Bridging the Gap: Local Field Potentials Offer a Peek Into the Brain of a Person With Parkinson Disease.

Clinically available deep brain recordings in patients with Parkinson disease (PD) offer insights into disease mechanisms and create a pathway for personalized treatment strategies. This case illustrates the transformative potential of recordings of neuronal firing in the form of local field potentials (LFPs) by detailing a patient's clinical trajectory for 6 months after deep brain stimulation (DBS) surgery to treat their PD symptoms. LFPs, obtained easily in clinic with a tablet interface to measure and track brain rhythms across the disease course, enriched the patient's clinical picture. Specifically, strong beta peaks were captured at initial programming, and, as the beta peaks diminished over the course of optimizing settings, symptoms improved. These signals may also reveal insights into the neural dynamics of PD such as hypersynchrony in basal ganglia circuitry. Furthermore, the ability to record chronically may unlock new understanding of neuronal dysfunction in PD, possibly enabling future adaptive DBS. In conclusion, identification, tracking, and modulation of LFPs correlated with subjective and objective clinical improvement in the case presented. The use of neurophysiologic signals in the future may lead to therapeutic innovations for our patients with PD.

Cerebrotendinous xanthomatosis tremor successfully controlled post-ventral intermediate nucleus-deep brain stimulation: a case report.

Cerebrotendinous xanthomatosis (CTX) is a rare autosomal recessive disorder caused by a deficiency of the sterol 27-hydroxylase enzyme. This deficiency results in excess production and accumulation of cholestanol, which can lead to many clinical findings within the first three decades of life, including progressive neurological dysfunction. This is a treatable condition with improvements in neurological and non-neurological symptoms upon the early initiation of replacement therapy. This case report details a 42 years-old left-handed male in whom deep brain stimulation (DBS) intervention was pursued due to a limiting tremor related to delayed diagnosis and treatment of CTX at 22 years old. The application of DBS in treating tremors in a CTX patient has not previously been reported. For our patient, application of DBS led to meaningful and longstanding tremor control benefits that have required minimal changes to stimulation parameters post-DBS. These improvements to tremor were achieved without negative impact to his other CTX related comorbidities.

Dopamine D1 Agonists: First Potential Treatment for Late-Stage Parkinson's Disease.

Current pharmacotherapy has limited efficacy and/or intolerable side effects in late-stage Parkinson's disease (LsPD) patients whose daily life depends primarily on caregivers and palliative care. Clinical metrics inadequately gauge efficacy in LsPD patients. We explored if a D1/5 dopamine agonist would have efficacy in LsPD using a double-blind placebo-controlled crossover phase Ia/b study comparing the D1/5 agonist PF-06412562 to levodopa/carbidopa in six LsPD patients. Caregiver assessment was the primary efficacy measure because caregivers were with patients throughout the study, and standard clinical metrics inadequately gauge efficacy in LsPD. Assessments included standard quantitative scales of motor function (MDS-UPDRS-III), alertness (Glasgow Coma and Stanford Sleepiness Scales), and cognition (Severe Impairment and Frontal Assessment Batteries) at baseline (Day 1) and thrice daily during drug testing (Days 2-3). Clinicians and caregivers completed the clinical impression of change questionnaires, and caregivers participated in a qualitative exit interview. Blinded triangulation of quantitative and qualitative data was used to integrate findings. Neither traditional scales nor clinician impression of change detected consistent differences between treatments in the five participants who completed the study. Conversely, the overall caregiver data strongly favored PF-06412562 over levodopa in four of five patients. The most meaningful improvements converged on motor, alertness, and functional engagement. These data suggest for the first time that there can be useful pharmacological intervention in LsPD patients using D1/5 agonists and also that caregiver perspectives with mixed method analyses may overcome limitations using methods common in early-stage patients. The results encourage future clinical studies and understanding of the most efficacious signaling properties of a D1 agonist for this population.

Frontostriatal and limbic contributions to cognitive decline in Parkinson's disease.

BACKGROUND AND PURPOSE: The circuitry underlying heterogenous cognitive profiles in Parkinson's disease (PD) remains unclear. The purpose of this study is to investigate whether structural changes in frontostriatal and limbic pathways contribute to different cognitive trajectories in PD. METHODS: We obtained clinical and multimodal MRI data from 120 control and 122 PD subjects without dementia or severe motor disability. T1/T2-weighted images estimated volume, and diffusion imaging evaluated fractional anisotropy (FA) of frontostriatal (striatum and frontostriatal white matter [FSWM]) and limbic (hippocampus and fornix) structures. Montreal Cognitive Assessment (MoCA) gauged total and domain-specific (attention/executive and memory) cognitive function. Linear mixed-effects models were used to compare MRI and cognitive progression over 4.5 years between controls and PD and evaluate associations between baseline MRI and cognitive changes in PD. RESULTS: At baseline, control and PD groups were comparable, except PD participants had smaller striatal volume (p < 0.001). Longitudinally, PD showed faster decline in hippocampal volume, FSWM FA, and fornix FA (ps < .016), but not striatal volume (p = .218). Total and domain-specific MoCA scores declined faster in PD (ps < .030). In PD, lower baseline hippocampal volume (p = .005) and fornix FA (p = .032), but not striatal volume (p = .662) or FSWM FA (p = .143), were associated with faster total MoCA decline. Baseline frontostriatal metrics of striatal volume and FSWM FA were associated with faster attention/executive decline (p < .038), whereas lower baseline hippocampal volume was associated with faster memory decline (p = .005). CONCLUSION: In PD, frontostriatal structural metrics are associated with attention/executive tasks, whereas limbic changes correlated with faster global cognitive decline, particularly in memory tasks.

Dynamics of Nigral Iron Accumulation in Parkinson's Disease: From Diagnosis to Late Stage.

BACKGROUND: Higher nigral iron has been reported in Parkinson's disease (PD). OBJECTIVE: The aim is to understand the dynamics of nigral iron accumulation in PD and its association with drug treatment. METHODS: Susceptibility magnetic resonance imaging data were obtained from 79 controls and 18 drug-naive (PDDN ) and 87 drug-treated (PDDT ) PD patients. Regional brain iron in basal ganglia and cerebellar structures was estimated using quantitative susceptibility mapping. Nigral iron was compared between PDDN and PDDT subgroups defined by disease duration (early [PDE, <2 years], middle [PDM, 2-6 years], and later [PDL, >6 years]). Associations with both disease duration and types of antiparkinson drugs were explored using regression analysis. RESULTS: Compared to controls, PDDN had lower iron in the substantia nigra (P = 0.018), caudate nucleus (P = 0.038), and globus pallidus (P = 0.01) but not in the putamen or red nucleus. In contrast, PDDT had higher iron in the nigra (P < 0.001) but not in other regions, compared to either controls or PDDN . Iron in the nigra increased with disease duration (PDE > PDDN [P = 0.001], PDM > PDE [P = 0.045]) except for PDM versus PDL (P = 0.226). Levodopa usage was associated with higher (P = 0.013) nigral iron, whereas lower nigral iron was correlated with selegiline usage (P = 0.030). CONCLUSION: Nigral iron is lower before the start of dopaminergic medication and then increases throughout the disease until it plateaus at late stages, suggesting increased iron may not be an etiological factor. Interestingly, PD medications may have differential associations with iron accumulation that need further investigation. © 2022 International Parkinson and Movement Disorder Society.

North American survey on impact of the COVID-19 pandemic shutdown on DBS care.

BACKGROUND: The initial COVID-19 pandemic shutdown led to the canceling of elective surgeries throughout most of the USA and Canada. OBJECTIVE: This survey was carried out on behalf of the Parkinson Study Group (PSG) to understand the impact of the shutdown on deep brain stimulation (DBS) practices in North America. METHODS: A survey was distributed through RedCap® to the members of the PSG Functional Neurosurgical Working Group. Only one member from each site was asked to respond to the survey. Responses were collected from May 15 to June 6, 2020. RESULTS: Twenty-three sites participated; 19 (83%) sites were from the USA and 4 (17%) from Canada. Twenty-one sites were academic medical centers. COVID-19 associated DBS restrictions were in place from 4 to 16 weeks. One-third of sites halted preoperative evaluations, while two-thirds of the sites offered limited preoperative evaluations. Institutional policy was the main contributor for the reported practice changes, with 87% of the sites additionally reporting patient-driven surgical delays secondary to pandemic concerns. Pre-post DBS associated management changes affected preoperative assessments 96%; electrode placement 87%; new implantable pulse generator (IPG) placement 83%; IPG replacement 65%; immediate postoperative DBS programming 74%; and routine DBS programming 91%. CONCLUSION: The COVID-19 pandemic related shutdown resulted in DBS practice changes in almost all North American sites who responded to this large survey. Information learned could inform development of future contingency plans to reduce patient delays in care under similar circumstances.

The D1/D5 Dopamine Partial Agonist PF-06412562 in Advanced-Stage Parkinson's Disease: A Feasibility Study.

BACKGROUND: Current drug treatments have little efficacy in advanced-to-end-stage Parkinson's disease (advPD), yet there are no reports of interventional trials in advPD. D1 dopamine agonists have the potential to provide benefit. OBJECTIVE: To determine the feasibility and safety of the selective D1/D5 dopamine partial agonist PF 06412562 in advPD. METHODS: A two-week, randomized, double blind, crossover phase Ib study in advPD patients compared standard-of-care (SoC) carbidopa/levodopa with PF 06412562. Each week, there was a Day 1 baseline evaluation with overnight levodopa washout, then treatment on Days 2 and 3 with either SoC or PF-06412562 (split dose 25 + 20 mg), followed by discharge on Day 4. Primary endpoints were safety and tolerability. Secondary endpoints were global clinical impression of change (GCI-C) rated by clinicians and caregivers. RESULTS: Eight advPD patients and their caregivers consented to participate and six were randomized (average disease duration: 22 y). None withdrew voluntarily. One participant with baseline Day 1 dehydration, pre-renal kidney injury, and autonomic dysfunction experienced symptomatic and serious hypotension after receiving PF-06412562 in Week 1 and was discontinued from the study. All other adverse events were rated mild (PF-06412562: n = 1, SoC: n = 0), moderate (PF-06412562: n = 1, SoC: n = 1), or severe but non-serious (PF-06412562: n = 3, SoC: n = 2). No clinically meaningful laboratory changes were observed. Among the five participants who completed the study, GCI-C favored PF-06412562 in two per clinicians' and four participants per caregivers' rating. CONCLUSION: PF-06412562 was tolerated in advPD patients. This study provides the feasibility for future safety and efficacy studies in this population with unmet needs.

Square Biphasic Pulse Deep Brain Stimulation for Parkinson's Disease: The BiP-PD Study.

BACKGROUND: Conventional Parkinson's disease (PD) deep brain stimulation (DBS) utilizes a pulse with an active phase and a passive charge-balancing phase. A pulse-shaping strategy that eliminates the passive phase may be a promising approach to addressing movement disorders. OBJECTIVES: The current study assessed the safety and tolerability of square biphasic pulse shaping (sqBIP) DBS for use in PD. METHODS: This small pilot safety and tolerability study compared sqBiP versus conventional DBS. Nine were enrolled. The safety and tolerability were assessed over a 3-h period on sqBiP. Friedman's test compared blinded assessments at baseline, washout, and 30 min, 1 h, 2 h, and 3 h post sqBIP. RESULTS: Biphasic pulses were safe and well tolerated by all participants. SqBiP performed as well as conventional DBS without significant differences in motor scores nor accelerometer or gait measures. CONCLUSION: Biphasic pulses were well-tolerated and provided similar benefit to conventional DBS. Further studies should address effectiveness of sqBIP in select PD patients.

Spatiotemporal gait parameters and tremor distribution in essential tremor.

BACKGROUND: Essential Tremor is characterized by an action tremor of the upper extremities, which may or may not be accompanied by a head, voice, leg or trunk tremor. Problems with gait and balance have also been identified in persons with Essential Tremor. Therefore, understanding gait performance is an important area of focus for clinicians and researchers. RESEARCH QUESTION: We sought to 1) conduct a factor analysis on a broad spectrum of spatiotemporal gait parameters 2) build upon the normative database of gait measures in persons with Essential Tremor 3) understand the influence of age on gait speed in persons with Essential Tremor and 4) identify the relationships between gait performance and clinical measures of disease severity. METHODS: Gait data and Tremor Rating Scale scores were retrospectively collected from one hundred and forty-two ambulatory participants with a diagnosis of Essential Tremor. A factor analysis was used to characterize spatiotemporal gait parameters and regression models were applied to associate tremor scores to gait performance factors. RESULTS: Three domains of gait performance factors were identified in persons with Essential Tremor. Specifically, we observed a pace, rhythm, and stability factor. In sum, these factors accounted for 91.9% of the variance in gait performance. Only the pace and stability factors were associated with disease severity, suggesting these factors are most sensitive to disease severity compared to the rhythm factor. Our linear regression analysis revealed a significant influence of age on gait speed. Gait speed decreased with age significantly by 0.64 cm/s/year. SIGNIFICANCE: Reference values for 12 gait parameters will be highly useful for assessing gait performance in individuals with Essential Tremor. Our observations suggest that a clinical assessment of gait and balance would be an important measure to consider in routine clinical practice when treating persons with Essential Tremor.

Multimodal MRI evaluation of parkinsonian limbic pathologies.

Previous multimodal magnetic resonance imaging (MRI) studies of parkinsonian syndromes have focused primarily on motor-related basal ganglia structures. The present study investigated MRI changes in nonmotor-related limbic structures in 35 Parkinson's disease, 16 multiple system atrophy parkinsonian subtype, 17 progressive supranuclear palsy, and 37 control subjects. Mean diffusivity (MD), fractional anisotropy, transverse relaxation rate (R2*), quantitative susceptibility mapping, and volume measurements were obtained from the amygdala, hippocampus, and nucleus accumbens (NAc) to examine differences between groups and to test for associations with clinical scores. Compared with controls, Parkinson's disease subjects had lower NAc volume; multiple system atrophy parkinsonian subtype subjects had higher NAc transverse relaxation rate; and progressive supranuclear palsy subjects had higher amygdala and hippocampus MD and lower hippocampus fractional anisotropy (p's ≤ 0.008). Among parkinsonian subjects, amygdala and hippocampus MD associated positively with Unified Parkinson's Disease Rating Scale nonmotor and activities of daily living scores (p's ≤ 0.005). Together, these findings support the inclusion of limbic structures in future MRI studies of parkinsonian syndromes.

Systemic effects of deep brain stimulation on synergic control in Parkinson's disease.

OBJECTIVE: We explored effects of deep brain stimulation (DBS) in patients with Parkinson's disease (PD) on the synergic control of fingers in a multi-finger force production task and of muscles in a task involving vertical posture. METHODS: The finger task involved the four fingers of a hand producing accurate total force followed by a targeted quick force pulse. The postural task involved releasing a load from extended arms. The analysis of synergies was performed within the framework of the uncontrolled manifold hypothesis. RESULTS: DBS led to no significant changes in indices of stability during steady-state phases. In contrast, DBS improved indices of agility, quantified as anticipatory synergy adjustments that reduced stability of salient performance variables in preparation to their quick change. There were moderate-to-strong correlations between indices of both stability and agility measured in the multi-finger force production and multi-muscle whole-body action. CONCLUSIONS: Our results point at systemic changes in synergic control in PD. They show that DBS is effective in improving only one components of synergic control related to agility in performance being relatively ineffective for the stability component. SIGNIFICANCE: The results show systemic brain mechanisms of synergies and suggest differential effects of DBS on indices of stability and agility.

Square biphasic pulse deep brain stimulation for essential tremor: The BiP tremor study.

BACKGROUND: Conventional deep brain stimulation (DBS) utilizes regular, high frequency pulses to treat medication-refractory symptoms in essential tremor (ET). Modifications of DBS pulse shape to achieve improved effectiveness is a promising approach. OBJECTIVES: The current study assessed the safety, tolerability and effectiveness of square biphasic pulse shaping as an alternative to conventional ET DBS. METHODS: This pilot study compared biphasic pulses (BiP) versus conventional DBS pulses (ClinDBS). Eleven ET subjects with clinically optimized ventralis intermedius nucleus DBS were enrolled. Objective measures were obtained over 3 h while ON BiP stimulation. RESULTS: There was observed benefit in the Fahn-Tolosa Tremor Rating Scale (TRS) for BiP conditions when compared to the DBS off condition and to ClinDBS setting. Total TRS scores during the DBS OFF condition (28.5 IQR = 24.5-35.25) were significantly higher than the other time points. Following active DBS, TRS improved to (20 IQR = 13.8-24.3) at ClinDBS setting and to (16.5 IQR = 12-20.75) at the 3 h period ON BiP stimulation (p = 0.001). Accelerometer recordings revealed improvement in tremor at rest (χ2 = 16.1, p = 0.006), posture (χ2 = 15.9, p = 0.007) and with action (χ2 = 32.1, p=<0.001) when comparing median total scores at ClinDBS and OFF DBS conditions to 3 h ON BiP stimulation. There were no adverse effects and gait was not impacted. CONCLUSION: BiP was safe, tolerable and effective on the tremor symptoms when tested up to 3 h. This study demonstrated the feasibility of applying a novel DBS waveform in the clinic setting. Larger prospective studies with longer clinical follow-up will be required.

Depressive Symptoms are Frequent in Atypical Parkinsonian Disorders.

OBJECTIVE: To compare the incidence and prevalence of depressive symptoms in atypical parkinsonian (APD) syndromes versus Parkinson disease (PD). METHODS: In a large retrospective patient cohort we analyzed the incidence and prevalence of depressive symptoms using the Beck Depression Inventory (BDI) and evaluated subjects longitudinally on subsequent visits. For individuals who followed in subsequent visits we calculated incidence rates in person-years as a measure of incidence. RESULTS: We identified 361 patients with APD including Progressive Supranuclear Palsy (PSP), Corticobasal Degeneration (CBD), Multiple System Atrophy (MSA) and Dementia with Lewy Bodies (DLB), and 2352 PD controls. The mean BDI values were significantly higher in APD (F=14.19, p < 0.001). A significantly higher proportion of APD subjects screened positive for depressive symptoms both at initial and subsequent patient visits (p < 0.001), which appeared to be more severe in the APD subgroups. UPDRS part III and disease duration weakly correlated with depressive symptoms. CONCLUSIONS: Our results suggest that the incidence and prevalence of depressive symptoms are higher in APD and appear also to be more severe than in PD. Depressive symptoms in APD are common and affect patients regardless of disease duration or motor severity.

Measures of impulsivity in Parkinson's disease decrease after DBS in the setting of stable dopamine therapy.

INTRODUCTION: Recent evidence suggests deep brain stimulation can alter impulse control. Our objective was to prospectively evaluate the effects of subthalamic nucleus (STN) and globus pallidus internus (GPi) deep brain stimulation on impulse control disorders (ICDs) in the setting of a conservative dopamine reduction strategy. METHODS: Patients (n = 37) undergoing de novo, unilateral STN or GPi DBS lead implantation were evaluated pre-operatively and 6-12 months post-operatively for the presence of ICDs using the Questionnaire for Impulsivity in Parkinson's disease (QUIP) and by clinical interview. RESULTS: Of the patients enrolled, 23 underwent electrode implantation in the globus pallidus internus and 14 were implanted in the subthalamic nucleus. Mean time to long term follow-up was 9.7 ± 2.4 months. Post-operative LEDD was not significantly lower than pre-operative LEDD (pre-op: 1238.53 ± 128.47 vs. post-op: 1178.18 ± 126.43, p = 0.2972, paired t-test). Mean QUIP scores were significantly lower at follow up compared to pre-operative baseline (1.51 ± 0.45 vs. 2.51 ± 0.58, p = 0.0447, paired t-test). Patients with ICDs pre-operatively (n = 14, 37.8%) had significant improvement in QUIP scores at follow-up (6.00 ± 0.94 vs. 2.64 ± 0.98, p = 0.0014, paired t-test). Improvement was not uniform across the cohort: 1 patient with ICD at baseline developed worsening symptoms, and 4 patients with no ICD pre-operatively developed clinically significant ICDs post-operatively. CONCLUSION: When LEDD is relatively unchanged following STN or GPi DBS for PD, ICD symptoms tend toward improvement, although worsening and emergence of new ICDs can occur. In the setting of stable LEDD, these findings suggest that the intrinsic effects of DBS may play a significant role in altering impulsive behavior.

Hospitalization and rehospitalization in Parkinson disease patients: Data from the National Parkinson Foundation Centers of Excellence.

BACKGROUND: Patients with Parkinson disease (PD) are at high risk of hospital encounters with increasing morbidity and mortality. This study aimed to determine the rate of hospital encounters in a cohort followed over 5 years and to identify associated factors. METHODS: We queried the data from the International Multicenter National Parkinson Foundation Quality Improvement study. Multivariate logistic regression with backward selection was performed to identify factors associated with hospital encounter prior to baseline visit. Kaplan-Meier estimates were obtained and Cox regression performed on time to hospital encounter after the baseline visit. RESULTS: Of the 7,507 PD patients (mean age 66.5±9.9 years and disease duration 8.9±6.4 years at baseline visit), 1919 (25.6%) had a history of a hospital encounter prior to their baseline visit. Significant factors associated with a history of a hospital encounter prior to baseline included race (white race: OR 0.49), utilization of physical therapy (OR 1.47), history of deep brain stimulation (OR 1.87), number of comorbidities (OR 1.30), caregiver strain (OR 1.17 per standard deviation), and the standardized Timed Up and Go Test (OR 1.21). Patients with a history of hospitalization prior to the baseline were more likely to have a re-hospitalization (HR1.67, P<0.0001) compared to those without a prior hospitalization. In addition, the time to hospital encounter from baseline was significantly associated with age and number of medications. In patients with a history of hospitalization prior to the baseline visit, time to a second hospital encounter was significantly associated with caregiver strain and number of comorbidities. CONCLUSION: Hospitalization and re-hospitalization were common in this cohort of people with PD. Our results suggest addressing caregiver burden, simplifying medications, and emphasizing primary and multidisciplinary care for comorbidities are potential avenues to explore for reducing hospitalization rates.

A Polysomnographic Study of Parkinson's Disease Sleep Architecture.

Sleep disturbance is a common nonmotor phenomenon in Parkinson's disease (PD) affecting patient's quality of life. In this study, we examined the association between clinical characteristics with sleep disorders and sleep architecture patterns in a PD cohort. Patients underwent a standardized polysomnography study (PSG) in their "on medication" state. We observed that male gender and disease duration were independently associated with obstructive sleep apnea (OSA). Only lower levodopa equivalent dose (LED) was associated with periodic limb movement disorders (PLMD). REM sleep behavior disorder (RBD) was more common among older patients, with higher MDS-UPDRS III scores, and LED. None of the investigated variables were associated with the awakenings/arousals (A/A). Sleep efficiency was predicted by amantadine usage and age, while sleep stage 1 was predicted by dopamine agonists and Hoehn & Yahr severity. The use of MAO-B inhibitors and MDS-UPDRS part III were predictors of sleep stages 2 and 3. Age was the only predictor of REM sleep stage and gender for total sleep time. We conclude that sleep disorders and architecture are poorly predictable by clinical PD characteristics and other disease related factors must also be contributing to these sleep disturbances.

Novel targets and stimulation paradigms for deep brain stimulation.

Deep brain stimulation (DBS) is an accepted therapy for appropriately selected patients with movement disorders and psychiatric disease. The recent advances in lead technology and the advent of novel stimulation parameters have spurred a number of improvements that will likely be implemented in the clinical setting. Although the mechanisms and biology of DBS remain poorly understood, the progress in our understanding of network level dysfunction has driven the introduction of a variety of new targets and approaches to the treatment of human disease. Here we summarize the recent advances in novel stimulation patterns and customized field shaping. We also review new targets, novel applications of DBS and the immediate and long-term horizon for this therapy.

Surprising prevalence of unrecognized vitamin D3 deficiency in fall and winter months in neuromuscular clinics in Central Pennsylvania: a pilot study.

OBJECTIVES: The Harvard biomarker study published in October 2013 in Neurology journal showed a deficiency of vitamin D in 17.6% patients with Parkinson disease compared with 9.3% controls (adults without neurological symptoms). Similar determination among neuromuscular disease patients is lacking. METHODS: A retrospective analysis of vitamin D levels was performed on 73 patients seen between September and March in the Neuromuscular Central Pennsylvania tertiary referral clinic. Patient selection was random. Patients with amyotrophic lateral sclerosis were excluded from this study. RESULTS: The prevalence of vitamin D deficiency was significantly above the Harvard Biomarker control values considering similar climatic and ethnic factors. CONCLUSIONS: Although 25-hydroxy-D3, produced in liver and skin, can be low in fall and winter, significant lower levels were seen (P > 000.1) among the patients seen randomly in our neuromuscular clinic compared with recently published controls. Similar studies from different geographical zones of the Unite States considering seasonal influences are worth studying. Whether checking vitamin D3 blood level should become a standard practice is the bigger issue.