyles

: Developmental vitamin D deficiency and risk of schizophrenia: A 10-year update. Schizophr Bull, 36:1073–1078, 2010.

23.

Morer

, Lázaro

, Sabater

, Massana

, Castro

, Graus

: Antineuronal antibodies in a group of children with obsessive-compulsive disorder and Tourette syndrome. J Psychiatr Res, 42:64–68, 2008.

24.

Murphy

, Gerardi

, Leckman

: Pediatric acute-onset neuropsychiatric syndrome. Psychiatr Clin North Am, 37:353–374, 2014.

25.

Nseir

, Mograbi

, Abu-Rahmeh

, Mahamid

, Abu-Elheja

, Shalata

: The association between vitamin D levels and recurrent group A streptococcal tonsillopharyngitis in adults. Int J Infect Dis, 16:e735–e738, 2012.

26.

Pavone

, Bianchini

, Parano

, Incorpora

, Rizzo

, Mazzone

, Trifiletti

: Anti-brain antibodies in PANDAS versus uncomplicated streptococcal infection. Pediatr Neurol, 30:107–110, 2004.

27.

Peelen

, Rijkers

, Meerveld-Eggink

, Meijvis

, Vogt

, Cohen Tervaert

, Hupperts

, Damoiseaux

: Relatively high serum vitamin D levels do not impair the antibody response to encapsulated bacteria. Eur J Clin Microbiol Infect Dis, 32:61–69, 2013.

28.

Rigante

: The protean visage of systemic autoinflammatory syndromes: A challenge for inter-professional collaboration. Eur Rev Med Pharmacol Sci, 14:1–18, 2010.

29.

Sanchez

, Relova

, Gallego

, Ben-Batalla

, Perez-Fernandez

: 1,25-Dihydroxyvitamin D3 administration to 6-hydroxydopamine-lesioned rats increases glial cell line-derived neurotrophic factor and partially restores tyrosine hydroxylase expression in substantia nigra and striatum. J Neurosci Res, 87:723–732, 2009.

30.

Shet

, Kaplan

: Clinical use and interpretation of group A streptococcal antibody tests: A practical approach for the pediatrician or primary care physician. Pediatr Infect Dis J, 21:420–426, 2002.

31.

Singer

, Hong

, Yoon

, Williams

: Serum autoantibodies do not differentiate PANDAS and Tourette syndrome from controls. Neurology, 65:1701–1707, 2005.

32.

Spaun

, Bentzon

, Olesen Larsen

, Hewitt

: International standard for antistreptolysin O. Bull WHO, 24:271–279, 1961.

33.

Stagi

, Bertini

, Rigante

, Falcini

: Vitamin D levels and effects of vitamin D replacement in children with periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome. Int J Pediatr Otorhinolaryngol, 78:964–968, 2014.

34.

Stagi

, Pelosi

, Strano

, Poggi

, Manoni

, de Martino

, Seminara

: Determinants of vitamin D levels in Italian children and adolescents: A longitudinal evaluation of cholecalciferol supplementation versus the improvement of factors influencing 25(OH)D status. Int J Endocrinol, 2014:583039, 2014.

35.

Stagi

, Rigante

, Lepri

, Bertini

, Matucci-Cerinic

, Falcini

: Evaluation of autoimmune phenomena in patients with pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS). Autoimmun Rev, 13:1236–1240, 2014.

36.

Stumpf

, Privette

: Light, vitamin D and psychiatry. Role of 1,25 dihydroxyvitamin D3 (soltriol) in etiology and therapy of seasonal affective disorder and other mental processes. Psychopharmacology (Berl), 97:285–294, 1989.

37.

Swedo

: Sydenham's chorea. A model for childhood autoimmune neuropsychiatric disorders. JAMA, 272:1788–1791, 1994.

38.

Swedo

, Grant

: Annotation: PANDAS: A model for human autoimmune disease. J Child Psychol Psychiatry, 46:227–234, 2005.

39.

Swedo

, Leckman

, Rose

: From research subgroup to clinical syndrome: Modifying the PANDAS criteria to describe PANS (Pediatric Acute-onset Neuropsychiatric Syndrome). Pediatr Therapeut, 2:1–8, 2012.

40.

Swedo

, Leonard

, Garvey

, Mittleman

, Allen

, Perlmutter

, Lougee

, Dow

, Zamkoff

, Dubbert

: Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections: Clinical description of the first 50 cases. Am J Psychiatry, 155:264–271, 1998.

41.

Swedo

, Rapoport

, Cheslow

, Leonard

, Ayoub

, Hosier

, Wald

: High prevalence of obsessive-compulsive symptoms in patients with Sydenham's chorea. Am J Psychiatry, 146:246–249, 1989.

42.

Swedo

, Seidlitz

, Kovacevic

, Latimer

, Hommer

, Lougee

, Grant

: Clinical presentation of pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections in research and community settings. J Child Adolesc Psychopharmacol, 25:26–30, 2015.

43.

Szymczak

, Pawliczak

: The active metabolite of vitamin D3 as a potential immunomodulator. Scand J Immunol, 83:83–91, 2016.

44.

van West

, Maes

: Activation of the inflammatory response system: A new look at the etiopathogenesis of major depression. Neuro Endocrinol Lett, 20:11–17, 1999.

45.

Webb

, Pilbeam

, Hanafin

, Holick

: An evaluation of the relative contributions of exposure to sunlight and of diet to the circulating concentrations of 25-hydroxyvitamin D in an elderly nursing home population in Boston. Am J Clin Nutr, 51:1075–1081, 1990.

46.

Williams

, Swedo

: Post-infectious autoimmune disorders: Sydenham's chorea, PANDAS and beyond. Brain Res, 1617:144–154, 2015.

47.

Yildiz

, Unuvar

, Zeybek

, Toptas

, Cacina

, Toprak

, Kilic

, Aydin

: The role of vitamin D in children with recurrent tonsillopharyngitis. Ital J Pediatr, 38:25, 2012.