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Clinical study (Prospective, Retrospective, Case Series)

Vitamin D and Neurological Status in Sturge-Weber Syndrome

Smegal, Lindsay F.a; Lin, Doris D.b; Cho, Andrewc; Cho, Subin (Claire)c; Kalb, Luther G.d,e; Cohen, Bernardf; Germain-Lee, Emily L.g; Comi, Anne M.a,h,i

Author Information
Journal of Vascular Anomalies: December 2021 - Volume 2 - Issue 4 - p e025
doi: 10.1097/JOVA.0000000000000025

Abstract

Introduction

Sturge-Weber syndrome (SWS), a neurocutaneous disorder commonly indicated by the presence of a port-wine birthmark, occurs in approximately one in 20,000 to 50,000 live births.1 Caused by a somatic mosaic R183 mutation in GNAQ, SWS is associated with vascular abnormalities of the brain, skin, and eyes.2,3 The severity of SWS varies significantly between individuals due to the different combinations of organs involved and the extent to which each organ is involved. For those with brain involvement, the hallmark leptomeningeal angiomatosis identifiable on contrast-enhanced magnetic resonance imaging (MRI) is associated with onset of seizures, ensuing atrophy, calcification, and brain injury. Approximately 75% of patients with brain involvement have seizure onset within the first year of life.4 This gives rise to a gamut of long-term consequences including developmental delays, hemiparesis,5 endocrine disorders,6-8 and cognitive impairments.9,10

Deficient and insufficient levels of vitamin D have been anecdotally noted in patients with SWS. The role of vitamin D in bone health has been well established through its relationship with calcium, a ubiquitous mineral also important in muscle and nerve health.11 Vitamin D facilitates calcium absorption. Thus, when vitamin D levels become too low, calcium absorption decreases, parathyroid hormone (PTH) increases, and the body draws calcium from bone. If calcium depletion from the skeletal system persists, poor bone health including rickets, osteomalacia, and even osteoporosis can occur.12 Some risk factors for vitamin D deficiency include increased melanin pigmentation,13 decreased sun exposure due to latitude and season,14 and anticonvulsant use.15 While the effects of vitamin D on bone health are well understood, other links to autoimmune disorders, cognition, cancer, and vascular function are still being elucidated. The extraskeletal effects of vitamin D are based on the principle that nuclear vitamin D receptors (VDR) are present in most cell types including endothelial and other vascular cells relevant in SWS.16 In addition, it is hypothesized that vitamin D acts by influencing gene transcription and regulating inflammatory processes.12

At present, little data exist on vitamin D in SWS. The goal of this study was to address this gap, as well as evaluate the association between vitamin D levels and neurological function in this population. We aimed to determine the frequency of vitamin D deficiency and insufficiency within the disorder and which subset of patients with SWS are most affected. We hypothesized that in patients with SWS, increases in serum vitamin D levels would correlate with neurologic improvements.

Materials and methods

Study population

Subjects were seen at the Hunter Nelson Sturge-Weber Syndrome Center at the Kennedy Krieger Institute as a part of a Johns Hopkins Institutional Review Board approved study. Patients seen in the clinic between 2009 and 2018 were selected as participants through a review of electronic and paper clinical records if they met the following criteria: informed consent, confirmed brain involvement, and at least one vitamin D level reported as a measure of serum 25-hydroxyvitamin D concentration. Two hundred nine patients had informed consent and confirmed brain involvement via MRI or radiology report. Of these, 70 patients had at least one recorded vitamin D level. The subject pool was narrowed further to 58 subjects by only including subjects under the age of 21 years at their most recent visit (Figure 1). Demographics and SWS characteristics were collected for each participant. Subjects with at least two vitamin D levels within 90 days from a clinic appointment (N = 29) were selected for analyses involving change in vitamin D level with respect to neurologic status.

F1
Figure 1.:
Flow diagram of vitamin D analyses where “vitamin D level type” = normal, abnormal, insufficient, deficient. AED indicates antiepileptic drug.

Vitamin D levels

The Endocrine Society defines vitamin D deficiency as a level less than 20 ng/mL, insufficiency as a level between 21 and 29 ng/mL, and a normal level between 30 and 100 ng/mL.17 These ranges were used to classify subjects into vitamin D status groups: normal versus abnormal, and normal versus insufficient versus deficient. For the purposes of this study, subjects who had a level of 20 ng/mL were constituted vitamin D deficient. All vitamin D levels were reported as a measure of serum 25-hydroxyvitamin D concentration. The extensiveness of vitamin D level records varied across subjects, therefore, the lowest and highest reported levels, regardless of vitamin D supplementation, were selected for subjects with multiple levels. Subjects who had one level were excluded in analyses involving change in vitamin D level. Each vitamin D level was associated with the closest clinic appointment in which medications and the SWS neuroscore, a neurological function score first described by Kelley and colleagues in 2005,18 were documented.

SWS neuroscore

Previously validated through quantitative EEG,19 perfusion imaging,20 and neuropsychological testing,21 the neuroscore has been adopted by SWS centers to prospectively assess neurologic function in infants, children, and adults with SWS during clinical and research appointments. The neuroscore is a composite score of four subscales: frequency of seizures, severity of hemiparesis, extent of visual field cut, and cognitive function, where higher scores indicate worse neurological function (Appendix 1, https://links.lww.com/JV9/A29). Neuroscores that were more than 90 days away from a corresponding vitamin D level were excluded. In cases where the closest neuroscore was completed after the vitamin D level was tested, medication lists and contact notes were consulted to ensure there was no change in vitamin D supplementation. Range and median difference in dates of the neuroscores from the vitamin D levels were calculated, where positive values signify the neuroscore was completed after the vitamin D level and negative values signify the neuroscore was completed before the vitamin D level.

MRI score

To further elaborate on extent of brain involvement, contrast-enhanced MRI data were considered for each subject. One subject was excluded due to prior neurosurgery. The lowest vitamin D level for each subject was associated with their closest contrast-enhanced MRI completed after a year of age (n = 43). A single neuroradiologist rater (DDL), blind to the neurological scores, assigned each MRI two sets of scores based on a modified scoring system as previously described.20 First, a score from 1 to 4 was assigned to the frontal, temporal, parietal, and occipital lobes for each hemisphere to denote severity of brain involvement (8–32). A score of 1 equated to no asymmetry; 2 to mild asymmetry, atrophy, or angiomatosis only; 3 to moderate asymmetry, angiomatosis, and mild atrophy; and 4 to severe asymmetry, angiomatosis, and severe atrophy. Second, the extent of brain involvement was determined by recording the total number of lobes involved (1–8). A lobe was considered involved by the presence of any asymmetry, atrophy, angiomatosis, or deep draining vessels.

Risk factor analyses

Additional analyses were completed to address differences in melanin concentration, amount of sun exposure, and anticonvulsant medication use, which are potential confounding factors that influence vitamin D levels. Average lowest vitamin D levels were compared between subjects with less melanin rich skin (Caucasians) and more melanin rich skin (Black or African Americans). Associations between race and vitamin D status were analyzed. Because amount of sun exposure decreases during the winter months and studies suggest people who reside above the 37° latitude are unable to produce sufficient amounts of vitamin D3 in the winter months,22 associations between season (spring, summer, fall, winter), residence type (below versus above 37° latitude) and vitamin D status were described. Subjects who had both their highest and lowest levels recorded during the winter and fall (October through March) or had both levels recorded in the spring and summer (April through September) were described. This was done because these subjects had a similar amount of sun exposure at the time of their highest and lowest vitamin D levels. Finally, the relationship between vitamin D and anticonvulsant use was considered by evaluating: (1) associations between levetiracetam, oxcarbazepine, carbamazepine, phenobarbital, lacosamide, topiramate, zonisamide, valproic acid, and lamotrigine versus vitamin D status, (2) associations between number of anticonvulsants and vitamin D status, and (3) correlative relationships between number of anticonvulsants and vitamin D level.

Statistical methodology

Chi-Square or Fisher’s Exact tests were used to examine bivariate associations between vitamin D status and categorical variables of interest, including use of a particular anticonvulsant, sex, race, residence type, season, neuroscore, and MRI scores. Given the non-normal distribution of several variables and the use of nonparametric scales (neuroscore and MRI scores), spearman bivariate correlations were used to evaluate relationships between vitamin D levels and the number of anticonvulsants, MRI scores, total neuroscore, and neuroscore sub-scales. Of note, correlations were conducted within demographic and SWS characteristic groups of interest. Finally, Mann-Whitney U tests, the nonparametric analogue to the Students t-test, were used to compare differences in vitamin D levels and neuroscores between groups. Figure 1 shows which statistical tests were employed for each hypothesis test. Alpha of 0.05 was set as the cutoff for statistical significance. All statistical analyses were completed using IBM SPSS Statistics 25.

Results

Participants

Demographic make-up of all subjects is as follows: 66% female, 60% Caucasian, 22% Black or African American, 12% Asian, 3% Hispanic or Latino, and 2% mixed race (Table 1). Eight subjects (14%) resided in states below 37-degrees latitude. Median subject age at their most recent visit was 10.2 years with a range from 1.4 to 19.9 years. Median difference in dates of the neuroscore from a vitamin D level was 16 days, with a range from –88 to 87days. With respect to brain involvement, 76% were unilaterally involved and 24% were bilaterally involved (Table 1). Seventy-five percent of subjects had a history of seizures within the first year of life and 7% never had a history of seizures.

Table 1. - Demographics and SWS Characteristics of Subjects
Demographics Total Normal Vitamin D Status Abnormal Vitamin D Status
Group N (N = 58) (N = 20) Abnormal Total (N = 38) Insufficient (N = 21) Deficient (N = 17)
Sex*
 Female N = 38 (66%) N = 17 (85%) N = 21 (55%) N = 11 (52%) N = 10 (59%)
 Male N = 20 (34%) N = 3 (15%) N = 17 (45%) N = 10 (48%) N = 7 (41%)
Race/Ethnicity*
 Caucasian N = 35 (60%) N = 15 (75%) N = 20 (53%) N = 15 (71%) N = 5 (29%)
 Black/African American N = 13 (22%) N = 3 (15%) N = 10 (26%) N = 3 (14%) N = 7 (41%)
 Asian N = 7 (12%) N = 1 (5%) N = 6 (16%) N = 2 (10%) N = 4 (24%)
 Hispanic or Latino N = 2 (3%) N = 1 (5%) N = 1 (3%) N = 0 (0%) N = 1 (6%)
 Mixed race N = 1 (2%) N = 0 (0%) N = 1 (3%) N = 1 (5%) N = 0 (0%)
Residence*
 Above 37 latitude N = 50 (86%) N = 16 (80%) N = 34 (89%) N = 20 (95%) N = 14 (82%)
 Below 37 latitude N = 8 (14%) N=4 (20%) N = 4 (11%) N = 1 (5%) N = 3 (18%)
Brain Involvement*
 Unilateral N = 44 (76%) N = 15 (75%) N = 29 (76%) N = 16 (76%) N = 13 (76%)
 Bilateral N = 14 (24%) N = 5 (25%) N = 9 (24%) N = 5 (24%) N = 4 (24%)
Skin involvement*
 None N = 5 (9%) N = 0 (0%) N = 5 (13%) N = 2 (10%) N = 3 (18%)
 Unilateral N = 36 (62%) N = 14 (70%) N = 22 (58%) N = 13 (62%) N = 9 (53%)
 Bilateral N = 17 (29%) N = 6 (30%) N = 11 (29%) N = 6 (29%) N = 5 (29%)
Eye involvement*
 None N = 23 (40%) N = 10 (50%) N = 13 (34%) N = 7 (33%) N = 6 (35%)
 Unilateral N = 23 (40%) N = 6 (30%) N = 17 (45%) N = 9 (43%) N = 8 (47%)
 Bilateral N = 12 (21%) N = 4 (20%) N = 8 (21%) N = 5 (24%) N = 3 (18%)
*Percentages rounded to the nearest whole number.

Associations between vitamin D status and sociodemographics

Vitamin D levels below 30 ng/mL were present in 38 of 58 subjects (66%). Of those with abnormal levels, vitamin D deficiency occurred in 17 (29%) subjects and vitamin D insufficiency occurred in 21 (36%) subjects.

MRI scores

Abnormally low vitamin D levels were associated with an MRI severity score greater than or equal to 16 [χ2 (1, N = 43) = 5.532, P = 0.027].

Sex

Abnormal vitamin D levels occurred more frequently in males compared to females (P = 0.040). Additionally, mean lowest vitamin D levels in males were lower than in females (20.5 ± 7.8 versus 27.0 ± 10.6; P = 0.046).

Race

Vitamin D deficiency was more common in Black or African Americans compared with Caucasians (P = 0.041). However, mean lowest vitamin D levels were not statistically different between Caucasians and Black or African Americans (26.6 ± 11.0 versus 22.4 ± 9.7 ng/mL; P = 0.281).

Amount of sun exposure

After excluding 8 subjects who resided below 37° latitude (Table 1), 34 of 50 subjects (68%) were vitamin D insufficient (40%) or deficient (28%). Residing below or above 37° latitude had no effect on frequency of abnormally low vitamin D levels (P = 0.428), nor on frequency of insufficiency or deficiency (P = 0.355). Additionally, season had no association with frequency of low vitamin D levels (P = 0.131), nor on insufficiency or deficiency specifically (P = 0.355).

Anticonvulsant use

There were no significant associations between low vitamin D levels and use of any particular anticonvulsant. There were no associations between number of anticonvulsants used and frequency of low vitamin D levels (P = 0.316), nor between using more than one anticonvulsant and frequency of low vitamin D levels [χ2 (1, N = 54) = 0.126, P = 0.783]. Considering the lowest recorded vitamin D levels for each subject, the relationship between vitamin D level and number of anticonvulsant drugs was not statistically significant (n = 29, r = –0.042, P = 0.830).

Vitamin D and neurologic status

Utilizing vitamin D levels within 90 days of a neurologic score as single cases (n = 83 levels), abnormal vitamin D levels (n = 31 levels) were associated with a higher (i.e., worse) total neurological score (median = 5 versus 4 in abnormal versus normal levels; P = 0.010) compared with normal vitamin D levels. Hemiparesis scores were also worse (median = 2 versus 0 in abnormal versus normal levels; P = 0.010). Subjects with a total neuroscore of at least 4 (n = 57 levels) were more likely to have an abnormal vitamin D level compared with subjects with a total neuroscore less than 4 (P = 0.007). Furthermore, a spearman’s bivariate correlation completed to evaluate the dose-dependent relationship between vitamin D level and neuroscore revealed weak correlations for improvement in total neurologic score (r = –0.248, P = 0.024) and hemiparesis score (P = –0.266, P = 0.015) as vitamin D level increased.

Regarding change in vitamin D level, mean lowest level ± SD was 27.6 ng/mL ± 8.8 ng/mL and mean highest level ±SD was 44.1 ng/mL ± 12.8 ng/mL (Supplementary Digital Table 1, https://links.lww.com/JV9/A28). At the time of the lowest level, 3 of 29 subjects were taking a vitamin D supplement, 9 were taking a multivitamin, and 17 were not taking any form of vitamin D supplement. Vitamin D dose ranged from 400 IU per day to 2000 IU per day and 28 of 29 subjects were taking at least one anticonvulsant, most frequently levetiracetam (18/29) and oxcarbazepine (13/29). When a deficient or insufficient vitamin D level was reported, subjects were contacted to either add a vitamin D supplement to their regimen or increase their current dose until the level was in a normal range. At the time of their highest level, 11 of 29 were on a vitamin D supplement, 7 of 29 were taking a multivitamin, and 11 were taking no form of vitamin D supplementation. Vitamin D dose ranged from 100 IU per day to 8000 IU per day and 28 of 29 subjects were on a least one anticonvulsant, where levetiracetam (16/29) and oxcarbazepine (14/29) were also the most frequently used.

In the most severely affected subjects, specifically those with bilateral brain involvement and an age of seizure onset less than or equal to 12 months, greater positive change in vitamin D level was correlated with greater improvement in hemiparesis score (n = 7, r = –0.791, P = 0.034; Figure 2). A trend was also noted for improvement in total neuroscore with increased positive change in vitamin D level (n = 7, r = –0.709, P = 0.074). These findings were not present in the whole group (n = 29, hemiparesis: r = –0.252, P = 0.188; total neuroscore: r = –0.067, P = 0.728), nor in subjects with only an age of seizure onset less than or equal to 12 months (n = 20, hemiparesis: r = –0.384, P = 0.095; total neuroscore: r = –0.004, P = 0.987). However, a trend between greater improvement in cognitive function and greater positive change in vitamin D level was noted in subjects with only bilateral brain involvement (n = 8, r = –0.687, P = 0.060). Further analysis in subjects with greater than three lobes of involvement with early seizure onset showed greater improvement in hemiparesis with increased positive change in vitamin D level (n = 10, r = –0.696, P = 0.025).

F2
Figure 2.:
Change in vitamin D level versus change in hemiparesis. Graph of the change in vitamin D levels and change in corresponding hemiparesis scores of subjects who had seizures within the first year of life and bilateral brain involvement. As change in vitamin D level increases, hemiparesis sub score decreases (improves) (n = 7, r = –0.791, P = 0.034).

Racial differences in vitamin D versus neurologic status

Black or African American subjects (n = 9) showed improvements in total neuroscore (r = –0.865, P = 0.003; Figure 3) and the hemiparesis subscale (r = –0.697, P = 0.037) as the positive change in vitamin D level increased. This correlation was not demonstrated in Caucasians (n = 13, total neuroscore: r = 0.215, P = 0.481; hemiparesis: r = –0.188, P = 0.538). Furthermore, Black or African American subjects with bilateral brain involvement and age of seizure onset within the first year of life (n = 5) showed a stronger correlation between improvements in total neuroscore (r = –0.975, P = 0.005; Figure 4) and a trend in hemiparesis (r = –0.866, P = 0.058) as the change in vitamin D level increased.

F3
Figure 3.:
Change in vitamin D level versus change in total neuroscore in Black or African Americans. Graph of the change in vitamin D levels and change in corresponding total neurological scores of subjects who identified as Black or African American. As change in vitamin D level increases, total neuroscore decreases (improves) (n = 9, r = –0.865, P = 0.003).
F4
Figure 4.:
Change in vitamin D level versus change in total neuroscore in severely affected Black or African Americans. Graph of the change in vitamin D levels and change in corresponding total neurological scores of subjects who identified as Black or African American who also had bilateral brain involvement and seizures within the first year of life. As change in vitamin D level increases, total neuroscore decreases (improves) (n = 5, r = –0.975, P = 0.005).

Other risk factors and neurologic status

Ten of 29 subjects (34%) had both their lowest and highest vitamin D levels during the winter or fall months (October through March). Six of 29 subjects (21%) had both their lowest and highest levels in the spring or summer months (April through September). There were no significant findings regarding the relationship between change in vitamin D level and change in neurologic score and sub scores in subjects where season type was held constant.

Discussion

In this study, a high prevalence of abnormally low vitamin D levels was found in a young cohort of SWS: 66% of subjects were either vitamin D deficient or insufficient. After excluding subjects who lived below 37° latitude, a slightly higher proportion (68%) were vitamin D deficient (28%) or insufficient (40%). Significant rates of vitamin D insufficiency and deficiency have been previously reported in children and adolescents living in the United States.23,24 A National Health and Nutritional Examination Survey administered between 2001 and 2004 with over 6000 subjects revealed that 70% of the children and adolescent population in the United States had either a vitamin D deficiency (9%) or insufficiency (61%).25 At higher latitudes, 68.25% of the population is suspected to have either a vitamin D deficiency (16.75%) or insufficiency (51.5%).26 While the total abnormal level rates are similar to these cohorts, a substantially higher proportion of vitamin D deficiency is found in patients with SWS compared with the general pediatric population. However, in a pediatric epilepsy population, an even higher proportion at 79.0% of subjects who were taking anticonvulsants had a vitamin D deficiency (61.5%) or insufficiency (17.5%),27 highlighting the confounding effects of medication use. It is plausible that both residence location and anticonvulsant treatment contributed to vitamin D deficiency or insufficiency in the SWS patient population. It is also possible that due to their conditions and presence of epilepsy, patients with SWS may be less active outdoors further contributing to the risk of lower vitamin D levels. In the current study, abnormal levels were found more frequently in males although the clinical significance of this finding is uncertain. Sex differences in vitamin D levels have been reported in adults; however, females typically exhibit lower levels.28-30 Within SWS, sex differences have been noted in cognitive function quality of life31 and suicide risk32 where males show poorer outcomes compared to females.

Even with a limited sample size, the current study provided evidence that in more severely affected individuals there are greater improvements in neurological function with greater increases in vitamin D, suggesting the extraskeletal effects of vitamin D, specifically in the vasculature. The potential effect of vitamin D in vascular health has been investigated in a few studies. Using Doppler sonography to measure brachial artery flow mediated dilatation (FMD), researchers studying the relationship between vitamin D and endothelial function found that otherwise healthy subjects with vitamin D deficiency showed endothelial dysfunction, indicated by lower FMD. Replacement of vitamin D in these deficient subjects then led to significantly improved endothelial function, indicated by an increase in FMD.33 The protective cardiovascular effects of vitamin D have been implicated in vascular disorders such as hereditary hemorrhagic telangiectasia (HHT), characterized by epistaxis, the most common symptom, and arteriovenous malformations and telangiectasia in the nose, lungs, brain, and liver.34 Higher vitamin D levels have been reported in patients with mild epistaxis compared with patients with severe epistaxis.35 An ongoing trial (NCT03981562) is further investigating the effects of vitamin D supplementation in HHT. Low concentrations of vitamin D also have a strong to moderate correlation with increased risk of stroke and vascular disease in healthy subjects.36 In the present study, subjects with bilateral brain involvement and early seizure onset showed greater improvements in hemiparesis with greater increases in vitamin D level. Subjects with more than three lobes involved and early seizure onset showed greater improvements in hemiparesis with greater increases in vitamin D level. As dysplastic venous vasculature is the underpinning of SWS, placing the brain at risk for venous stasis and impaired blood flow, those patients with greater extent and severity of brain involvement may display more heightened vulnerability in response to low vitamin D levels. We therefore postulate that the greater improvements in neurological function, with greater increases in vitamin D level, may be due to vitamin D mediated action on the vasculature. Additional plausible mechanisms of action may be provided by the effects of vitamin D in nerve health and regulation of inflammatory processes. It is also possible that attention to nutritional status simply contributes to one’s general well-being in addition to physical health. To establish causal relationship and unravel the underlying mechanism, further in vivo and in vitro studies need to be explored.

Factors such as melanin pigmentation, place of residence, season, and anticonvulsant use are important to consider when evaluating vitamin D levels. People with melanin rich skin, such as African Americans, have reduced ultraviolet light absorption, which is further exacerbated by residence in northern climates, leading to a decrease in vitamin D synthesis.13 In the present study, subjects that identified as Black or African Americans were more likely to have a vitamin D deficiency and had a lower average vitamin D level compared with Caucasians, although the difference between mean lowest levels was not statistically significant. With greater increases in vitamin D level, Black or African Americans demonstrated greater improvements in overall neurologic function and hemiparesis, relationships that were not demonstrated in Caucasian subjects. Subjects who identified as Black or African American with more extensive brain involvement also showed greater improvements in neurologic function with greater increases in vitamin D level, alluding to the compounding effects of skin pigmentation and extent of brain involvement on vitamin D level with respect to neurologic function. Further study is needed in larger numbers of subjects to confirm and extend these results.

Fifty percent of subjects (4/8) who resided below the 37° northern latitude had vitamin D levels within the abnormal range, suggesting place of residence alone may not have a determinate influence on vitamin D levels in SWS. However, the current study is limited by a small sample size and prior studies have clearly demonstrated the relationship between latitude and vitamin D level.22,26 There were no significant findings in regard to season. Future study design can be improved by focusing on subjects with SWS located in northern latitudes and evaluating neurologic status in conjunction with vitamin D levels during winter months when vitamin D levels are lowest. No significant correlations between vitamin D levels and number of anticonvulsants, nor any associations between vitamin D deficiency or insufficiency and a particular anticonvulsant were found. It is hypothesized that certain anticonvulsants, such as phenobarbital, cause a decrease in vitamin D levels, and thus risk poor bone health by inducing cytochrome p450 enzymes.37 While we did not find the number or type of anticonvulsants to be an influence on vitamin D level, Durá-Travé et al in studying 90 children with epilepsy found that just being on an anticonvulsant may affect vitamin D levels, including the newer generation of drugs such as levetiracetam, which is independent of liver cytochrome p450[15]. The effect of using an anticonvulsant versus not using an anticonvulsant was not assessed in the present study because the majority (97%) of the subjects were using an anticonvulsant at the time of their vitamin D labs.

Limitations and conclusion

This is the first report of low vitamin D levels in SWS and a potential role for treatment. Therefore, more research is needed to address the limitations of this study. In rare diseases research, small sample sizes are a common limitation; future multicenter studies would help address this issue. As a retrospective cross sectional study, there are inherent limitations. Rater reliability for the current MRI scoring system is imperfect; more quantitative measures validated through machine learning in the future would be helpful here. Care provided by SWS specialists likely played a role in the change of the neuroscore through medications and therapies. Finally, correlation is not causation, especially when many potential confounders have not been fully evaluated. Based on this pilot data, future studies should focus on subjects with more extensive involvement to further investigate the effects of vitamin D on neurological function. Clinically, it is recommended that patients with SWS, who are taking seizure medications and who live in temperate locations, should have vitamin D levels checked annually during the winter with low levels treated as indicated.

Acknowledgments

We acknowledge and thank the research participants and their families for their willingness to participate and contribute to research.

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Keywords:

Sturge-Weber syndrome; vitamin D; neurologic function; neuroscore; seizures; anticonvulsants

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