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Background: 22q11.2 microdeletion is the most common microdeletion syndrome in humans with a prevalence of 13 per 100 000 live births, and it is a multisystem condition with variable phenotypic presentations. Methods: We present a case of an adult patient with Dandy-Walker syndrome who presented to our epilepsy clinic with 2 years of new-onset seizures and cognitive decline and 1 year of psychotic symptoms. Results: Patient had a non-revealing autoimmune and malignancy work-up. Continuous scalp vEEG study showed bursts of 1-2 Hz generalized fronto-centrally predominant spike or polyspike and slow wave discharges. Several myoclonic jerks were time-locked with the generalized discharges indicative of cortical myoclonus. MRI brain revealed periventricular nodular heterotopia in addition to findings suggestive of Dandy-Walker syndrome. Array-based comparative genomic hybridization demonstrated a 22q11.2 microdeletion seen in 22q11.2 deletion syndrome. Conclusion: Our case illustrates the challenges of diagnosing genetic disorders in adults especially when the initial diagnosis is dependent on a number of factors, including the patient's age, the severity of the phenotypic features, and the awareness of the physician.
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OBJECTIVE: Functional seizures are common among people with traumatic brain injury (TBI). Subjective cognitive concerns refer to a person's own perception of problems with cognitive functioning in everyday life. The authors investigated the presence and correlates of subjective cognitive concerns and the response to neurobehavioral therapy among adults with TBI and functional seizures (TBI+FS group). METHODS: In this observational study, participants in the TBI+FS group (N=47) completed a 12-session neurobehavioral therapy protocol for seizures, while participants in the comparison group (TBI without seizures) (N=50) received usual treatment. Subjective cognitive concerns, objective cognition, mental health, and quality of life were assessed before and after treatment. Data collection occurred from 2018 to 2022. RESULTS: Baseline subjective cognitive concerns were reported for 37 (79%) participants in the TBI+FS group and 20 (40%) participants in the comparison group. In a multivariable regression model in the TBI+FS group, baseline global mental health (ß=-0.97) and obsessive-compulsive symptoms (ß=-1.01) were associated with subjective cognitive concerns at baseline. The TBI+FS group had fewer subjective cognitive concerns after treatment (η2=0.09), whereas the TBI comparison group showed a nonsignificant increase in subjective cognitive concerns. CONCLUSIONS: Subjective cognitive concerns are common among people with TBI and functional seizures and may be related to general mental health and obsessive-compulsive symptoms. Evidence-based neurobehavioral therapy for functional seizures is a reasonable treatment option to address such concerns in this population, although additional studies in culturally diverse samples are needed. In addition, people with functional seizures would likely benefit from rehabilitation specifically targeted toward cognitive functioning.
Subject(s)
Brain Injuries, Traumatic , Seizures , Humans , Brain Injuries, Traumatic/complications , Brain Injuries, Traumatic/rehabilitation , Male , Female , Adult , Seizures/etiology , Seizures/psychology , Seizures/therapy , Middle Aged , Cognitive Dysfunction/etiology , Cognitive Dysfunction/rehabilitation , Cognitive Dysfunction/therapy , Cognitive Dysfunction/physiopathology , Quality of Life , Cognition/physiology , Cognitive Behavioral Therapy , Young AdultABSTRACT
Cognitive functioning impacts clinical symptoms, treatment response, and quality of life in adults with functional/nonepileptic seizures (FS/NES), but no study to date examines effects of behavioral FS/NES treatment on cognition in these patients. We hypothesized that there would be a reduction in cognitive symptoms in participants with FS/NES and traumatic brain injury (TBI) following neurobehavioral therapy (NBT). We also hypothesized that select seizure-related, medication, subjective cognitive, and mental health symptoms would be negatively correlated with improvements in cognitive performance after NBT. Participants were 37 adults with TBI + FS/NES and 35 adults with TBI only, recruited from medical centers in the northeastern or southeastern U.S. TBI + FS/NES participants completed a 12 session NBT intervention, and TBI without seizures participants were not treated. All participants completed pre-post assessments of cognition (Montreal Cognitive Assessment [MoCA]) and baseline sociodemographic factors and mental health symptoms. Pre-post MoCA scores increased significantly in TBI + FS/NES participants (28/37 [75.7%] improved) but not in TBI comparisons (10/35 [28.6%] improved). Language, memory, and visuospatial/executive functions, but not attention, improved over time in the TBI + FS/NES group. Gains in cognition were concentrated in those TBI + FS/NES participants with likely baseline cognitive impairments (MoCA total score <26), and 9/17 of these participants moved from the "impaired" range at baseline (<26) to the "intact" range at endpoint (≥26). Lastly, participants taking fewer medications and reporting lower subjective cognitive difficulties at baseline showed larger pre-post MoCA total score improvements. Overall, results from this study suggest the potential for positive change in cognition in FS/NES and co-occurring TBI using evidence-based psychotherapy.
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OBJECTIVE: The aim of this study was to assess potential drug-drug interactions between highly purified cannabidiol (CBD) and anti-seizure medications (ASMs). METHODS: Our group previously reported that in a sample of adults and children receiving CBD in an open-label expanded access program, there were several ASMs noted to increase in serum levels with increasing doses of CBD. We analyzed if an increased number of observations over time resulted in changes in potential interactions and if potential interactions were associated with time since enrollment, demographics, or the overall rating of adverse effects. RESULTS: In 169 participants (80 adults), with increasing weight-based CBD dose, there were associated increases in serum levels of clobazam and N-desmethylclobazam, free valproate, felbamate, and topiramate in the adult and pediatric arms combined, levetiracetam in the pediatric arm only, and permapanel in the adult arm only. There were no associations noted in these level changes with time since enrollment, biological sex, and adverse events profile scores. SIGNIFICANCE: This study confirms some previously identified interactions with CBD and identifies other potential pharmacokinetic interactions; however, the clinical significance of these observations is likely minor, and there is no effect of time on these findings.
Subject(s)
Cannabidiol , Adult , Humans , Child , Cannabidiol/therapeutic use , Anticonvulsants/therapeutic use , Clobazam/pharmacokinetics , Clobazam/therapeutic use , Topiramate , Drug InteractionsABSTRACT
OBJECTIVE: We aimed to prospectively quantify changes in white matter morphology after neurobehavioral therapy (NBT) for functional seizures (FS) using neurite orientation dispersion and density imaging (NODDI). We hypothesized that patients with FS would exhibit white matter plasticity in the uncinate fasciculus, fornix/stria terminalis, cingulum, and corticospinal tract following NBT that would correlate with improvements in affective symptoms, postconcussive symptoms, and quality of life (QOL). METHODS: Forty-two patients with traumatic brain injury (TBI) and FS (TBI+FS) underwent NBT and provided pre-/postintervention neuroimaging and behavioral data; 47 controls with TBI without FS (TBI-only) completed the same measures but did not receive NBT. Changes in neurite density, orientation dispersion (orientation dispersion index [ODI]), and extracellular free water (FW) were compared between groups. RESULTS: Significant ODI increases in the left uncinate fasciculus in TBI+FS (mean difference = 0.017, p = 0.039) correlated with improvements in posttraumatic symptoms (r = -0.395, p = 0.013), QOL (r = 0.474, p = 0.002), emotional well-being (r = 0.524, p < 0.001), and energy (r = 0.474, p = 0.002). In TBI-only, ODI decreased (mean difference = -0.008, p = 0.047) and FW increased (mean difference = 0.011, p = 0.003) in the right cingulum. FW increases correlated with increased psychological problems (r = 0.383, p = 0.013). In TBI+FS, NBT resulted in FS decreases of 3.5 seizures per week. None of the imaging changes correlated with FS frequency. INTERPRETATION: We identified white matter changes after NBT in patients with FS that were associated with improved psychosocial functioning. NODDI could be incorporated into future mechanistic assessments of interventions in patients with FS. ANN NEUROL 2023;94:350-365.
Subject(s)
White Matter , Humans , White Matter/diagnostic imaging , Brain , Quality of Life , Neurites , Seizures/diagnostic imagingABSTRACT
Anecdotal reports of the benefits of cannabis and its components in the treatment of epilepsy have been reported for millennia. However, only recently randomized controlled trial data in support of cannabidiol (CBD) became available resulting in its FDA approval for the treatment of seizures and epilepsy. One of the most common and debilitating comorbidities of epilepsy is cognitive impairment. This impairment has a multifactorial etiology including network dysfunction due to seizures, negative cognitive side effects from anti-seizure medications (ASMs), and mood disturbances. Knowing the effects of a particular ASM (either positive or negative) is vital for providers to counsel patients on expected side effects, and may result in choosing a particular regimen over the other if the patient already suffers from significant cognitive deficits. Unlike most other ASMs and other well-studied cannabinoids such as Δ9-tetrahydrocannabinol, CBD has been shown to have additional mechanisms of action (MOA) that result in neuroprotective, anti-inflammatory, anti-oxidant, and neurogenesis effects. These additional MOAs suggest that the use of CBD could lead to other actions including positive effects on cognition that may be independent of seizure control. This targeted review discusses the currently available data on CBD's effects on cognition in epilepsy. First, we review the proposed mechanisms by which CBD could exert effects on cognition. Then, we present the pre-clinical/animal data investigating cognitive effects of CBD in seizure/epilepsy models. Finally, we discuss the available human data, including the studies in people with epilepsy that included cognitive evaluations pre- and on-CBD, and studies investigating if CBD has any effects on brain structure or function in areas pertinent to memory and cognitive functions.
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OBJECTIVE: To evaluate the safety, efficacy, and tolerability of highly purified cannabidiol (CBD) for the treatment of seizures in children and adults with treatment-resistant epilepsy (TRE) in an open-label, expanded access program (EAP). METHODS: One hundred sixty-nine participants (89 children and 80 adults) with TRE received plant-derived highly purified CBD (Epidiolex® in the U.S.; 100â¯mg/mL oral solution) with a starting dose of 5â¯mg/kg/day divided twice per day and titrated to a maximum dose of 50â¯mg/kg/day over the study period to seizure control and tolerability and followed for up to 2â¯years. Seizure frequency (calendars) and severity (Chalfont Seizure Severity Score; CSSS) were collected at every study visit. Adverse Events were reported at/between study visits as required, and participants also completed Adverse Events Profile (AEP) which generates a numerical representation of AEs. Response to CBD was defined as ≥50% reduction in seizure frequency. Given non-normal distribution of seizure frequency, a log transformation was applied after which the generalized least squares regression model for longitudinal data was used. RESULTS: Evidence from the adjusted model revealed a significant mean reduction in seizure frequency compared to baseline in children and adults at all time points (1â¯month and 1 and 2â¯years). Percentage of children achieving ≥50% seizure frequency reduction was 44% at month 1, and 41% at year 1, and 61% reduction at year 2, while adult responder rates were 34% at month 1, 53% at year 1, and 71% at year 2 (all Pâ¯<â¯0.0001). CSSS showed a sustained reduction from baseline to all 3 time points. Children displayed 52% seizure reduction at month 1, a 51% reduction at year 1, and 75% reduction at year 2. Seizure reductions in adults were 60%, 81%, and 85%, respectively (all Pâ¯<â¯0.0001). While there were no significant differences between seizure frequency reduction between children and adults at all time points, there was a significant difference in seizure severity reduction at year 1, with adults reporting greater improvement in seizure severity (Pâ¯<â¯0.001). The most commonly reported adverse events in the study period were diarrhea, sedation, and decreased appetite. AEP revealed significant improvement from baseline at multiple time points in adults and children, and the mean AEP scores were always lower compared to baseline over the duration of the study. SIGNIFICANCE: Our study provides further evidence of sustained seizure frequency and severity reduction over two years of treatment with highly purified CBD in TRE. In addition, CBD was generally well tolerated with minority of participants experiencing adverse events resulting in stopping CBD.
Subject(s)
Cannabidiol , Drug Resistant Epilepsy , Epilepsy , Adult , Anticonvulsants/adverse effects , Cannabidiol/therapeutic use , Child , Drug Resistant Epilepsy/drug therapy , Epilepsy/drug therapy , Humans , Seizures/drug therapy , Treatment OutcomeABSTRACT
OBJECTIVE: To further evaluate the relationship between the clinical profiles and limbic and motor brain regions and their connecting pathways in psychogenic nonepileptic seizures (PNES). Neurite Orientation Dispersion and Density Indices (NODDI) multicompartment modeling was used to test the relationships between tissue alterations in patients with traumatic brain injury (TBI) and multiple psychiatric symptoms. METHODS: The sample included participants with prior TBI (TBI; N = 37) but no PNES, and with TBI and PNES (TBI + PNES; N = 34). Participants completed 3T Siemens Prisma MRI high angular resolution imaging diffusion protocol. Statistical maps, including fractional anisotropy (FA), mean diffusivity (MD), neurite dispersion [orientation dispersion index (ODI)] and density [intracellular volume fraction (ICVF), and free water (i.e., isotropic) volume fraction (V-ISO)] signal intensity, were generated for each participant. Linear mixed-effects models identified clusters of between-group differences in indices of white matter changes. Pearson's r correlation tests assessed any relationship between signal intensity and psychiatric symptoms. RESULTS: Compared to TBI, TBI + PNES revealed decreases in FA, ICVF, and V-ISO and increases in MD for clusters within cingulum bundle, uncinate fasciculus, fornix/stria terminalis, and corticospinal tract pathways (cluster threshold α = 0.05). Indices of white matter changes for these clusters correlated with depressive, anxiety, PTSD, psychoticism, and somatization symptom severity (FDR threshold α = 0.05). A follow-up within-group analysis revealed that these correlations failed to reach the criteria for significance in the TBI + PNES group alone. INTERPRETATION: The results expand support for the hypothesis that alterations in pathways comprising the specific PNES network correspond to patient profiles. These findings implicate myelin-specific changes as possible contributors to PNES, thus introducing novel potential treatment targets.
Subject(s)
Anisotropy , Magnetic Resonance Imaging , Nerve Net/anatomy & histology , White Matter/pathology , Adult , Brain Injuries, Traumatic/diagnosis , Diffusion Magnetic Resonance Imaging/methods , Diffusion Tensor Imaging/methods , Female , Humans , Magnetic Resonance Imaging/methods , Male , Middle Aged , Myelin Sheath/metabolism , Neurites/pathology , Neurites/ultrastructure , Seizures/psychology , White Matter/physiopathologyABSTRACT
OBJECTIVE: We aimed to determine changes in working memory and functional connectivity via functional magnetic resonance imaging (fMRI)-modified Sternberg task after treatment with highly purified cannabidiol (CBD, Epidiolex®; 100â¯mg/mL) in patients with treatment-resistant epilepsy (TRE). METHODS: Twenty patients with TRE (mean age: 35.8â¯years; 7 male) performed fMRI Sternberg task before receiving CBD ("PRE") and after reaching stable dosage of CBD (15-25â¯mg/kg/day; "ON"). Each patient performed 2 runs of the modified Sternberg task during PRE and ON fMRI. Twenty-three healthy controls (HCs; mean age: 25â¯years; 11 M) also completed the task. All were presented with a sequence of 2 or 6 letters and instructed to remember them (encoding). After a delay, a single letter was shown, and participants recalled if letter was shown in sequence (retrieval). Paired t-tests were used to analyze accuracy/response times. For each subject, event-related modeling of encoding (2 and 6 letters) and retrieval was performed. Paired t-tests controlling for seizure frequency change and scanner type were performed to assess changes in neural recruitment during encoding and retrieval in key regions of interest. RESULTS: There was nonsignificant increase in mean modified Sternberg task accuracy from PRE to ON-CBD (28.6 vs. 32.1%). PRE and ON accuracy was worse than HCs (75.5%, pâ¯<â¯0.001). ON-PRE comparison revealed increased activation in the right inferior frontal gyrus (IFG) during 6-letter encoding. ON-HC comparison revealed increased activation in bilateral IFG and insula during 2-letter encoding. PRE-HC comparison revealed decreased activation in the left middle frontal gyrus during 6-letter encoding. None of these activations were associated with working memory performance. SIGNIFICANCE: Treatment-resistant epilepsy results in poorer working memory performance and lower neural recruitment compared with HCs. Treatment with CBD results in no significant changes in working memory performance and in significant increases in neural activity in regions important for verbal memory and attention compared with HCs during memory encoding.
Subject(s)
Cannabidiol , Epilepsy , Adult , Humans , Magnetic Resonance Imaging , Male , Memory Disorders/drug therapy , Memory Disorders/etiology , Memory, Short-TermABSTRACT
OBJECTIVE: Resting-state (rs) network dysfunction is a contributing factor to treatment resistance in epilepsy. In treatment-resistant epilepsy (TRE), pharmacological and nonpharmacological therapies have been shown to improve such dysfunction. In this study, our goal was to prospectively evaluate the effect of highly purified plant-derived cannabidiol (CBD; Epidiolex®) on rs functional magnetic resonance imaging (fMRI) functional connectivity (rs-FC). We hypothesized that CBD would change and potentially normalize the rs-FC in TRE. METHODS: Twenty-two of 27 participants with TRE completed all study procedures including longitudinal pre-/on-CBD rs-fMRI (8M/14F, mean ageâ¯=â¯36.2⯱â¯15.9â¯years, TRE durationâ¯=â¯18.3⯱â¯12.6â¯years); there were no differences in age (pâ¯=â¯0.99) or sex (pâ¯=â¯0.15) between groups. Assessments collected included seizure frequency (SF), Chalfont Seizure Severity Scale (CSSS), Columbia Suicide Severity Rating Scale (C-SSRS), Adverse Events Profile (AEP), and Profile of Mood States (POMS). Twenty-three healthy controls (HCs) received rs-fMRI and POMS once. RESULTS: Participants with TRE showed average decrease of 71.7% in SF (pâ¯<â¯0.0001) and improved CSSS, AEP, and POMS confusion, depression, and fatigue subscores (all pâ¯<â¯0.05) on-CBD with POMS scores becoming similar to those of HCs. Paired t-tests showed significant pre-/on-CBD changes in rs-FC in cerebellum, frontal areas, temporal areas, hippocampus, and amygdala with some of them correlating with improvement in behavioral measures. Significant differences in rs-FC between pre-CBD and HCs were found in cerebellum, frontal, and occipital regions. After controlling for changes in SF with CBD, these differences were no longer present when comparing on-CBD to HCs. SIGNIFICANCE: This study indicates that highly purified CBD modulates and potentially normalizes rs-FC in the epileptic brain. This effect may underlie its efficacy. This study provides Class III evidence for CBD's normalizing effect on rs-FC in TRE.
Subject(s)
Cannabidiol , Drug Resistant Epilepsy , Epilepsy , Adult , Cannabidiol/therapeutic use , Drug Resistant Epilepsy/diagnostic imaging , Drug Resistant Epilepsy/drug therapy , Humans , Magnetic Resonance Imaging , Middle Aged , Seizures , Young AdultABSTRACT
During the 25 years since the US Congress passed the Dietary Supplement Health and Education Act (DSHEA), the law that transformed the US Food and Drug Administration's (FDA's) authority to regulate dietary supplements, the dietary supplement market has grown exponentially. Retail sales of herbal products, a subcategory of dietary supplements, have increased 83% from 2008 to 2018 ($4.8 to $8.8 billion USD). Although consumers often equate "natural" with "safe", it is well recognized by scientists that constituents in these natural products (NPs) can result in toxicity. Additionally, when NPs are co-consumed with pharmaceutical agents, the precipitant NP can alter drug disposition and drug delivery, thereby enhancing or reducing the therapeutic effect of the object drug(s). With the widespread use of NPs, these effects can be underappreciated. We present a summary of a symposium presented at the Annual Meeting of the Society of Toxicology 2019 (12 March 2019) that discussed potential toxicities of NPs alone and in combination with drugs.
Subject(s)
Biological Products/adverse effects , Legislation, Food , Pharmaceutical Preparations , Biological Products/administration & dosage , Dietary Supplements , Humans , Marketing , Pharmaceutical Preparations/administration & dosage , United States , United States Food and Drug AdministrationABSTRACT
OBJECTIVE: We have previously shown that cannabidiol (CBD; Epidiolex®) significantly affects levels of clobazam/N-desmethylclobazam, rufinamide, topiramate, zonisamide, and eslicarbazepine. In the present study, we tested whether the presence of concomitant clobazam affected seizure frequency and severity (treatment response) 12â¯weeks after initiation of therapy with CBD in patients with treatment-resistant epilepsy (TRE). The secondary questions were whether the presence of any of the other antiepileptic drugs (AEDs) had an effect on seizure frequency or severity at 12, 24, or 48â¯weeks after therapy initiation. METHODS: One hundred and thirty-two adults and children with TRE receiving CBD were studied prospectively. Participants were separated into two groups - either taking (CBDâ¯+â¯clobazam) or not taking concomitant clobazam (CBDâ¯-â¯clobazam). In the secondary analyses, participants were divided into groups depending on whether they were taking at least 1/4 of the other AEDs shown to interact with CBD (iAED). Seizure counts and Chalfont Seizure Severity Scale (CSSS) were obtained at baseline, 12, 24, and 48â¯weeks. Groups were compared at each respective time point in the study using generalized estimating equations (GEE) analyses. RESULTS: All groups demonstrated statistically significant reductions in seizure frequency and severity from baseline (all Pâ¯<â¯0.05). When participants on CBDâ¯+â¯clobazam were compared with CBDâ¯-â¯clobazam, there were no significant differences in seizure frequency and severity reduction between the groups at 12â¯weeks (both Pâ¯>â¯0.05). When comparing groups with iAEDs vs. group without iAEDs, independent of coadministration of clobazam, no differences in treatment response were observed (all Pâ¯>â¯0.05). Longitudinal analyses up to 48â¯weeks after therapy initiation did not reveal any differences in treatment response between groups. CONCLUSION: These analyses suggest that concomitant to CBD, AEDs may not have an effect on reducing seizure frequency and severity in patients with TRE.
Subject(s)
Anticonvulsants/pharmacology , Cannabidiol/pharmacology , Clobazam/pharmacology , Drug Resistant Epilepsy/drug therapy , Adolescent , Adult , Child , Drug Interactions , Female , Humans , Male , Treatment Outcome , Young AdultABSTRACT
BACKGROUND: Memory deficits are very common in epilepsy, but no standard of care exists to effectively manage them. OBJECTIVE: We assessed effectiveness of cognitive rehabilitation (CR) on memory and neural plasticity in people with epilepsy (PWE) reporting memory impairments. METHODS: Nine PWE completed 6 weekly sessions adapted from 2 generic CR programs enriched with information regarding epilepsy. Participants completed neuropsychological, mood, and quality of life (QOLIE-31) measures prior and after completion of CR; 5/9 participants also completed pre- and post-CR fMRI while performing a verbal paired associates learning task. FMRI data were analyzed using group spatial independent components analysis methods; paired t-tests compared spatial activations for pre-/post-CR. RESULTS: Improvements were seen in immediate recall in Rey Auditory Verbal Learning Task, QOLIE-31, and read word recognition in paired associates task (all p's≤0.05). FMRI changes comparing pre-to-post CR were noted through increased activation in the left inferior frontal gyrus (IFG) and anterior cingulate and decreased activation in the left superior temporal gyrus; also noted were decreased activations in the default mode network (DMN), right cingulate, right middle temporal gyrus, right supramarginal gyrus, and increased DMN activation in the left cuneus. CONCLUSIONS: This study demonstrates feasibility of conducting CR program in PWE with fMRI as a mechanistic biomarker. Improvements in cognition and cortical plasticity await confirmation in larger samples.
Subject(s)
Epilepsy/diagnostic imaging , Epilepsy/therapy , Magnetic Resonance Imaging/methods , Memory Disorders/diagnostic imaging , Memory Disorders/therapy , Neurological Rehabilitation/methods , Adult , Association Learning/physiology , Cognition/physiology , Epilepsy/psychology , Female , Humans , Male , Memory Disorders/psychology , Mental Status and Dementia Tests , Middle Aged , Neuroimaging/methods , Neurological Rehabilitation/psychology , Neuropsychological Tests , Pilot Projects , Young AdultABSTRACT
Cognitive dysfunction is a common comorbidity in adults with treatment-resistant epilepsy (TRE). Recently, cannabidiol (CBD) has demonstrated efficacy in epilepsy treatment. However, our understanding of CBD's cognitive effects in epilepsy is limited. We examined long-term cognitive effects of CBD in adults with TRE as part of an ongoing prospective, open-label safety study. Twenty-sevenadults with TRE (mean age: 34[SD +14], female 52%) enrolled in the UAB CBD program completed standardized cognitive testing (NIH Toolbox Cognition Battery (NIHTB-CB)) at pre-CBD administration baseline and at one-yearfollow-up. Participants were receiving stable CBD dose at the time of one-year testing (mean=36.5mg/kg/day). The NIHTB-CB consisted of two global composite scales (Fluid and Crystallized) and seven individual tests measuring aspects of working memory, episodic memory, executive function, processing speed, and language. All participants had recorded Chalfont Seizure Severity Scale (CSSS) scores at each visit. Statistical analyses consisted of t-test, Pearson correlation coefficient, and linear regression. At baseline, cognitive test performance was below average for both global composite scales (Fluid: 71 [±18] range: 46-117) and Crystallized (76 [±15] range: 59-112)]. Longitudinal analysis revealed no significant group change across the two global composite scales. Of the seven individual cognitive tests, none changed significantly over time. No correlation was found between the cognitive change scores and CBD dose (all P's≥0.21). Change in cognitive test performance was not associated change in seizure severity rating. These findings are encouraging and indicate that long-term administration of pharmaceutical grade CBD is overall cognitively well-tolerated in adults with TRE.
Subject(s)
Cannabidiol/therapeutic use , Cognitive Dysfunction/psychology , Drug Resistant Epilepsy/drug therapy , Adult , Cognition , Compassionate Use Trials , Drug Resistant Epilepsy/psychology , Executive Function , Female , Humans , Language , Longitudinal Studies , Male , Memory, Episodic , Memory, Short-Term , Mental Status and Dementia Tests , Middle Aged , Prospective Studies , Seizures/drug therapy , Treatment Outcome , Young AdultABSTRACT
OBJECTIVE: The objective of this study was to determine the relationship between cannabidiol (CBD) dose, CBD plasma level, and seizure control in a large open-label single-center study. METHODS: All participants with treatment-refractory epilepsy participating in our expanded access program (EAP) were approached for participation. Highly purified grade CBD (Epidiolex®) dosing was weight-based and could be increased every 2â¯weeks by 5â¯mg/kg/day up to a maximum dosage of 50â¯mg/kg/day depending on tolerance and seizure control. Seizure counts were obtained at each visit with frequency calculated per 2-week periods. Cross-sectional plasma peak levels of CBD were obtained ~4â¯h after dosing in consecutively presenting patients. RESULTS: We evaluated 56 adults and 44 children (100 total; 54 female) at two time points - one before initiating CBD and one at the time of CBD plasma level testing. There was a positive linear correlation between CBD dosage (range from 5 to 50â¯mg/kg/day) and level (range from 7.1-1200â¯ng/mL) in all participants (râ¯=â¯0.640; pâ¯<â¯0.001). The quantile regression model supported the notion of increased CBD levels being associated with improvement in seizure frequency after adjusting for age - specifically, a 100â¯ng/mL increase in CBD level was associated with approximately two counts reduction in seizure frequency per time period (1.87 96% confidence interval [CI] 0.34-3.39; pâ¯=â¯0.018). In participants with the same CBD level, differences in seizure improvement did not depend on age (pâ¯=â¯0.318). CONCLUSIONS: In this open-label study, we found evidence of a linear correlation between CBD dosage and plasma levels, and that higher dose/levels are associated with a higher response rate for seizure improvement. Children and adults responded to CBD similarly. However, seizure control response rates suggest children may respond to lower dosages/plasma levels than adults. Findings reported in this study are specific to Epidiolex® and should not be extrapolated to other CBD products.
Subject(s)
Anticonvulsants/pharmacology , Cannabidiol/blood , Cannabidiol/pharmacology , Drug Resistant Epilepsy/blood , Drug Resistant Epilepsy/drug therapy , Adolescent , Adult , Anticonvulsants/administration & dosage , Cannabidiol/administration & dosage , Child , Cross-Sectional Studies , Female , Humans , Male , Middle Aged , Young AdultABSTRACT
Patients with treatment-resistant epilepsy (TRE) frequently exhibit memory and attention deficits that contribute to their poor personal and societal outcomes. We studied the effects of adjunct treatment with pharmaceutical grade cannabidiol (CBD) oral solution (Epidiolex®; Greenwich Biosciences, Inc.) on attention control processes related to stimulus conflict resolution in patients with TRE. Twenty-two patients with TRE underwent 3â¯T magnetic resonance imaging (MRI) before receiving (PRE) and after achieving a stable dose of CBD (ON). Functional MRI (fMRI) data were collected while patients performed 2 runs of a flanker task (FT). Patients were instructed to indicate via button press the congruent (CON) and incongruent (INC) conditions. We performed t-tests to examine with FT attention control processes at PRE and ON visits and to compare the 2 visits using derived general linear model (GLM) data (INC - CON). We performed generalized psychophysiological interaction (gPPI) analyses to assess changes in condition-based functional connectivity on FT. Median time between fMRI visits was 10â¯weeks, and median CBD dose at follow-up was 25â¯mg/kg/d. From PRE to ON, participants experienced improvements in seizure frequency (SF) (pâ¯=â¯0.0009), seizure severity (Chalfont Seizure Severity Scale (CSSS); pâ¯<â¯0.0001), and mood (Total Mood Disturbance (TMD) score from Profile of Mood States (POMS); pâ¯=â¯0.0026). Repeated measures analysis of variance showed nonsignificant improvements in executive function from 34.6 (23.5)% to 41.9 (22.4)% CON accuracy and from 34.2 (25.7)% to 37.6 (24.4)% INC accuracy (pâ¯=â¯0.199). Change in CON accuracy was associated with change in INC accuracy (rSâ¯=â¯0.81, pâ¯=â¯0.0005). Participants exhibited CBD-induced increases in fMRI activation in the right superior frontal gyrus (SFG) and right insula/middle frontal gyrus (MFG) and decrease in activation for both regions at ON relative to PRE (corrected pâ¯=â¯0.05). The subset of patients who improved in FT accuracy with CBD showed a negative association between change in right insula/MFG activation and change in accuracy for the INC condition (rSâ¯=â¯-0.893, pâ¯=â¯0.0068). The gPPI analysis revealed a CBD-induced decrease in condition-based functional connectivity differences for the right SFG seed region (corrected pâ¯=â¯0.05). Whole-brain regression analysis documented a negative association of change in right insula/MFG condition-based connectivity with change in INC accuracy (corrected pâ¯=â¯0.005). Our results suggest that CBD modulates attention control processing in patients with TRE by reducing right SFG and right insula/MFG activation related to stimulus conflict resolution and by dampening differences in condition-based functional connectivity of the right SFG. Our study is the first to provide insight into how CBD affects the neural substrates involved in attention processing and how modulation of the activity and functional connectivity related to attentional control processes in the right insula/MFG may be working to improve cognitive performance in TRE.
Subject(s)
Attention/drug effects , Cannabidiol/therapeutic use , Cerebral Cortex/drug effects , Cerebral Cortex/diagnostic imaging , Drug Resistant Epilepsy/diagnostic imaging , Magnetic Resonance Imaging/methods , Adult , Attention/physiology , Cannabidiol/pharmacology , Cerebral Cortex/physiology , Child , Drug Resistant Epilepsy/drug therapy , Executive Function/drug effects , Executive Function/physiology , Female , Humans , Male , Middle Aged , Prefrontal Cortex/diagnostic imaging , Prefrontal Cortex/drug effects , Prefrontal Cortex/physiology , Prospective Studies , Young AdultABSTRACT
Treatment-resistant epilepsy (TRE) is associated with low quality of life (QOL). Cannabidiol (CBD) may improve QOL, but it is unclear if such improvements are independent of improvements in seizure control. Our aim was to compare QOL at baseline and after 1â¯year of treatment with CBD. We hypothesized that QOL would improve independent of changes in seizure frequency (SF) or severity, mood, or adverse events. We assessed QOL using Quality of Life in Epilepsy-89 (QOLIE-89) in an open-label study of purified CBD (Epidiolex®) for the treatment of TRE. All participants received CBD, starting at 5â¯mg/kg/day and titrated to 50â¯mg/kg/day in increments of 5â¯mg/kg/day. We collected QOLIE-89 in adult participants at enrollment and after 1â¯year of treatment, or at study exit if earlier. We analyzed if the change in QOLIE-89 total score could be explained by the change in SF, seizure severity (Chalfont Seizure Severity Scale, CSSS), mood (Profile of Moods States, POMS), or adverse events (Adverse Event Profile, AEP). Associations among the variables were assessed using bivariate tests and multiple regression. Fifty-three participants completed enrollment and follow-up testing, seven at study termination. Mean QOLIE-89 total score improved from enrollment (49.4⯱â¯19) to follow-up (57⯱â¯21.3; pâ¯=â¯.004). We also saw improvements in SF, POMS, AEP, and CSSS (all pâ¯≤â¯.01). Multivariable regression results showed QOLIE-89 at follow-up associated with improvements in POMS at follow-up (pâ¯=â¯.020), but not with AEP, CSSS, or SF (pâ¯≥â¯.135). Improvement in QOL after treatment with CBD is associated with better mood but not with changes in SF, seizure severity, or AEP. Cannabidiol may have beneficial effects on QOL and mood that are independent of treatment response.
Subject(s)
Anticonvulsants/therapeutic use , Cannabidiol/therapeutic use , Drug Resistant Epilepsy/drug therapy , Quality of Life , Adult , Drug Resistant Epilepsy/diagnosis , Drug Resistant Epilepsy/psychology , Female , Follow-Up Studies , Health Status Indicators , Humans , Male , Middle Aged , Quality of Life/psychology , Severity of Illness Index , Treatment OutcomeABSTRACT
Cannabis use is associated with changes in brain structure and function; its neurotoxic effects are largely attributed to Δ9-tetrahydrocannabidiol. Whether such effects are present in patients with epilepsy exposed to a highly-purified cannabidiol isolate (CBD; Epidiolex®; Greenwich Biosciences, Inc.) has not been investigated to date. This preliminary study examines whether daily CBD dose of 15-25â¯mg/kg produces cerebral macrostructure changes and, if present, how they relate to changes in seizure frequency. Twenty-seven patients with treatment-resistant epilepsy were recruited from the University of Alabama at Birmingham CBD Program. Participants provided seizure frequency diaries (SF), completed the Chalfont Seizure Severity Scale (CSSS) and Adverse Events Profile (AEP), and underwent MRI before CBD (baseline) and after achieving a stable CBD dosage (on-CBD). We examined T1-weighted structural images for gray matter volume (GMV) and cortical thickness changes from baseline to on-CBD in 18 participants. Repeated measures t-tests confirmed decreases in SF [t(17)â¯=â¯3.08, pâ¯=â¯0.0069], CSSS [t(17)â¯=â¯5.77, pâ¯<â¯0.001], and AEP [t(17)â¯=â¯3.04, pâ¯=â¯0.0074] between the two time-points. Voxel-level paired samples t-tests did not identify significant changes in GMV or cortical thickness between these two time-points. In conclusion, short-term exposure to highly purified CBD may not affect cortical macrostructure.
ABSTRACT
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. 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.
Subject(s)
Anticonvulsants/therapeutic use , Epilepsy/drug therapy , Medical Marijuana/therapeutic use , Anticonvulsants/metabolism , Anticonvulsants/pharmacology , Cannabidiol/metabolism , Cannabidiol/pharmacology , Cannabidiol/therapeutic use , Cannabis , Drug Resistant Epilepsy/diagnosis , Drug Resistant Epilepsy/drug therapy , Drug Resistant Epilepsy/metabolism , Endocannabinoids/metabolism , Endocannabinoids/pharmacology , Endocannabinoids/therapeutic use , Epilepsies, Myoclonic/diagnosis , Epilepsies, Myoclonic/drug therapy , Epilepsies, Myoclonic/metabolism , Epilepsy/diagnosis , Epilepsy/metabolism , Epileptic Syndromes/diagnosis , Epileptic Syndromes/drug therapy , Epileptic Syndromes/metabolism , Humans , Lennox Gastaut Syndrome/diagnosis , Lennox Gastaut Syndrome/drug therapy , Lennox Gastaut Syndrome/metabolism , Medical Marijuana/metabolism , Medical Marijuana/pharmacology , Randomized Controlled Trials as Topic/methods , Retrospective Studies , Seizures/diagnosis , Seizures/drug therapy , Seizures/metabolism , Spasms, Infantile/diagnosis , Spasms, Infantile/drug therapy , Spasms, Infantile/metabolism , TRPV Cation Channels/agonists , TRPV Cation Channels/metabolism , Treatment OutcomeABSTRACT
The objective of this study was to characterize the changes in adverse events, seizure severity, and frequency in response to a pharmaceutical formulation of highly purified cannabidiol (CBD; Epidiolex®) in a large, prospective, single-center, open-label study. We initiated CBD in 72 children and 60 adults with treatment-resistant epilepsy (TRE) at 5â¯mg/kg/day and titrated it up to a maximum dosage of 50â¯mg/kg/day. At each visit, we monitored treatment adverse events with the adverse events profile (AEP), seizure severity using the Chalfont Seizure Severity Scale (CSSS), and seizure frequency (SF) using seizure calendars. We analyzed data for the enrollment and visits at 12, 24, and 48â¯weeks. We recorded AEP, CSSS, and SF at each follow-up visit for the weeks preceding the visit (seizures were averaged over 2-week periods). Of the 139 study participants in this ongoing study, at the time of analysis, 132 had 12-week, 88 had 24-week, and 61 had 48-week data. Study retention was 77% at one year. There were no significant differences between participants who contributed all 4 data points and those who contributed 2 or 3 data points in baseline demographic and AEP/SF/CSSS measures. For all participants, AEP decreased between CBD initiation and the 12-week visit (40.8 vs. 33.2; pâ¯<â¯0.0001) with stable AEP scores thereafter (all pâ¯≥â¯0.14). Chalfont Seizure Severity Scale scores were 80.7 at baseline, decreasing to 39.2 at 12â¯weeks (pâ¯<â¯0.0001) and stable CSSS thereafter (all pâ¯≥â¯0.19). Bi-weekly SF decreased from a mean of 144.4 at entry to 52.2 at 12â¯weeks (pâ¯=â¯0.01) and remained stable thereafter (all pâ¯≥â¯0.65). Analyses of the pediatric and adult subgroups revealed similar patterns. Most patients were treated with dosages of CBD between 20 and 30â¯mg/kg/day. For the first time, this prospective, open-label safety study of CBD in TRE provides evidence for significant improvements in AEP, CSSS, and SF at 12â¯weeks that are sustained over the 48-week duration of treatment.