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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5203_Библиотеки_им_академика_М_И_Перельмана.pdf
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the three xed-ratio combinations (1:3, 1:1, and 3:1). This study aimed to investigate whether the benets of these drug combinations could extend to improving
lung function. The results demonstrated that combining tiagabine with carbamazepine or lamotrigine not only conferred greater protection against HBO2-induced
seizures but also allowed for the use of lower doses, thereby minimizing side effects
and mitigating acute lung damage [800].
Evidence-Based Medical Research
Research on the effects of evidence-based medicine on ASMs provides some evidence for the formulation of clinical drug protocols and the innovation of scientic
research ideas.
Gianni Cutillo etal. conducted a systematic review aiming to evaluate the efcacy of ASMs in controlling focal to bilateral tonic–clonic seizures (FBTCS), particularly at night, which are a signicant risk factor for sudden death in epilepsy
(SUDEP). The researchers searched various online databases for all post-1990 randomized, double-blinded, and placebo-controlled clinical trials of FDA-approved
ASMs, specically describing a reduction in FBTCS.They compared these reductions, where possible, to reductions in the onset of focal impairment of consciousness (FIA). Among the ASMs studied, topiramate (TPM) emerged as the most
extensively researched, followed by tiagabine (TGB), brivaracetam (BRV), and
lamotrigine (LTG). The TPM trials showed a reduction in FBTCS ranging from
44.8% to 100% (4.5–99% lower than placebo), while TGB exhibited reductions
ranging from 21.8% to 46.7% (21.8–61% higher than placebo). BRV and LTG also
demonstrated reductions, with BRV ranging from 33.9% to 82.1% (11.6–57.4%
higher than placebo) and LTG ranging from 55.2% (20.3–52% higher than placebo). The authors underscored the need for future studies to uniformly report
reductions in FBTCS episodes, including nocturnal events, to inform ASM choices
effectively and minimize FBTCS occurrences, thereby mitigating the risk of
SUDEP [801].
Wei-Chih Yeh etal. conducted a meta-analysis to investigate the effects of ASMs
on polysomnography parameters by searching for randomized controlled trials
(RCTs) in the PubMed, Embase, and Cochrane Central databases up to February
2021. Among the 18 eligible RCTs identied, the effects of ve major categories of
ASMs on sleep structure were analyzed: sodium channel blockers, calcium channel
blockers, GABA enhancers, synaptic vesicular glycoprotein 2A (SV2A) ligands,
and broad-spectrum ASMs. Calcium channel blockers and GABA enhancers were
found to signicantly increase slow wave sleep (SWS) times compared to placebo.
GABA enhancers also decreased the percentage of rapid eye movement (REM)
sleep, while calcium channel blockers signicantly improved sleep efciency (SE).
Sodium channel blockers, SV2A ligands, and broad-spectrum ASMs did not affect
SWS, REM sleep, or SE.Subgroup analysis revealed that gabapentin, pregabalin,
and tiagabine increased the percentage of SWS time, while tiagabine also reduced
REM sleep time, and pregabalin increased SE.Levetiracetam did not affect SWS,
REM sleep, or SE.This meta-analysis highlighted the varying effects of different
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ASMs on sleep parameters, indicating the importance of individualized treatment
approaches in managing epilepsy [802].
Side Effects
Tiagabine-associated status epilepticus (SE) is a rare but serious complication of
tiagabine. A case report described a 30-year-old man who experienced super refractory SE following tiagabine poisoning. After 72 h under general anesthesia, he
achieved complete recovery and was discharged from the ICU on the 16th day.
Patients with tiagabine-related SE exhibit distinct characteristics. Systemic convulsive SE can arise from voluntary or involuntary tiagabine poisoning, presenting
signicant treatment challenges. The electroclinical manifestations of tiagabineassociated SE vary depending on the underlying pathophysiological mechanism and
may pose life-threatening risks. Typically, recovery occurs following tiagabine discontinuation and SE management, with treatment escalation guided by response to
prior anticonvulsant therapy [803].
Use ofTiagabine inOther Diseases
One study revealed that tiagabine protects dopaminergic neurons from neurotoxins
by inhibiting microglial activation. Pretreatment with tiagabine decreased microglial activation, partially safeguarded the nigrostriatal axis, and ameliorated motor
decits in a methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of
Parkinson’s disease (PD). Notably, in MPTP-treated GAT1 knockout mice, the protective effect of tiagabine was abolished. In another PD model, the inhibitory effects
of tiagabine and subsequent neuroprotective effects on microglia were conrmed
through intranigral infusion of lipopolysaccharide (LPS). Moreover, preconditioning with GABAergic drugs inhibited the LPS-induced inammatory activation of
BV-2 microglia and mitigated the toxicity of conditioned medium to SH-SY5Y
cells. A reduction in nuclear translocation of nuclear factor κb (NF-κB) and suppression of inammatory mediator production are potential mechanisms underlying
this effect. These ndings suggest that tiagabine can impede the activation of nigrostriatal microglia, potentially representing a novel therapeutic approach for
Parkinson’s disease [804].
Another study evaluated the role of tiagabine in a kainic acid-induced model of
cerebellar injury in rats. Tiagabine was administered intraperitoneally to adult rats
with kainic acid-induced cerebellar dystonia. Various assessments, including light
beam walking devices, telemetry electromyography (EMG) recording, and histological validation, were performed to conrm postoperative dystonia symptoms in
the rats. The study revealed repetitive stiffness indicative of involuntary dystonia
spasms, alongside high dystonia scores and amplitudes, conrming twisting movements in rats. The results demonstrated that tiagabine effectively reduced dystonia
spasms, as evidenced by EMG recordings and behavioral evaluations of rats walking through the light beam. This nding suggests that tiagabine may serve as an
alternative therapeutic agent for dystonia treatment [805].
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Basic Research
Tiagabine, a novel antiseizure medication, operates by inhibiting GABA transporter- 1, thereby enhancing GABAergic signaling. However, its efcacy in chronic
epilepsy models with neurobehavioral and neuroinammatory conditions has been
underexplored. Sana Javaid etal. investigated the real-time effects of tiagabine on
electroencephalogram (EEG) activity, behavioral performance, and mRNA expression in mice treated with pentetrazol (PTZ). Male BALB/c mice received tiagabine
(0.5, 1, or 2mg/kg) for 21days, along with PTZ injections (40mg/kg) every other
day for a total of 11 injections, and seizure progression was monitored via
EEG. Behavioral experiments conrmed the anxiolytic and cognition-enhancing
effects of tiagabine. In vitro analysis revealed that a 2mg/kg dose of tiagabine mitigated seizure development and reduced epileptic spike discharge while also exerting a dose-dependent antianxiety effect and protecting against PTZ-induced
cognitive impairment. Tiagabine reduced oxidative stress, regulated BDNF/TrkB
signaling, and suppressed neuroinammatory markers by enhancing GABAergic
regulation. Overall, tiagabine may reduce epilepsy occurrence and improve associated neuropsychiatric effects by modulating oxidative stress, BDNF/TrkB signaling, and neuroinammation [806].
During this study, Ismail FS etal. observed limited evidence on the effects of
ASMs on glial cells. They investigated the role of tiagabine (TGB) and zonisamide
(ZNS) in an inammatory astroglia-microglia coculture model. Various concentrations of ZNS (10, 20, 40, 100μg/mL) or TGB (1, 10, 20, 50μg/mL) were added to
cocultures under physiological conditions (M5) or inammatory conditions (M30).
TGB exhibited toxicity under both physiological and pathological conditions, while
ZNS had limited effects on glial cell viability, especially at lower concentrations.
TGB reduced microglial activation and enhanced resting microglia under inammatory conditions, suggesting that it has anti-inammatory effects. ZNS did not signicantly alter the microglial phenotype. TGB disrupted gap junction coupling
under noninammatory conditions, possibly contributing to its antiepileptic activity, while ZNS disrupted glial gap junction communication under inammatory
conditions, potentially enhancing its antiseizure effects. TGB and ZNS differentially modulate glial cell characteristics, indicating the potential for new ASMs targeting glial cells as adjunctive therapies to traditional neuron-targeting ASMs [625].
Research has explored whether chronic administration of the GABAergic drug
tiagabine and the dopamine mimetic pramipexole following trauma inuences
behavioral outcomes and plasma levels of corticosterone, testosterone, or
17β-estradiol in both female and male mice. These drugs were investigated for their
potential to ameliorate GABAergic and dopaminergic decits associated with posttraumatic stress disorder (PTSD). The animals underwent a single prolonged stress
procedure (mSPS), and after 13days of treatment with tiagabine (10 mg/kg) or
pramipexole (1mg/kg) once daily, PTSD-like phenotypes were assessed using a
fear conditioning paradigm. Plasma hormone levels were measured shortly after the
conditioned fear assessment. Exposure to mSPS increased conditioned fear
responses in both male and female mice. However, while plasma corticosterone
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levels decreased in males, elevated levels were observed in females. Trauma led to
increased plasma testosterone levels in both sexes but had no signicant effect on
17β-estradiol levels. Pramipexole reduced trauma-related behavioral manifestations
in both sexes, whereas tiagabine reduced them only in females. Although neither
compound affected corticosterone levels in stressed animals, tiagabine further
increased testosterone levels in females. The study revealed a sex-dependent effect
of tiagabine in a mouse model of PTSD-like symptoms, while pramipexole did not
demonstrate such an effect, and steroid hormone levels did not predict the efcacy
of PTSD treatment [807].
Other Research
Tiagabine, primarily prescribed as an antiepileptic medication for managing partial
seizures in humans, has shown promise in treating various nonepileptic conditions,
such as anxiety, chronic pain, and sleep disorders. However, the incidence of tachycardia, a common nonneurological adverse effect, prompted Magdalena Kowalska
etal. to conduct pharmacological and numerical studies assessing the potential cardiovascular risks of tiagabine. Molecular docking analysis methods were employed
to describe the chemical interaction between tiagabine and human voltage-gated ion
channels (VGICs). The in silico results suggested that the reported adverse cardiac
effects of tiagabine cannot be directly attributed to its interaction with VGICs, a
nding supported by invitro organ studies and invivo electrocardiogram measurements. The study concluded that tiagabine-induced tachycardia and other cardiac
complications are not directly caused by the drug’s effects on ventricular depolarization and repolarization [795].
Moreover, tiagabine hydrochloride overdose, while effective in reducing seizure
frequency, can lead to adverse effects such as speech disorders, depression, and
suicidal tendencies. Thus, establishing a convenient and sensitive analysis method
for tiagabine (TGB) is crucial for guiding its clinical use. Zhen Zou etal. introduced
a novel uorescence initiation detection method for detecting TGB in urine, which
also revealed the presence of a uorescent dye [808]. Additionally, to elucidate the
interaction of TGB with plasma proteins, other studies have investigated its binding
to human serum albumin (HSA) and bovine serum albumin (BSA). VP capillary
differential scanning calorimetry (DSC) measurements indicated that TGB slightly
enhanced the thermal stability of these proteins. The isothermal titration calorimetry (ITC) results demonstrated moderate binding between TGB and HSA/BSA, as
conrmed by uorescence analysis. Furthermore, thermodynamic parameters suggested that hydrophobicity plays a signicant role in TGB-protein complex formation. Competitive binding experiments with classic uorescence probes revealed
shared binding sites between TGB and dansulfosarcosine on HSA and BSA.Spectral
analysis indicated no signicant conformational changes in HSA and BSA upon
interaction with TGB.Overall, these ndings offer valuable insights into the mechanism of the interaction of TGB with serum albumin, aiding its utilization in the
biomedical eld [809].
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2.2 New Antiseizure Medications under Study
2.2.1 Cannabidiol
2.2.1.1 Drug Characteristics
[Chemical name] (−)-trans-2-p-mentha-1,8-dien-3-yl-5-pentylresorcinol
(−)-trans-Cannabidiol,2-(6-Isopropenyl-3-methyl-2-cyclohexen-1-yl)-5pentyl- 1,3-benzenediol
[Chemical formula]
[Molecular formula] C21H30O
2
[Molecular weight] 314.462
[Indications] Seizures associated with Lennox–Gastaut syndrome (LGS), Dravet
syndrome (DS), or tuberous sclerosis (TSC) in patients 1year of age and older.
[Packing specications] 100mg/mL.
[Usage and dosage] In patients with LGS or DS,the starting dose is 2.5mg/kg
orally twice daily (5mg/kg/day); after 1week, the dose can be increased to 5mg/kg,
and nally to a maintenance dose of 10mg/kg/day twice a day; patients who need to
further reduce seizures may benet from increasing the dose to the recommended
maximum maintenance dose of 10mg/kg twice daily (20mg/kg/day) if a dose of
5mg/kg/dose is tolerated, or from increasing the dose 2.5mg/kg weekly twice daily
if tolerated. For those patients who require rapid titration from 10 to 20mg/kg/day,
the dose should be increased at least every other day. The use of a dose of 20mg/kg/
day reduced the rate of seizures to some extent compared with the recommended
maintenance dose of 10mg/kg/day, but there was an increase in adverse reactions.
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In patients with TSC, the starting dose is 2.5mg/kg orally twice daily (5mg/kg/
day); to increase to 2.5mg/kg twice a day (5mg/kg/day) per week; if tolerated, it is
recommended to increase to the maintenance dose of 12.5 mg/kg twice daily
(25mg/kg/day). For patients requiring a more rapid increase to 25mg/kg/day, the
dose should be increased at least every other day.
[Adverse effects] Common adverse effects include liver injury, drowsiness and
sedation, suicidal behavior and thoughts, and hypersensitivity reactions. Elevated
serum transaminase levels usually occur in the rst 2months of treatment and are
related to drug dosage, especially in patients taking valproate concomitantly. Liver
injury can be relieved after discontinuation. Patients with elevated levels of transaminases exceeding three times the ULN and bilirubin exceeding two times the
ULN should discontinue medication. Cannabidiol can cause drowsiness and sedation, which are more common in the early stages of treatment and may weaken with
continued treatment. The hypersensitivity reactions caused by cannabidiol can manifest as itching, erythema, and vascular edema, which can be treated with corticosteroids and antihistamines.
2.2.1.2 Clinical andPreclinical Research
Cannabidiol (CBD), the main chemical component in cannabis, acts as an antiseizure agent through a complex network of signals. Epidiolex was approved as a
CBD-rich drug for the treatment of Dravet syndrome (DS) and Lennox–Gastaut
syndrome (LGS) in children by the FDA in 2018. In 2020, the drug was approved
by the FDA for the treatment of epilepsy associated with tuberous sclerosis (TSC).
In the UK, New Zealand and Israel, standardized medical cannabis has been
approved for clinical use, bringing new hope for the treatment of refractory epilepsy.
Cannabidiol forDravet Syndrome andLennox–Gastaut Syndrome
An ongoing expanded access program of cannabidiol in treatment-resistant Dravet
syndrome and Lennox–Gastaut syndrome was conducted in Italy [810], in which 82
patients in 30 centers with at least 3months of treatment were included in the effectiveness analysis. They found that at 3months of follow-up, compared to the baseline, the percentage of patients with at least a 50% reduction in seizure frequency
was 40.2% (plus 1.2% seizure-free).
Boudewijn Gunning etal. [538] analyzed four randomized, controlled phase 3
trials, including a total of 396 patients with LGS (49% on clobazam) and 318
patients with DS (64% on clobazam). Patients received plant-derived, highly puried CBD medicine (Epidiolex
®
in the USA; Epidyolex® in Europe; 100mg/mL oral
solution) at a dose of 10 or 20mg/kg/day, or placebo for 14weeks. CBD treatment
resulted in a reduction in primary seizure frequency vs. placebo in the overall population and in patients receiving clobazam. The antiseizure efcacy of CBD was also
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demonstrated across other endpoints vs. placebo (≥50% response rate, total seizure
frequency, number of seizure-free days) in the overall populations and in patients
receiving clobazam.There were higher incidences of somnolence and sedation in
patients taking CBD and clobazam. Most incidences of elevated transaminase levels
occurred in patients taking concomitant valproate and, to a lesser extent, clobazam.
This study indicates that add-on CBD was effective in reducing seizures in the overall population and in conjunction with clobazam.
To estimate the time to onset of CBD treatment effects in patients with Dravet
syndrome (DS), Jennifer Madan Cohen etal. [811] conducted a post hoc analysis
of two randomized controlled trials, GWPCARE1 and GWPCARE2. Patients
received highly puried CBD (Epidiolex in the United States; 100mg/mL oral
solution) 10 mg/kg/day (CBD10; GWPCARE2) or 20 mg/kg/day (CBD20;
GWPCARE 1 & 2), or matching placebo for 14 weeks. Treatment started at
2.5mg/kg/day, reached 10mg/kg/day on day 7, and went up to 20mg/kg/day on
day 11 during the 14-day titration period. Overall, 124 patients received placebo
and 194 received CBD (CBD10, n=64; CBD20, n=130). Differences in convulsive seizure reduction rates between placebo and CBD emerged during titration
and became signicant by day 12 for CBD20 and day 13 for CBD10. Additionally,
differences in the 50% responder rate between placebo and CBD became apparent
during titration.
Onset of the rst reported AE occurred during the titration period in 48.4% of
placebo patients and 54.1% of CBD patients. The three most common AEs, somnolence, decreased appetite, and diarrhea, resolved within 4weeks of onset in the
majority of CBD-treated patients. The therapeutic effect of CBD for DS may start
within 2weeks of treatment in some patients. Although AEs lasted longer for CBD
than placebo, most resolved within the 14-week study period.
Cannabidiol’s Effects onTuberous Sclerosis-Related Epilepsy andOther
Epilepsy Syndromes
To evaluate efcacy and safety of 25mg/kg/day (CBD25) and 50 mg/kg/day
(CBD50) cannabidiol dosages vs. placebo against seizures associated with TSC,
Elizabeth A Thiele [812] conducted a double-blinded, placebo-controlled randomized clinical trial. Eligible patients were those with a clinical diagnosis of
TSC and medication-resistant epilepsy. Of the 224 included patients, 75 were
randomized to CBD25, 73 to CBD50, and 76 to placebo, with 201 completing
treatment. The percentage reduction from baseline in the type of seizures considered the primary endpoint was 48.6% for the CBD25 group, 47.5% for the CBD50
group, and 26.5% for the placebo group; the percentage reduction from placebo
was 30.1% for the CBD25 group and 28.5% for the CBD50 group. The most common adverse events were diarrhea and somnolence, which occurred more frequently with cannabidiol use than that of placebo. Twenty-eight patients taking
cannabidiol (18.9%) had elevated liver transaminase levels vs. none taking
placebo.
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It was revealed that cannabidiol signicantly reduced the number of TSCassociated seizures compared with placebo. The 25mg/kg/day dosage had a better
safety prole than the 50mg/kg/day dosage.
In the subsequent open-label extension experiments [813], median treatment
time was 267 days at a 27 mg/kg/day mean modal dose. Most patients had an
adverse event (AE). Most common AEs were diarrhea, seizure, and decreased appetite. AEs led to permanent discontinuation in 6% of patients. Median percentage
reductions in seizure frequency (12-week windows across 48weeks) were 54–68%.
Seizure responder rates (≥50%, ≥75%, 100% reduction) were 53–61%, 29–45%,
and 6–11% across 12-week windows for 48weeks. Improvement on the S/CGIC
scale was reported by 87% of patients/caregivers at 26weeks. In patients with TSC,
long-term add-on CBD treatment was well-tolerated and sustainably reduced seizures through 48weeks, with most patients/caregivers reporting global improvement.
A retrospective analysis [814] found that CBD takes effect within 6–10days of
treatment. The most common adverse reactions being were diarrhea, decreased
appetite, and drowsiness, which disappeared after 16weeks of treatment.
Simona Lattanzi etal. [815] conducted a systematic review aimed to summarize
the effects of pharmaceutical-grade CBD in patients with epileptic conditions, especially developmental and epileptic encephalopathies other than Dravet syndrome
and Lennox–Gastaut syndrome. It included 42 studies through database and trial
registry searches. CBD was found to be equally effective in treating other epileptic
syndromes in children and adults, including CDKL5 deciency disorder and
Aicardi, Dup15q, and Doose syndromes, SYNGAP1 encephalopathy, and epilepsy
with myoclonic absences. It is suggested that a highly puried, plant-derived CBD
oil-based solution is effective in the treatment of a broad range of epilepsy disorders
and etiologies, which provides preliminary support for additional research.
Application ofCannabidiol inRefractory Epilepsy
Tyler E Gaston etal. [816] conducted a 2-year follow-up of 169 participants (89
children and 80 adults) treated with highly puried CBD in order to evaluate the
safety, efcacy, and tolerability of CBD for the treatment of seizures in children and
adults with medication-resistant epilepsy. The results revealed a signicant mean
reduction in seizure frequency compared to baseline in children and adults at all
time points (1month, 1 and 2years). Percentage of children achieving 50% seizure
frequency reduction was 44% at month 1, 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. Chalfont Seizure Severity Scores (CSSSs) showed a sustained reduction from
baseline to all three time points. Children displayed a 52% seizure reduction at
month 1, a 51% reduction at year 1, and a 75% reduction at year 2. Seizure reductions in adults were 60%, 81%, and 85% at these time points, respectively (all
P<0.0001). While there were no signicant differences in seizure frequency reduction between children and adults at all time points, there was a signicant difference
in seizure severity reduction at year 1, with adults reporting greater improvement in
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seizure severity (P< 0.001). The most commonly reported adverse events in the
study were diarrhea, sedation, and decreased appetite.
A study by Sandip Patel etal. [817] also conrmed the long-term efcacy of CBD
in the treatment of refractory epilepsy. By following 54 patients with refractory epilepsy for up to 60months (median 45.5months), they found that CBD maintained its
efcacy for controlling seizures from Year 1 to the most recent study visit. The percentage of seizure responders remained similar at these time points (41.7–42.6%), and
the seizure response rate was also maintained. Efcacy was also seen over a broad
dose range, and at doses up to 50mg/kg/day. CBD was particularly effective for controlling seizures in the setting of tuberous sclerosis complex and for reducing epileptic
spasms and absence seizures. CBD was generally well- tolerated, with drowsiness and
diarrhea as the primary adverse reactions. This study demonstrates that CBD does not
lose its efcacy in controlling seizures over a treatment period of up to 60months and
is an effective, safe, and well-tolerated ASM for long-term use.
However, in an observational study of medical marijuana as a treatment for
medication- resistant epilepsies, 29 subjects with medication-resistant epilepsies
were treated with medical marijuana for ≥24weeks and no signicant differences
in convulsive seizure frequency, seizure duration, postictal duration, or use of rescue medications compared to baseline were found. However, the doses of CBD used
in this study were lower than those in prior studies. Randomized trials with larger
cohorts are needed [818].
Cannabidiol oil (CBD) has been approved as an antiseizure medication for the
treatment of uncommon types of epilepsy occurring in children: Dravet syndrome,
Lennox–Gastaut syndrome, and Tuberous Sclerosis Complex. There are few publications related to the use of CBD in adult patients with focal drug-resistant epilepsy.
The objective of this study was to evaluate the efcacy, tolerability, safety, and
changes in quality of life of adjuvant treatment with CBD for at least 6months in
adult patients with drug-resistant focal epilepsy. From a total of 44 patients, 5% of
patients were seizure-free, 32% of patients reduced their seizure numbers by more
than 80%, and 87% of patients reduced their monthly seizure numbers by 50%.
Eleven percent presented a decrease of less than 50% in seizure frequency. The
average nal dose was 335mg/day, orally administered. Thirty-four percent of
patients reported mild adverse events and no patients reported severe adverse
effects. At the end of the study, most patients had a signicant improvement in the
quality of life in all the items evaluated. Adjuvant treatment with CBD in adult
patients with drug-resistant focal epilepsy was effective, safe, well-tolerated, and
associated with a signicant improvement in their quality of life [819].
Camilo Espinosa-Jovel etal. [820] evaluated the efcacy and safety of CBD for
the treatment of drug resistant epilepsy of different etiologies in patients >2years of
age in a multicenter retrospective study. Seventy-eight patients with a median age of
24 years and a wide spectrum of mainly structural and genetic etiologies were
included. Patients were using a median of three antiseizure drugs and had a median
of 30 monthly seizures before starting CBD.The median treatment time with CBD
was 14months. The efcacy analysis at the last available visit showed that mean
percent reduction in seizures, ≥50% reduction in seizure frequency and seizure
freedom were achieved in 67.8%, 68.8% and 11.5% of patients, respectively. They
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found no signicant impact of concomitant clobazam use on the efcacy and safety
of CBD.In the safety analysis, 28.2% (n=22) of patients presented adverse events
related to CBD and the drug-retention rate was 78.2%. Based on these ndings,
highly puried CBD should be considered as an adjuvant therapy for drug resistant
epilepsy, regardless of its underlying cause or specic syndrome. Nevertheless, this
assumption should be validated through further controlled trials.
Cannabidiol Effects onEEG andCognitive Behavior inPatients
withRefractory Epilepsy
To assess the longitudinal impact of CBD on the electroencephalogram (EEG) of
children and adults, Leslie Grayson etal. [821] evaluated EEG changes before starting CBD, after approximately 12weeks of CBD (FU1), and after approximately
1year of CBD therapy (FU2). They found that at FU1, the adult group showed
signicant decrease in interictal discharge (IED)/minute, while a nonsignicant
decrease was observed among children. The difference in changes over time
between participant groups was signicant after adjusting for last CBD dose. At
FU2, both groups showed signicant reductions from baseline after controlling for
last CBD dose. There was no signicant correlation between changes in seizure
frequency and EEG IED frequency at each timepoint. This longitudinal EEG study
shows that highly puried plant-derived CBD has positive effects on interictal epileptiform discharge frequency but no effects on other EEG measures (background
frequency, focal slowing, reactivity, frequency of ictal discharges).
Aline Herlopian etal. [822] analyzed the EEG changes of 52 patients treated
with CBD and found that 88.4% of patients had EEG changes. Eighty-nine percent
of these patients had changes in their backgrounds, 74% in IEDs, and 46% in ictal
ndings. At the post-CBD EEG, 83% had a reduction in the frequency of the most
predominant seizure type, and 25% reported subjective cognitive improvement. Of
these patients, 88% and 92% had corresponding EEG changes, respectively. The
study revealed electrographic changes in association with the CBD treatment.
Despite these changes, a substantial association between specic electrographic
ndings and clinical outcomes was not established.
Metternich B, et al. [823] conducted neuropsychological tests on 39 patients
with treatment-resistant epilepsy at baseline (T0) and after 3months of CBD treatment (T1) to determine the cognitive and behavioral effects of CBD on children and
adults. No signicant cognitive decline was observed in any of the included measures. There was a signicant improvement on a measure of selective attention and
on a caregiver-rated behavioral measure in patients treated with CBD.
The Role ofCannabidiol inEpilepsy inChildren
A retrospective cohort study [824] including 78 patients treated with off-label cannabidiol in Denmark was performed. In 51 patients with seizure frequency registration,
31.4% had ≥50% seizure reduction at 3months of treatment, 31.1% at 6months,