Abstract
The skin, a self-regulating protective barrier organ, is empowered with sensory and computing capabilities to counteract the environmental stressors to maintain and restore disrupted ...cutaneous homeostasis. These complex functions are coordinated by a cutaneous neuro-endocrine system that also communicates in a bidirectional fashion with the central nervous, endocrine, and immune systems, all acting in concert to control body homeostasis. Although UV energy has played an important role in the origin and evolution of life, UV absorption by the skin not only triggers mechanisms that defend skin integrity and regulate global homeostasis but also induces skin pathology (e.g., cancer, aging, autoimmune responses). These effects are secondary to the transduction of UV electromagnetic energy into chemical, hormonal, and neural signals, defined by the nature of the chromophores and tissue compartments receiving specific UV wavelength. UV radiation can upregulate local neuroendocrine axes, with UVB being markedly more efficient than UVA. The locally induced cytokines, corticotropin-releasing hormone, urocortins, proopiomelanocortin-peptides, enkephalins, or others can be released into circulation to exert systemic effects, including activation of the central hypothalamic-pituitary-adrenal axis, opioidogenic effects, and immunosuppression, independent of vitamin D synthesis. Similar effects are seen after exposure of the eyes and skin to UV, through which UVB activates hypothalamic paraventricular and arcuate nuclei and exerts very rapid stimulatory effects on the brain. Thus, UV touches the brain and central neuroendocrine system to reset body homeostasis. This invites multiple therapeutic applications of UV radiation, for example, in the management of autoimmune and mood disorders, addiction, and obesity.
UV energy triggers skin-protective responses against stress, coordinated by the cutaneous-neuroendocrine system, and activates central neuroendocrine system pathways that regulate global homeostasis.
Basic science data indicate potential neuroprotective effects of cannabinoids in traumatic brain injury (TBI). We aimed to evaluate the effects of pre-TBI recreational cannabis use on TBI outcomes.
...We used i2b2 (a scalable informatics framework; www.i2b2.org) to identify all patients presenting with acute TBI between 1/1/2014 and 12/31/2016, then conducted a double-abstraction medical chart review to compile basic demographic, urine drug screen (UDS), Glasgow Coma Scale (GCS), and available outcomes data (mortality, modified Rankin Scale (mRS), duration of stay, disposition (home, skilled nursing facility, inpatient rehabilitation, other)) at discharge and at specific time points thereafter. We conducted multivariable nested ordinal and logistic regression analyses to estimate associations between cannabis use, other UDS results, demographic factors, and selected outcomes.
i2b2 identified 6396 patients who acutely presented to our emergency room with TBI. Of those, 3729 received UDS, with 22.2% of them testing positive for cannabis. Mortality was similar in patients who tested positive vs negative for cannabis (3.9% vs 4.8%; p = 0.3) despite more severe GCS on admission in the cannabis positive group (p = 0.045). Several discharge outcome measures favored the cannabis positive group who had a higher rate of discharge home vs other care settings (p < 0.001), lower discharge mRS (p < 0.001), and shorter duration of hospital stay (p < 0.001) than the UDS negative group. Multivariable analyses confirmed mostly independent associations between positive cannabis screen and these post-TBI short- and long-term outcomes.
This study adds evidence about the potentially neuroprotective effects of recreational cannabis for short- and long-term post-TBI outcomes. These results need to be confirmed via prospective data collections.
•We present a novel method for lesion delineation in individual T1 MRI scans.•We compared our method with manual delineation for a large group of stroke patients.•Our method reliably predicted lesion ...extents and volumes.•Our method identified lesion effects that pose challenges for manual delineation.•Our method can be used for lesion-symptom mapping and clinical volume estimation.
Manual lesion delineation by an expert is the standard for lesion identification in MRI scans, but it is time-consuming and can introduce subjective bias. Alternative methods often require multi-modal MRI data, user interaction, scans from a control population, and/or arbitrary statistical thresholding.
We present an approach for automatically identifying stroke lesions in individual T1-weighted MRI scans using naïve Bayes classification. Probabilistic tissue segmentation and image algebra were used to create feature maps encoding information about missing and abnormal tissue. Leave-one-case-out training and cross-validation was used to obtain out-of-sample predictions for each of 30 cases with left hemisphere stroke lesions.
Our method correctly predicted lesion locations for 30/30 un-trained cases. Post-processing with smoothing (8mm FWHM) and cluster-extent thresholding (100 voxels) was found to improve performance.
Quantitative evaluations of post-processed out-of-sample predictions on 30 cases revealed high spatial overlap (mean Dice similarity coefficient=0.66) and volume agreement (mean percent volume difference=28.91; Pearson's r=0.97) with manual lesion delineations.
Our automated approach agrees with manual tracing. It provides an alternative to automated methods that require multi-modal MRI data, additional control scans, or user interaction to achieve optimal performance. Our fully trained classifier has applications in neuroimaging and clinical contexts.
Summary
Objective
To identify potential pharmacokinetic interactions between the pharmaceutical formulation of cannabidiol (CBD; Epidiolex) and the commonly used antiepileptic drugs (AEDs) through an ...open‐label safety study. Serum levels were monitored to identify interactions between CBD and AEDs.
Methods
In 39 adults and 42 children, CBD dose was started at 5 mg/kg/day and increased every 2 weeks by 5 mg/kg/day up to a maximum of 50 mg/kg/day. Serum AED levels were obtained at baseline prior to CBD initiation and at most study visits. AED doses were adjusted if it was determined that a clinical symptom or laboratory result was related to a potential interaction. The Mixed Procedure was used to determine if there was a significant change in the serum level of each of the 19 AEDs with increasing CBD dose. AEDs with interactions seen in initial analysis were plotted for mean change in serum level over time. Subanalyses were performed to determine if the frequency of sedation in participants was related to the mean serum N‐desmethylclobazam level, and if aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels were different in participants taking concomitant valproate.
Results
Increases in topiramate, rufinamide, and N‐desmethylclobazam and decrease in clobazam (all p < 0.01) serum levels were seen with increasing CBD dose. Increases in serum levels of zonisamide (p = 0.02) and eslicarbazepine (p = 0.04) with increasing CBD dose were seen in adults. Except for clobazam and desmethylclobazam, all noted mean level changes were within the accepted therapeutic range. Sedation was more frequent with higher N‐desmethylclobazam levels in adults (p = 0.02), and AST/ALT levels were significantly higher in participants taking concomitant valproate (p < 0.01).
Significance
Significantly changed serum levels of clobazam, rufinamide, topiramate, zonisamide, and eslicarbazepine were seen. Abnormal liver function test results were noted in participants taking concomitant valproate. This study emphasizes the importance of monitoring serum AED levels and LFTs during treatment with CBD.
Intractable epilepsy can be challenging for patients and for their families. Disability rates in patients are high, causing tremendous physical and emotional burden on family caregivers. ...Additionally, caregivers may experience affiliate stigma, where they perceive and internalize the negative societal views of a condition and exhibit a psychological response. Affiliate stigma has been rarely studied in caregivers of those with intractable epilepsy. This study examined the relationship between affiliate stigma and the levels of burden experienced by caregivers, as well as how these levels may vary between those caring for children and adults.
This cross-sectional approach used a self-administered survey offered to caregivers of family members with confirmed diagnoses of intractable epilepsy. We measured burden with the 30-item Carer's Assessment of Difficulties Index (CADI) and affiliate stigma with a six-item scale examining caregivers' perceptions of stigma directed toward themselves and their family members with epilepsy. Four nested ordinary-least-squares regression models were estimated using stigma scale scores to predict levels of perceived burden adjusting for demographic variables. Age of the patient with epilepsy was dichotomized (pediatric/adult) to assess a possible moderating effect of patient's age on the relationship between stigma and caregiver burden.
Respondents (N = 136) were predominantly White (83%), female (75%), and married (69%), with an average age of 43 years. Patients with epilepsy were 52% male with ages ranging from 2 to 82 years. Each of the regression models yielded positive associations (p < 0.001) between perceived levels of caregiver burden and affiliate stigma. Additionally, the age of the family member with epilepsy moderated (p < 0.05) the effect, with the relationship stronger for caregivers of adults.
In a highly select group of patients with refractory epilepsy recruited mostly from a cannabidiol (CBD) clinic, this study demonstrated that caregivers experience affiliate stigma, which is significantly associated with higher burden levels. Additionally, this study identified specific needs, which when met, may improve caregivers' physical and mental health.
•Familial caregivers in intractable epilepsy experience affiliate stigma.•There is a positive relationship between stigma and burden levels for caregivers.•Relationship between stigma and burden is stronger in caregivers of adults.
Abstract Photosensitivity, which is the hallmark of photosensitive epilepsy (PSE), is described as an abnormal EEG response to visual stimuli known as a photoparoxysmal response (PPR). The PPR is a ...well-recognized phenomenon, occurring in 2–14% of patients with epilepsy but its pathophysiology is not clearly understood. PPR is electrographically described as 2–5 Hz spike, spike-wave, or slow wave complexes with frontal and paracentral prevalence. Diagnosis of PPR is confirmed using intermittent photic stimulation (IPS) as well as video monitoring. The PPR can be elicited by certain types of visual stimuli including flicker, high contrast gratings, moving patterns, and rapidly modulating luminance patterns which may be encountered during e.g., watching television, playing video games, or attending discotheques. Photosensitivity may present in different idiopathic (genetic) epilepsy syndromes e.g. juvenile myoclonic epilepsy (JME) as well as non-IGE syndromes e.g. severe myoclonic epilepsy of infancy. Consequently, PPR is present in patients with diverse seizure types including absence, myoclonic, and generalized tonic-clonic (GTC) seizures. Across syndromes, abnormalities in structural connectivity, functional connectivity, cortical excitability, cortical morphology, and behavioral and neuropsychological function have been reported. Treatment of photosensitivity includes antiepileptic drug administration, and the use of non-pharmacological agents, e.g. tinted or polarizing glasses, as well as occupational measures, e.g. avoidance of certain stimuli.
Highly purified cannabidiol (CBD) has demonstrated efficacy with an acceptable safety profile in patients with Lennox‐Gastaut syndrome or Dravet syndrome in randomized, double‐blind, add‐on, ...controlled phase 3 trials. It is important to consider the possibility of drug‐drug interactions (DDIs). Here, we review six trials of CBD (Epidiolex/Epidyolex; 100 mg/mL oral solution) in healthy volunteers or patients with epilepsy, which investigated potential interactions between CBD and enzymes involved in drug metabolism of common antiseizure drugs (ASDs). CBD did not affect CYP3A4 activity. Induction of CYP3A4 and CYP2C19 led to small reductions in exposure to CBD and its major metabolites. Inhibition of CYP3A4 activity did not affect CBD exposure and caused small increases in exposure to CBD metabolites. Inhibition of CYP2C19 activity led to a small increase in exposure to CBD and small decreases in exposure to CBD metabolites. One potentially clinically important DDI was identified: combination of CBD and clobazam (CLB) did not affect CBD or CLB exposure, but increased exposure to major metabolites of both compounds. Reduction of CLB dose may be considered if adverse reactions known to occur with CLB are experienced when it is coadministered with CBD. There was a small increase of exposure to stiripentol (STP) when coadministered with CBD. STP had no effect on CBD exposure but led to minor decreases in exposure to CBD metabolites. Combination of CBD and valproate (VPA) did not cause clinically important changes in the pharmacokinetics of either drug, or 2‐propyl‐4‐pentenoic acid. Concomitant VPA caused small increases in exposure to CBD metabolites. Dose adjustments are not likely to be necessary when CBD is combined with STP or VPA. The safety results from these trials were consistent with the known safety profile of CBD. These trials indicate an overall low potential for DDIs between CBD and other ASDs, except for CLB.
Purpose of Review
For millennia, there has been interest in the use of
cannabis
for the treatment of epilepsy. However, it is only recently that appropriately powered controlled studies have been ...completed. In this review, we present an update on the research investigating the use of cannabidiol (CBD), a non-psychoactive component of
cannabis
, in the treatment of epilepsy.
Recent Findings
While the anticonvulsant mechanism of action of CBD has not been entirely elucidated, we discuss the most recent data available including its low affinity for the endocannabinoid receptors and possible indirect modulation of these receptors via blocking the breakdown of anandamide. Additional targets include activation of the transient receptor potential of vanilloid type-1 (TRPV1), antagonist action at GPR55, targeting of abnormal sodium channels, blocking of T-type calcium channels, modulation of adenosine receptors, modulation of voltage-dependent anion selective channel protein (VDAC1), and modulation of tumor necrosis factor alpha release. We also discuss the most recent studies on various artisanal CBD products conducted in patients with epilepsy in the USA and internationally. While a high percentage of patients in these studies reported improvement in seizures, these studies were either retrospective or conducted via survey. Dosage/preparation of CBD was either unknown or not controlled in the majority of these studies. Finally, we present data from both open-label expanded access programs (EAPs) and randomized placebo-controlled trials (RCTs) of a highly purified oral preparation of CBD, which was recently approved by the FDA in the treatment of epilepsy. In the EAPs, there was a significant improvement in seizure frequency seen in a large number of patients with various types of treatment-refractory epilepsy. The RCTs have shown significant seizure reduction compared to placebo in patients with Dravet syndrome and Lennox-Gastaut syndrome. Finally, we describe the available data on adverse effects and drug-drug interactions with highly purified CBD. While this product is overall well tolerated, the most common side effects are diarrhea and sedation, with sedation being much more common in patients taking concomitant clobazam. There was also an increased incidence of aspartate aminotransferase and alanine aminotransferase elevations while taking CBD, with many of the patients with these abnormalities also taking concomitant valproate. CBD has a clear interaction with clobazam, significantly increasing the levels of its active metabolite N-desmethylclobazam in several studies; this is felt to be due to CBD’s inhibition of CYP2C19. EAP data demonstrate other possible interactions with rufinamide, zonisamide, topiramate, and eslicarbazepine. Additionally, there is one case report demonstrating need for warfarin dose adjustment with concomitant CBD.
Summary
Understanding of CBD’s efficacy and safety in the treatment of TRE has expanded significantly in the last few years. Future controlled studies of various ratios of CBD and THC are needed as there could be further therapeutic potential of these compounds for patients with epilepsy.
Use of cannabinoid therapies is on the rise in the United States, but responses of healthcare professionals and their knowledge of these therapies have been mixed. More information is needed about ...factors associated with healthcare professionals' attitudes and knowledge about medical cannabis. We conducted an online survey of US-based neurologists, nurse practitioners (NPs)/nurses, and pharmacists in August–September of 2018 (n = 451). We constructed perceived knowledge and attitudes scales and a knowledge index from multiple items and assessed state cannabis laws, participant's sociodemographics, workplace type and policies, and patient population. We used ordinary least-squares regression to examine associations among study variables. Over 80% of participants supported use and legalization of medical cannabis, especially cannabidiol (CBD) for epilepsy and when prescribed by a medical provider, but 40–50% (depending on item) felt unfamiliar with cannabinoid pharmacology and clinical applications. A total of 43% favored legal recreational cannabis. Pharmacists scored higher on the knowledge test than neurologists and NPs/nurses, but NPs/nurses had more favorable attitudes than neurologists and higher perceived knowledge than pharmacists. Both knowledge indicators predicted attitudes. State cannabis access and favorable workplace policies were associated with higher knowledge and more favorable attitudes. Healthcare professionals see potential in cannabis therapies but report significant knowledge gaps. Professional cannabinoid education is needed to address growing patient and provider demand for knowledge about cannabinoid therapies.
•Eighty percent of healthcare professionals supported use of cannabinoids for epilepsy.•Forty-three percent favored legal recreational cannabis.•Cannabinoid knowledge was modest, with pharmacists scoring highest on test.•Neurologists were more cautious than nurses in their assessment of medical cannabis.•Professional cannabis education is needed to close knowledge gaps.
Mild traumatic brain injury (mTBI) is a significant public health care burden in the United States. However, we lack a detailed understanding of the pathophysiology following mTBI and its relation to ...symptoms and recovery. With advanced magnetic resonance imaging (MRI), we can investigate brain perfusion and oxygenation in regions known to be implicated in symptoms, including cortical gray matter and subcortical structures. In this study, we assessed 14 mTBI patients and 18 controls with susceptibility weighted imaging and mapping (SWIM) for blood oxygenation quantification. In addition to SWIM, 7 patients and 12 controls had cerebral perfusion measured with arterial spin labeling (ASL). We found increases in regional cerebral blood flow (CBF) in the left striatum, and in frontal and occipital lobes in patients as compared to controls (p = 0.01, 0.03, 0.03 respectively). We also found decreases in venous susceptibility, indicating increases in venous oxygenation, in the left thalamostriate vein and right basal vein of Rosenthal (p = 0.04 in both). mTBI patients had significantly lower delayed recall scores on the standardized assessment of concussion, but neither susceptibility nor CBF measures were found to correlate with symptoms as assessed by neuropsychological testing. The increased CBF combined with increased venous oxygenation suggests an increase in cerebral blood flow that exceeds the oxygen demand of the tissue, in contrast to the regional hypoxia seen in more severe TBI. This may represent a neuroprotective response following mTBI, which warrants further investigation.
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