Journal of Neurology Research Reviews & Reports

Introduction

Cerebral palsy (CP) is defined as a movement and postural disorder resulting from a non-progressive lesion of an immature brain [1]. PC is described as a condition characterized by abnormal tone, posture and movement and is clinically classified according to the predominant motor syndrome – spastic hemiplegia, spastic diplegia, spastic quadriplegia and extrapyramidal or dyskinetic [2].

The Pathogenesis of CP is Currently Divided into Four Main Stages

Fetal, prenatal, perinatal and postpartum [3].

As part of early rehabilitation, secondary diseases should be prevented or stopped in children with CP so that functional abilities can be positively influenced. One therapeutic option would be daily vitamin D supplementation (Vit D suppl) for four indications. This pluripotent therapeutic agent should be discussed in the rehabilitation plan as a cost-effective measure that is easy to implement worldwide.

In CP, the prevalence of hypovitaminosis D has been observed to be between 19% and 53%, and serum 25-hydroxyvitamin D [25(OH) D] levels should be checked in principle [4-11].

Monitoring is easily possible by determining 25(OH)D [s25(OH) D], Ca, and phosphate in the blood. There is sufficient evidence of severe inflammatory processes and neuroimmunological dysregulations in CP and vitamin D may contribute to achieving immunological homeostasis.

Attenuation of Chronic Neuroinflammation

CP patients showed increased levels of eight cytokines (IFN-γ, GM-CSF, TNF-α, IL-2, IL-4, IL-6, IL-17A and IL-12) compared to control subjects , including IFN-γ, GM-CSF, TNF-α, IL-2, IL-4, IL-6, IL-17A, BAFF, IL-12p70 and IL-10, which were also increased in the cerebrospinal fluid of patients with CP [12]. Increased pro-inflammatory cytokines such as IL-1ß, IL-6 and TNF-alpha have been verified both postnatal and later in life in PC, and increased IL-6 levels are associated with increased pro-inflammatory IL-17A. This cytokine constellation leads to disruption of the blood-brain barrier (BBB) and enables the infiltration of harmful immune cells [3]. The inflammasome of the NOD-like receptor family pyrin domain -containing protein 3 (NLRP3) is also involved in the inflammatory cascade, and calcitriol inhibits the overactivation of the NLRP3 inflammasome, which also has a beneficial effect on infection defense [13,14].

s25(OH)D levels, as established biomarkers for vitamin status, D status showed a significant inverse correlation with proinflammatory cytokines such as IL-1ß, IL-6, IL-8 and IL-17 A [15-19]. The active metabolite of vitamin D, calcitriol, promotes the development of forkhead box protein 3 (FOXP 3)+ regulatory T cells (Treg) and IL-10-producing T regulatory type 1 (TR1) cells . In T cells, 1,25(OH)2D3 reduces the production of IL-2, IL-17 and interferon-γ (IFN γ) and attenuates the cytotoxic activity and proliferation of CD4+ and CD8+ T cells [20-22]. A significant increase in serum Concentrations of IL-10 (and TGF-β1) indicate an anti- inflammatory effect of vitamin D supplementation [20].

Macrophages / microglia are defense cells of the immune system and are characterized by binary M1/M2 macrophage polarization. The polarization of macrophages / microglia is an important regulatory factor in the development of inflammation processes [23]. Calcitriol promotes the polarization of M2 macrophages by increasing the expression of T cells immunoglobulin mucin3 (Tim- 3), which leads to a decrease in TNFα and IL-6 and an increase in IL-10 [21,24]. Vit D thus indirectly inhibits Th47 cells and Th4 by inhibiting the production of IL-6 and TNFα by macrophages [21].

To achieve immunological homeostasis, a relatively high Vit D supplement dose of at least 1000IU/ day in children seems to be necessary, which is not associated with hypercalcemia or other adverse effects [18,25,26].

Bone Health in CP

Another indication for Vit D suppl is reduced bone mineral density (BMD) in children with CP. Children with CP can be affected by mild to multiple disabilities. When 77% of non- ambulatory children with CP have low bone mineral density (BMD) and an increased risk of fractures (about 4% per year), especially of the vertebrae and distal femur, attention to bone health is a sine qua non [27,28].

Vitamin D deficiency is a major factor in reduced BMD in children with CP [6]. Treatment with antiepileptic drugs increases the risk of hypovitaminosis [8]. In addition, there is an association between bone loss and IL- 17 with reduced vitamin D levels [29].

Adequate vitamin D intake in childhood improved bone mineralization and, in combination with high-dose vitamin D supplementation before birth and later in life, reduced the risk of bone fractures [30]. A positive correlation between s25(OH) D levels and total BMD and an inverted U- shaped relationship between serum calcium and total BMD were verified [31].

A study indicated that serum 25(OH)Vit-D levels were lower in pediatric patients with fractures. S25(OH)Vit-D ≤ 50 nmol /L was associated with increased fracture risk in children [32].

A correlation was also found between s25(OH) D and bone turnover markers osteocalcin (OC) and β- cross-laps (β- CTx) in children . An increase in s25(OH)D values by 10 nmol /L was significantly associated with a decrease in β- CTx by 10.5 ng /L [33].

Increased serum IL-35 levels were associated with increased 25(OH)VitD3, suggesting that IL-35 may play an important role in bone health and the immune system [34]. IL-35 induces the expansion of lymphocytes into regulatory B (135-Breg) and T cells (iTR35) [35].

Low vitamin D levels in children with CP are also associated with decreased muscle strength, balance, muscle pain, paresthesia, and poor muscular coordination [36].

Prevention of PC

As part of proactive therapy, PC in pregnancy should be diagnosed early and high- dose Vit D suppl should be administered immediately. A 60% lower rate of premature births and thus also prevention of PC could be achieved with high- dose Vit D supplementation with s25 (OH)D values ≥ 40 ng / mL [37,38]. As part of prenatal care, this option should be offered to every pregnant woman and thus indirectly contribute to reducing CP [39]. If biomarkers or imaging procedures indicate a suspicion of possible PC in pregnancy, Vit D suppl could be a possible intervention [40,41].

Numerous studies have shown that hypovitaminosis D is associated with the occurrence of pre-eclampsia, premature birth, low birth weight , low gestational age ( small infants ), indication for cesarean section and gestational diabetes [42,43]. Effects of hypovitaminosis D on the newborn and on child development in terms of poor immune and skeletal development, allergies and respiratory infections have shown that neural, musculoskeletal, and psychomotor growth as well as bone health are negatively affected [43].

For women who want to have children, as part of prevention for the course of pregnancy and for maternal and child health, it is crucial to start Vit D suppl at least 2 months before conception ( before placentation and trophoblast invasion) with around 5000 IU/ day Vit D to achieve an optimal Vit D serum level ( serum level over 100nmol/L=40ng/mL) [44].

Vit D deficiency can also be the cause of recurrent embryo implantation failure and recurrent fetal loss [45-47].

The influence of Vit D on placental genes expression and inflammation within the placenta creates an optimal starting position for the children [46-48].

To prevent PC, a proactive approach could also be used to prevent infection both during pregnancy and during PC.

Infection Prophylaxis

Lack of standard guidelines for adjunctive vitamin D therapy in diseases with an immunological basis/component could promote complications such as infections. Preventive measures are therefore justified because multiorgan dysfunction in PC is generally accepted [49].

The most common cause of morbidity and mortality in people with CP is respiratory disease [50].

In PC, a high rate of carriage of abnormal bacteria/potential pathogens, antibiotic-resistant bacteria and infections have been observed [51,52]. The complex pathology has not yet led to evidence-based treatment guidelines for respiratory diseases in PC [53]. In PC, a higher complication rate is also to be expected in influenza infections [54].

Urinary tract infections (UTI) in children with CP range from 8.5% to 56.7% in industrialized countries, while in Africa, particularly in Nigeria, a prevalence of 38.5% has been found [55].

Hypovitaminosis D can increase susceptibility to respiratory tract infections (Covid- 19)/ urinary tract infections [56-58]. From the beginning of fetal development and throughout life, Vit D exerts its effects on the lungs. Any vitamin D dysfunction during fetal development has long-term consequences for lung health after birth. The fetus is solely dependent on the supply of Vit D from the mother. Many cells in the lung express the Vit D receptor (VDR) and respond to 1,25(OH)2D3 [59].

Calcitriol increases the physical barrier by creating integrity in the mucous membranes of the respiratory and urogenital tract through integrity of Tight Junctions (TJs), Adherence junctions (AJs) and E-cadherin [60]. The promotion of TJs by Vit D is also beneficial because the BBB is disrupted in Covid-19 [61].

Structure of the Blood–Brain Barrier (BBB). (A) The blood–brain barrier (BBB) consists of endothelial cells, pericytes, astrocytes, and the basement membrane. The neurovascular unit (NVU) is composed of endothelial cells, pericytes, and astrocytes of the BBB and neurons, oligodendrocytes, and microglia, which closely communicate with each other in order to regulate brain homeostasis. (B) Tight junctions (claudin-5, occludin, ZO-1, ZO- 2, and ZO-3) and adhesion junctions (JAMs and VE-cadherin) between BBB endothelial cells (BBB-ECs) form the BBB. (C) Transcellular migration of lymphocytes involves the following 4 steps: (1) in the rolling process, activated lymphocytes slow their flow speed due to the interaction of VLA-4 from the surface of lymphocytes with vascular cell adhesion molecules 1 (VCAM-1) on BBB-ECs; (2) in adhesion pathways, the lymphocytes adhere to endothelial cells and transverse the BBB by coupling the VLA- 4 and LFA-1 expressed on lymphocytes with the endothelial cell receptor (VCAM-1 and intracellular adhesion molecules (ICAM-1); (3) during adhesion, interaction between VCAM-1 and ICAM on BBB-ECs and their ligands (LFA-1 and VLA-4) on leukocytes induces the arrest of immune cells from the blood by the brain endothelial cells; and (4) interaction between ICAM-1 and ICAM-2 and their ligands (LFA-1 and LFA-2) is involved in crawling and migration.

Figure 1: from Shimizu F et al. Blood-Brain- Barrier Disruption in Neuroimmunological Disease.(2024) Int J Mol Sci;25(19):10625

1,25(OH)2D3 promotes the formation of the antimicrobial peptides (AMPs) ß- defensin 2 and cathelicidin 2 [63]. Calcitriol reduces the production of proinflammatory cytokines and chemokines in various cells of the lung [59,60].

Inhibition of NLRP3 inflammasome activation by Vit D may also be helpful in respiratory infections [64].

An s25(OH)D level <20 ng/ mL increased the risk of UTI, just as an s25(OH)D level < 20 ng/ mL can lead to an increased risk of respiratory diseases [65,66]. Most studies defined 25(OH)D levels below 20 ng /mL as deficient and levels above 20 ng /mL and below 30 ng /mL as insufficient [65]. The importance of the daily dose of Vit D (dose-effect relationship) was demonstrated by the fact that the mean s25(OH)D level in UTI was 7.73 ng/ mL lower than in control subjects [65]. In acute infections, a loading dose of Vit D is required [67].

A Vit D supplement at a dosage of 10,000 IU/kg (max. 400,000 IU) significantly increased 25(OH)D3 levels in critically ill pediatric patients [68].

In adults, s25(OH)D levels of over 50 ng/ mL were necessary to overcome infections (including Covid-19) [69,70]. A Vit D suppl of over 1000 IU/day was beneficial in preventing colds/flu [71,72].

A liquid, oily, ready-to-use Formulation of Vit D (e.g. Vit D drops day) facilitates the possibility of a complication-free and safe application even in tube feeding. A current study in the United Kingdom (UK) is investigating PC patients with gastrostomy / jejunostomy require a Vit D supplement [73].

Discussion

There is currently a growing call to recognize chronic inflammation as a comorbidity in CP. A broad immunomodulatory and anti- inflammatory strategy is warranted [74]. In summary, by 2025 there will be sufficient pathoimmunological evidence to show that children with CP benefit significantly from relatively high- dose daily vitamin D supplementation throughout their lives.

A reduction in chronic inflammation in the CNS by sealing the BBB and positive effects on the skeletal system can be expected [62,75]. With increasing age, children showed lower s25(OH)D values [76]. Vitamin D supplementation helps improve reduced muscle performance and reduce the potential risk of falls [77,78]. Secondary sarcopenia (muscle atrophy and weakness due to disuse, inflammation or malnutrition) is no longer in doubt in PC and a beneficial effect of Vit D suppl is evident [79,80]. Vit D is involved in the transcription of a number of proteins essential for skeletal muscle function and therefore Vit D is essential for muscle function and muscle strength [79]. The susceptibility of children with PC to non-traumatic fractures continues into adulthood and therefore Vit D intervention is necessary for skeletal health across the lifespan [81]. Evidence-based health benefits of vitamin D for the general population and recommendations exist, and this message applies even more to individuals with PC [82].

A benefit can only be expected if the s25[OH]D values are between 40 and 70ng/mL and, depending on individual absorption, can be achieved with an intake of around 4000-6000 IU/day Vit D [82].

If the Endocrine Society recommends vitamin D supplementation for healthy children and adolescents aged 1 to 18 years to prevent infections, it should be a mandatory part of treatment management for CP patients [83]. In addition to the usefulness of vitamin D as a potential adjuvant form of therapy, the pluripotency of this hormone during pregnancy should also be part of the global prevention strategy to prevent PC.

Conclusions

Optimizing the resilience of parents/caregivers when caring for individuals with PC is an essential factor in the long-term therapy of this patient group. This resilience is at risk if comorbidities occur alongside the underlying PC disease. A proactive action to prevent chronic inflammation, fractures, infections, comorbidities through the transmission of new pathophysiological/pathoimmunological findings by general practitioners and neurologists is required. The increase in disability can be slowed down by sufficient s25(OH)D values. In order to combat PC preventively, all pregnant women should take advantage of this inexpensive, easy-to-implement and widely available adjuvant therapy from the beginning of pregnancy up to and including the breastfeeding period.

Conflict of Interest: The author declares that there is no conflict of interest.

Ethical Approval and Consent to Participate: Not applicable.

Financing: No financial support

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