The Role of Cannabidiol in Neurological Disorders.

None: Cannabis has been used for both recreational and medicinal purposes for more than 4 millennia. Cannabis has been studied in various medical disorders including neurological disorders. There are well-known risks of long-term use of cannabis, including low motivation, lowered cognitive capabilities, and diminished IQ and brain mass. Cannabinoids are compounds in cannabis that are known to have therapeutic potential. The most abundant chemicals in cannabinoids are delta-9-tetrahydrocannabinol and cannabidiol. Delta-9-tetrahydrocannabinol has psychotropic effects that limits its use as a pharmacotherapeutic agent. Cannabidiol is a nonpsychotropic chemical and therefore has become a compound of interest for clinical researchers to study its therapeutic potential. This article reviews the efficacy and safety of cannabidiol in various neurological disorders in humans.

Does Early Recognition of Treatment Failure and Changing Anti-Epilepsy Medication Regimen Improve Short-Term Seizure Remission Rates In Childhood Absence Epilepsy?

PURPOSE: To study the role of early serial EEGs in improving seizure freedom rates after initiation of ethosuximide or valproic acid for childhood absence epilepsy. METHODS: Retrospective data analysis study of AED naive patients with childhood absence epilepsy undergoing treatment at the community-based epilepsy clinic. Due to small sample size Fisher's exact test was used to determine two-tailed p value at less than 0.05 statistical significance.. RESULTS: At 2-month study period 71.4% patients in the ethosuximide and 87.5% in the valproic acid group achieved seizure freedom, with EEG normalization in 21.4% and 50% respectively. At 6-month study period, in patients continuing ethosuximide, seizure freedom and EEG normalization rates were 89.5% and 52.6% respectively; while in patients continuing valproic acid, results were 100% and 78.6% respectively. Both at 2-month and 6-month study periods, a trend towards higher seizure freedom was noted in patients with typical versus non-typical epileptiform discharges at baseline with the valproic acid group showing a superior response. CONCLUSION: Although no statistically significant difference in response rates was noted, 1) a shift towards higher seizure freedom with valproic acid; 2) improved response after switching to valproic acid at 2 months, if warranted; and 3) superior response rate in patients with typical EEG epileptiform discharges at baseline were observed. A larger study is needed to define the role of early serial EEGs to delineate higher drug failure probability; and to determine the importance of non-typical EEG characteristics at baseline in relation to the choice of AED and long-term outcome Keywords: childhood absence epilepsy, ethosuximide, valproic acid, non-typical epileptiform discharges.

Mechanisms of Action and Pharmacokinetics of Cannabis.

None: At least 100 cannabis species are compounds known as cannabinoids, a molecule with a 21-carbon terpenophenolic skeleton. Cannabinoids produce more than 100 naturally occurring chemicals, the most abundant of which are Δ-9-tetrahydrocannabinol (THC), cannabidiol (CBD), terpenes, and flavonoids. THC and CBD bind with cannabinoid receptors (CB1 and CB2), which are present in the brain and many organs. Metabolism of cannabis is determined by the route of consumption. When inhaled, THC and its metabolites enter the bloodstream rapidly via the lungs; they achieve peak levels within 6 to 10 minutes and reach the brain and various organs. The bioavailability of inhaled THC is 10% to 35%. After THC is absorbed, it travels to the liver where most of it is eliminated or metabolized to 11-OH-THC or 11-COOH-THC. The remaining THC and its metabolites enter the circulation. The bioavailability of ingested THC is only 4% to 12%. THC is highly lipid soluble and is therefore rapidly taken up by fat tissue. The plasma half-life of THC is 1 to 3 days in occasional users and 5 to 13 days in chronic users. The bioavailability of CBD via inhalation is 11% to 45%, whereas that of oral CBD is 6%. CBD has high lipophilicity and therefore is rapidly distributed in the brain, adipose tissue, and other organs. CBD is hydroxylated to 7-OH-CBD and 7-COOH-CBD by cytochrome P450 enzymes CYP3A4 and CYP2C9 in the liver and is excreted mainly in feces and less in urine. The plasma half-life of CBD is 18 to 32 hours.

Effectiveness at 24 Months of Single-Source Generic Carbamazepine, Lamotrigine, or Levetiracetam in Newly Diagnosed Focal Epilepsy.

BACKGROUND: Kaiser Permanente advocates using single-source generics for brand-name drugs. We compared the effectiveness of 3 different-generation generic antiepileptic drugs (AEDs) in patients with focal epilepsies. OBJECTIVE: To compare the effectiveness of the 3 most commonly used AEDs (carbamazepine [CBZ], lamotrigine [LTG], and levetiracetam [LEV]) after 24-month monotherapy. METHODS: This is a retrospective data analysis of 646 consecutive AED-naive patients aged 1-88 years treated with CBZ, LTG, or LEV between 2006 and 2012 with dosing adjustments permitted during the first 6 months. Chi-squared test with p < 0.05 was used to calculate seizure-freedom and tolerability rates. RESULTS: At the end of the 24-month study period, 65.69% patients in the CBZ group continued to remain seizure free, 25.98% were drug failures, and 8.33% dropped out due to adverse events, with the corresponding numbers being 66.49%, 23.94%, and 9.57% in the LTG group and 72.44%, 12.99%, and 14.57% in the LEV group. Rash was the most common adverse event for CBZ (3.43%) and LTG (6.38%), and mood changes were the most commen adverse event for LEV (7.87%). Among the 3 groups (n = 646), AED tolerance rates and AED retention rates showed no significant difference (p = 0.08 and p = 0.23, respectively). Seizure-freedom rate difference among the 3 groups (n = 574) was significant (p = 0.003), and seizure-freedom rate for LEV was superior to CBZ (p = 0.001) and to LTG (p = 0.006). CONCLUSION: At the end of the 24-month study period, in a head-to-head comparison of single-source bioequivalent generic formulations, superior seizure-freedom rate and comparable tolerability and retention rates for LEV were observed when compared with CBZ and LTG.

Cannabis and Neuropsychiatric Disorders: An Updated Review.

Cannabis plant has the scientific name called Cannabis sativa L. Cannabis plant has many species, but there are three main species including Cannabis sativa, Cannabis indica and Cannabis ruderalis. Over 70 compounds isolated from cannabis species are called cannabinoids (CBN). Cannabinoids produce over 100 naturally occurring chemicals. The most abundant chemicals are delta-9-tetrahydrocannabinol (THC) and Cannabidiol (CBD). THC is psychotropic chemical that makes people feel "high" while CBD is nonpsychotropic chemical. However, cannabinoid chemicals are not found only in the cannabis plant, they are also produced by the mammalian body, called endocannabinoids and in the laboratory, called synthesized cannabinoids. Endocannabinoids are endogenous lipid-based retrograde neurotransmitters that bind to cannabinoid receptors, and cannabinoid receptor proteins that are expressed throughout the mammalian central nervous system including brain and peripheral nervous system. There are at least two types of endocannabinoid receptors (CB1 and CB2) which are G-protein coupled receptors. CB1 receptors are particularly abundant in the frontal cortex, hippocampus, basal ganglia, hypothalamus and cerebellum, spinal cord and peripheral nervous system. They are present in inhibitory GABA-ergic neurons and excitatory glutamatergic neurons. CB2 receptor is most abundantly found on cells of the immune system, hematopoietic cells and glia cells. CB2 is mainly expressed in the periphery under normal healthy condition, but in conditions of disease or injury, this upregulation occurs within the brain, and CB2 is therefore expressed in the brain in unhealthy states. Cannabis and cannabinoid are studied in different medical conditions. The therapeutic potentials of both cannabis and cannabinoid are related to the effects of THC, CBD and other cannabinoid compounds. However, the "high" effect of THC in cannabis and cannabinoid may limit the clinical use, particularly, the study on the therapeutic potential of THC alone is more limited. This review emphasizes the therapeutic potential of CBD and CBD with THC. CBD has shown to have benefit in a variety of neuropsychiatric disorders including autism spectrum disorder, anxiety, psychosis, neuropathic pain, cancer pain, HIV, migraine, multiple sclerosis, Alzheimer disease, Parkinson disease, Huntington disease, hypoxic-ischemic injury and epilepsy. CBD is generally well tolerated. Most common adverse events are diarrhea and somnolence. CBD also shows significantly low abuse potential.

Neuromodulation Therapy with Vagus Nerve Stimulation for Intractable Epilepsy: A 2-Year Efficacy Analysis Study in Patients under 12 Years of Age.

To study the efficacy of vagus nerve stimulation (VNS) therapy as an adjunctive treatment for intractable epilepsy in patients under 12 years of age, we analyzed 2-year postimplant data of 35 consecutive patients. Of the 35 patients, 18 (51.4%) at 6 months, 18 (51.4%) at 12 months, and 21 (60.1%) at 24 months showed ≥50% reduction in seizure frequency (responders). Although incremental seizure freedom was noted, no patient remained seizure-free throughout the 3 study periods. Partial response (≥50% seizure reduction in 2 or less study periods) was seen in 8 (22.9%) patients. Twelve patients (34.3%) were nonresponders. Out of 29 patients with primary generalized epilepsy, 20 (68.9%) and, out of 6 patients with focal epilepsy, 3 (50%) had ≥50% seizure control in at least one study period. No major complications or side effects requiring discontinuation of VNS therapy were encountered. We conclude that (1) patients with intractable primary generalized epilepsy respond better to VNS therapy, (2) cumulative effect of neuromodulation with improving responder rate to seizure freedom with continuation of VNS therapy is noted, and (3) VNS therapy is safe and is well tolerated in children receiving implant under 12 years of age.

Efficacy of Pinus radiata bark extract and vitamin C combination product as a prophylactic therapy for recalcitrant migraine and long-term results.

PURPOSE: This was the open-label study to evaluate the potential benefit of Pinus radiata bark extract and vitamin C as a treatment for migraine. METHODS: Fifty outpatients with chronic migraine refractory to at least two prophylactic medications were treated with an antioxidant formulation of 1200 mg Pinus radiata bark extract and 150 mg vitamin C daily for 3 months. Patients completed migraine disability assessment (MIDAS) questionnaires at the beginning and end of the study to assess migraine impact on work, school, domestic and social activities over the three months prior to enrollment and the three month treatment period. Patients continued existing pharmacologic medications during the study. Patients who were responders were assessed for migraine impact using MIDAS questionnaires every 3 months for 12 months. RESULTS: Twenty nine patients (58%) showed improvement in MIDAS score, number of headache days and headache severity score over the 3 months of treatment. Mean MIDAS score significantly improved from 30.3 days at baseline to 14.4 days; mean number of headache days significantly reduced from 47.9 days at baseline to 25.9 days, and mean headache severity reduced from 8.1 out of 10 to 5.6 after 3 months therapy. The responders who continuously took Pinus radiata bark extract and vitamin C combination for 12 months experienced ongoing migraine relief with more than 50% reduction of frequency and severity of headaches. CONCLUSION: These data suggest that the antioxidant therapy used in this study may be beneficial in the treatment of migraine possibly reducing headache frequency and severity.

Evaluation of maturation and function of visual pathways in neonates: role of flash visual-evoked potentials revisited.

The purpose of our study was to establish the guidelines for interpreting neonatal flash visual-evoked potentials (FVEPs) by examining the correlation between maturation of the waveforms and conceptual age (CA). We retrospectively analyzed 220 consecutive neonatal FVEPs performed on premature and full-term infants. The CA of the participants ranged from 28 to 52 weeks. The FVEPs were categorized into 6 groups according to CA: 28 to 31+ weeks, 32 to 35+ weeks, 36 to 39+ weeks, 40 to 43+ weeks, 44 to 47+ weeks, and 48 to 52 weeks. The data were analyzed in each group and compared among these 6 groups. The waveforms changed from 28 weeks to 52 weeks of CA. In the CA age range 28 to 31+ weeks N3 was well visualized, followed by P3. The morphology of P2 including both latency and amplitude became prominent starting from CA age range 32 to 35+ weeks. The triphasic waveform with clear negative-positive-negative components (N2-P2-N3) presented after 32 weeks. Mean P2 latencies decreased steadily with increasing age. Mean amplitudes of all waveforms (P2-N3 and N3-P3) varied except that of N2-P2 which increased steadily with CA. We conclude that FVEPs can be useful in the evaluation of maturation and function of the visual pathway in neonates. The FVEP is abnormal when the waveforms N3 and P3 are nondetectable in neonates at 28 weeks of CA or older; and when the waveform P2 is non-detectable, or has low amplitude or prolonged latency, in neonates at 36 weeks of CA or older.

Acute levetiracetam overdose presented with mild adverse events.

PURPOSE: Overdose of levetiracetam may produce neurotoxicity. CASE REPORT: We reported a patient with epilepsy who took an overdose of 63 grams of levetiracetam with mild adverse events. The patient presented mild blurred vision and mild ataxia that rapidly subsided within one day with supportive care. The laboratory tests showed mild leucopenia and mild thrombocytopenia that gradually returned to normal within 2 months. CONCLUSION: The pharmacokinetics, tolerability and adaptation of levetiracetam might play a role in the mild adverse events of levetiracetam overdose in our patient.

The mechanisms of medically refractory temporal lobe epilepsy.

The mechanisms underlying the refractory temporal lobe epilepsy (TLE) are not well understood. Several explanations for refractory TLE are (1) an overexpression of P-glycoprotein (P-gp) encoded by multiple drug resistance 1 (MDR1) gene and other efflux transporters such as multidrug resistance protein (MRP) in the cerebrovascular endothelium in or around the region of the epileptic focus may lead to drug resistance in epilepsy; (2) the loss of antiepileptic drug sensitivity at certain target sites in the brain, including the sodium ion channel and the gamma aminobutyric acid (GABA)A receptor; and (3) seizures beget seizures by means of a cascade of events that include various types of neuronal damage, sprouting of neuronal axons and new synapse formations that establish aberrant glutamatergic synapses. TLE may be a progressive neurological disorder that requires early and effective treatment. Early recognition of refractory TLE and referral for epilepsy surgery may prevent years of unnecessary seizure activity and its consequences.

Scalp-recorded auditory P300 event-related potentials in new-onset untreated temporal lobe epilepsy.

We studied scalp-recorded auditory event-related potentials (ERPs) of 30 untreated patients with new-onset temporal lobe epilepsy and 30 age- and sex-matched normal controls. This study was designed to eliminate the effects of intractability of seizures and chronic use of antiepileptic drugs on P300 auditory ERPs. There were no statistically significant differences in both latency and amplitude of P300 between the two groups. Similar methods were also used to analyze component latencies and amplitudes of ERPs of 9 patients who had hippocampal sclerosis with comparison to control subjects. There were no statistically significant differences between these two groups as well. Our study evidently does not support temporal lobe sources of P300 scalp-recorded auditory ERPs. We also conclude that the scalp-recorded auditory ERPs procedure is not a useful tool to evaluate temporal lobe epilepsy.

Use of a pine bark extract and antioxidant vitamin combination product as therapy for migraine in patients refractory to pharmacologic medication.

OBJECTIVE: To evaluate the potential benefit of a pine bark extract and antioxidant vitamin combination product in the treatment of migraine headache. BACKGROUND: This was an uncontrolled preliminary study to investigate the potential of an antioxidant formulation as therapy for migraine headache. METHODS: Twelve patients with a long-term history of migraine with and without aura who had failed to respond to multiple treatments with beta-blockers, antidepressants, anticonvulsants, and 5-hydroxytryptamine receptor agonists were selected for the study. They were treated with 10 capsules of an antioxidant formulation of 120 mg pine bark extract, 60 mg vitamin C, and 30 IU vitamin E in each capsule daily for 3 months. Following enrollment patients completed a migraine disability assessment (MIDAS) questionnaire to give a baseline measure of migraine impact on work, school, domestic, and social activities over the previous 3 months. Patients were then treated for 3 months with the antioxidant formulation while continuing to receive existing pharmacologic medications. A second MIDAS was given at the conclusion of the treatment period. RESULTS: There was a significant mean improvement in MIDAS score of 50.6% for the 3-month treatment period compared with the 3 months prior to baseline (P < .005). The treatment was also associated with significant reductions in number of headache days and headache severity score. Mean number of headache days was reduced from 44.4 days at baseline (95% CI 28.9 to 59.8) to 26.0 days (95% CI 5.3 to 46.7; P < .005) after 3 months' therapy and mean headache severity was reduced from 7.5 of 10 (95% CI 6.7 to 8.4) to 5.5 (95% CI 4.1 to 7.0; P < .005). CONCLUSION: These data suggest that the antioxidant therapy used in this study may be beneficial in the treatment of migraine possibly reducing headache frequency and severity. Further clinical investigation into the efficacy of antioxidant as therapy for chronic migraine is warranted.

Screening of EEG referrals by neurologists leads to improved healthcare resource utilization.

The objective of this study was to determine if screening by a neurologist of all non-neurologist electroencephalogram (EEG) referrals prior to approval reduces the number of inappropriate requests. This retrospective survey included 600 consecutive EEG requisitions referred to the Anaheim Kaiser Permanente Neurodiagnostic Laboratory to rule out epilepsy. Patients with established epilepsy referred for a repeat EEG for management issues were excluded. Three groups of EEG referrals were analyzed. Each group consisted of 200 EEGs (100 pediatric and 100 adult EEGs). The first group was referred directly by non-neurologists, the second group was referred by non-neurologists with scrutiny by a neurologist, and the third group was referred by a neurologist directly. In the pediatric group, the ratio of abnormal EEG vs normal EEG was 1:3.35 in the first group, 1:0.69 in the second group and 1:0.33 in the third group. In the adult group, the ratio of abnormal EEGs vs normal EEGs was 1:2.23 in the first group, 1:0.82 in the second group and 1:0.45 in the third group. In the combined pediatric and adult groups, the ratio of abnormal EEG vs normal EEG was 1:2.70 in the first group, 1:0.75 in the second group and 1:0.39 in the third group. There was a significant difference between the results of the EEGs ordered by non-neurologists directly versus non-neurologists with scrutiny (p=.334, chi-square test). Scrutiny by a neurologist of EEG referrals from non-neurologists led to a reduction in the number of normal EEG results. This suggests that inappropriate EEG requests for non-epileptic patients that yield normal EEG results are significantly reduced with scrutiny. This can help reduce the indiscriminate overuse of EEGs by non-neurologists thereby leading to better utilization of healthcare resources.

Social communication in children with epilepsy.

BACKGROUND: This study examined measures of social communication that involve the use of language in formulating and organizing thoughts and its relationship with seizure-related, developmental, cognitive, and behavioral variables in 92 children with complex partial seizure disorder (CPS), 51 with primary generalized epilepsy (PGE), and 117 normal children, aged 5.1-16.9 years. METHODS: Coding the children's speech samples with the Kiddie Formal Thought Disorder Rating Scale (Caplan et al., 1989) and Halliday and Hasan's (1976) analysis of cohesion demonstrated social communication deficits in both seizure disorder groups. RESULTS: The CPS patients had both formal thought disorder and cohesion deficits and the PGE group had mild cohesion deficits. IQ, as well as fronto-temporal and bilateral spike and wave activity were associated with the severity of the social communication deficits of the CPS group. The social communication deficits of the PGE group, however, were related to IQ and seizure control. CONCLUSIONS: Recurrent CPS and PGE and fronto-temporal localization of epileptic activity might impair the development of children's communication skills.