1) A review of studies on cannabidiol (CBD) therapy for seizures in tuberous sclerosis complex (TSC) found limited evidence. Open-label studies showed CBD reduced seizure frequency over 1-5 years.
2) A randomized controlled trial of 224 patients found CBD reduced seizure frequency by 48-47% compared to 26% for placebo over 16 weeks. Around 36-40% of CBD patients had at least a 50% reduction in seizures.
3) More research is still needed to understand predictors of response, optimal use in treatment algorithms, interactions with other antiseizure drugs, and effects on cognitive/behavioral issues in TSC.
Identifying Significant Antipsychotic-Related Side Effects in Patients on a Community Psychiatric Rehabilitation Unit-A Feasibility Study of The Glasgow Antipsychotic Side-Effect Scale (GASS) by Ahmed Saeed Yahya* in crimson publishers: Journal of Physical Medicine and Rehabilitation
Antipsychotic side-effects are common and are an important determinant of non-adherence and consequent relapse. Most rating scales for the identification of these are lengthy and complicated. This report reviews the medical literature on the Glasgow antipsychotic side-effect scale (GASS)-a brief and validated rating scale to measure the unwanted effects of antipsychotics. We administered the GASS to fourteen in-patients in a United Kingdom-based Community Psychiatric Rehabilitation Unit. The objective was to establish the utility of the GASS in this setting and to make recommendations on how this tool could be used in clinical practice to improve adherence to antipsychotic medication.
https://crimsonpublishers.com/epmr/fulltext/EPMR.000529.php
For more Open access journals in Crimson Publishers
Please click on: https://crimsonpublishers.com/
For more articles in Examines in Physical Medicine & Rehabilitation
Please click on: https://crimsonpublishers.com/epmr/
Cardiac Enzyme Responses among Marijuana Smokersasclepiuspdfs
Aim: This study was carried out to determine the activity of aspartate aminotransferase (AST) and creatine kinase (CK) in marijuana smokers. Materials and Methods: Twenty confirmed marijuana smokers and 20 apparently non-smokers (control) between the ages of 20 and 40 years were selected for this study. The level of AST and CK were carried out by standard methods. Results: The level of AST (44.49 ± 5.18IU/L) in marijuana smokers was significantly increased when compared with the control (28.28 ± 6.12IU/L) (P ˂ 0.05). Furthermore, the level of CK (295.84 ± 6.58 IU/L) in marijuana smokers was significantly increased when compared with the control (110.03 ± 11.80 IU/L) (P ˂ 0.05)). Conclusion: The results obtained probably indicate that marijuana smokers are more likely to develop a cardiac problem. Hence, smoking of marijuana is not beneficial to health as it may be linked with myocardial infarction.
Effect of Transcranial Direct Current Stimulation (Tdcs) on the Consumption o...semualkaira
Migraine is a disorder that has a pulsating, unilateral character, which worsens with physical exertion and hinders the quality of life of people who suffer from it. Even though
there are several comorbidities related to the disease, pain control
is the main objective and neuromodulation can be used in patients
who have some drug intolerance or capacity for non-pharmacological management.
Effect of Transcranial Direct Current Stimulation (Tdcs) on the Consumption o...semualkaira
Migraine is a disorder that has a pulsating, unilateral character, which worsens with physical exertion and hinders the quality of life of people who suffer from it. Even though
there are several comorbidities related to the disease, pain control
is the main objective and neuromodulation can be used in patients
who have some drug intolerance or capacity for non-pharmacological management.
This study compared outcomes of patients with MDR/XDR Acinetobactor baumannii pneumonia treated with tigecycline or colistin. 70 patients received either tigecycline (n=30) or colistin (n=40). There were no significant differences in clinical outcomes between the two groups except nephrotoxicity, which only occurred in the colistin group. While the study indicates comparable efficacy, limitations include its small size, retrospective design, and exclusions. Further large randomized studies are still needed to properly evaluate tigecycline and optimal treatment combinations for MDR infections.
Report Back from San Antonio Breast Cancer Symposium (SABCS 2022)bkling
Curious about the latest developments in Early-Stage Breast Cancer and Metastatic Breast Cancer Research? Join us as Dr. Anne Blaes, the Division Director of Hematology/Oncology/Transplantation and Professor in Hematology/Oncology at the University of Minnesota, breaks down the most recent developments released at the annual San Antonio Breast Cancer Symposium regarding early-stage and metastatic breast cancer research.
Deutetrabenazine, a drug for Tardive DyskinesiaIlkin Bakirli
This randomized controlled trial evaluated the efficacy and safety of deutetrabenazine for treating tardive dyskinesia. 117 patients were randomized to receive either deutetrabenazine or placebo for 12 weeks. Deutetrabenazine significantly reduced abnormal involuntary movements as measured by the AIMS scale compared to placebo. While treatment success rates on clinical scales slightly favored deutetrabenazine, the results were not statistically significant. Deutetrabenazine was well tolerated and allowed continued use of other psychiatric medications. The study provides Class I evidence that deutetrabenazine may be an effective and well-tolerated treatment for tardive dyskinesia.
Identifying Significant Antipsychotic-Related Side Effects in Patients on a Community Psychiatric Rehabilitation Unit-A Feasibility Study of The Glasgow Antipsychotic Side-Effect Scale (GASS) by Ahmed Saeed Yahya* in crimson publishers: Journal of Physical Medicine and Rehabilitation
Antipsychotic side-effects are common and are an important determinant of non-adherence and consequent relapse. Most rating scales for the identification of these are lengthy and complicated. This report reviews the medical literature on the Glasgow antipsychotic side-effect scale (GASS)-a brief and validated rating scale to measure the unwanted effects of antipsychotics. We administered the GASS to fourteen in-patients in a United Kingdom-based Community Psychiatric Rehabilitation Unit. The objective was to establish the utility of the GASS in this setting and to make recommendations on how this tool could be used in clinical practice to improve adherence to antipsychotic medication.
https://crimsonpublishers.com/epmr/fulltext/EPMR.000529.php
For more Open access journals in Crimson Publishers
Please click on: https://crimsonpublishers.com/
For more articles in Examines in Physical Medicine & Rehabilitation
Please click on: https://crimsonpublishers.com/epmr/
Cardiac Enzyme Responses among Marijuana Smokersasclepiuspdfs
Aim: This study was carried out to determine the activity of aspartate aminotransferase (AST) and creatine kinase (CK) in marijuana smokers. Materials and Methods: Twenty confirmed marijuana smokers and 20 apparently non-smokers (control) between the ages of 20 and 40 years were selected for this study. The level of AST and CK were carried out by standard methods. Results: The level of AST (44.49 ± 5.18IU/L) in marijuana smokers was significantly increased when compared with the control (28.28 ± 6.12IU/L) (P ˂ 0.05). Furthermore, the level of CK (295.84 ± 6.58 IU/L) in marijuana smokers was significantly increased when compared with the control (110.03 ± 11.80 IU/L) (P ˂ 0.05)). Conclusion: The results obtained probably indicate that marijuana smokers are more likely to develop a cardiac problem. Hence, smoking of marijuana is not beneficial to health as it may be linked with myocardial infarction.
Effect of Transcranial Direct Current Stimulation (Tdcs) on the Consumption o...semualkaira
Migraine is a disorder that has a pulsating, unilateral character, which worsens with physical exertion and hinders the quality of life of people who suffer from it. Even though
there are several comorbidities related to the disease, pain control
is the main objective and neuromodulation can be used in patients
who have some drug intolerance or capacity for non-pharmacological management.
Effect of Transcranial Direct Current Stimulation (Tdcs) on the Consumption o...semualkaira
Migraine is a disorder that has a pulsating, unilateral character, which worsens with physical exertion and hinders the quality of life of people who suffer from it. Even though
there are several comorbidities related to the disease, pain control
is the main objective and neuromodulation can be used in patients
who have some drug intolerance or capacity for non-pharmacological management.
This study compared outcomes of patients with MDR/XDR Acinetobactor baumannii pneumonia treated with tigecycline or colistin. 70 patients received either tigecycline (n=30) or colistin (n=40). There were no significant differences in clinical outcomes between the two groups except nephrotoxicity, which only occurred in the colistin group. While the study indicates comparable efficacy, limitations include its small size, retrospective design, and exclusions. Further large randomized studies are still needed to properly evaluate tigecycline and optimal treatment combinations for MDR infections.
Report Back from San Antonio Breast Cancer Symposium (SABCS 2022)bkling
Curious about the latest developments in Early-Stage Breast Cancer and Metastatic Breast Cancer Research? Join us as Dr. Anne Blaes, the Division Director of Hematology/Oncology/Transplantation and Professor in Hematology/Oncology at the University of Minnesota, breaks down the most recent developments released at the annual San Antonio Breast Cancer Symposium regarding early-stage and metastatic breast cancer research.
Deutetrabenazine, a drug for Tardive DyskinesiaIlkin Bakirli
This randomized controlled trial evaluated the efficacy and safety of deutetrabenazine for treating tardive dyskinesia. 117 patients were randomized to receive either deutetrabenazine or placebo for 12 weeks. Deutetrabenazine significantly reduced abnormal involuntary movements as measured by the AIMS scale compared to placebo. While treatment success rates on clinical scales slightly favored deutetrabenazine, the results were not statistically significant. Deutetrabenazine was well tolerated and allowed continued use of other psychiatric medications. The study provides Class I evidence that deutetrabenazine may be an effective and well-tolerated treatment for tardive dyskinesia.
Report Back from 2023 San Antonio Breast Cancer Symposium (SABCS)bkling
Curious about the latest information released about Early-Stage Breast Cancer at the annual San Antonio Breast Cancer Symposium? To help explain it all, we are thrilled to have Dr. Sherry Shen, medical oncologist and clinical investigator on the Breast Medicine Service at Memorial Sloan Kettering Cancer Center (MSK), as our presenter. Join us to hear about the different sessions and data that were presented at SABCS.
Hairy Cell Leukemia (HCL) is a rare subtype of B-cell chronic lymphoid leukemia which was first described by Bertha Bouroncle in 1958 [1]. The annual incidence of HCL is approximately 0.3 cases per 100,000 and the disease comprises 2-3% of all leukaemia?s in the Western world [2,3]...
This document summarizes recent advances in therapies for hairy cell leukemia (HCL). It discusses how purine nucleoside analogs like cladribine and pentostatin were previously the standard first-line treatment for HCL, achieving high response rates. However, many patients eventually relapse. The document then describes several promising new targeted therapies that are being studied for relapsed/refractory HCL, including the immunotoxin moxetumomab pasudotox, BRAF inhibitors like vemurafenib, and the BTK inhibitor ibrutinib. Ongoing clinical trials are evaluating these novel agents to determine their efficacy and safety in treating HCL.
Hairy Cell Leukemia (HCL) is a rare subtype of B-cell chronic lymphoid leukemia which was first described by Bertha Bouroncle in 1958 [1]. The annual incidence of HCL is approximately 0.3 cases per 100,000 and the disease comprises 2-3% of all leukaemia?s in the Western world [2,3]...
Hairy Cell Leukemia (HCL) is a rare subtype of B-cell chronic lymphoid leukemia which was first described by Bertha Bouroncle in 1958 [1]. The annual incidence of HCL is approximately 0.3 cases per 100,000 and the disease comprises 2-3% of all leukaemia?s in the Western world [2,3]...
Hairy Cell Leukemia (HCL) is a rare subtype of B-cell chronic lymphoid leukemia which was first described by Bertha Bouroncle in 1958 [1]. The annual incidence of HCL is approximately 0.3 cases per 100,000 and the disease comprises 2-3% of all leukaemia?s in the Western world
Hairy Cell Leukemia (HCL) is a rare subtype of B-cell chronic lymphoid leukemia which was first described by Bertha Bouroncle in 1958 [1]. The annual incidence of HCL is approximately 0.3 cases per 100,000 and the disease comprises 2-3% of all leukaemia?s in the Western world
Peptide Drug Conjugates (PDCs) Novel Targeted Therapeutics For Cancer.pdfDoriaFang
Peptide-drug conjugates (PDCs) are the next generation of targeted therapies after ADCs. PDCs has been developed as targeted therapeutic candidates for cancer, COVID-19, metabolic diseases, etc.
This randomized, double-blind, placebo-controlled crossover clinical trial studied the effects of coenzyme Q10 supplementation on oxidative stress and antioxidant enzyme activity in glazers occupationally exposed to cadmium. 40 male glazers were randomly assigned to receive either coenzyme Q10 (60 mg twice daily) or placebo for 2 months, with a 1-month washout period in between. The study measured markers of oxidative stress and antioxidant enzyme activity at baseline and after each treatment period. The results showed that coenzyme Q10 supplementation significantly reduced oxidative stress markers and improved antioxidant enzyme activity compared to placebo.
This document discusses the potential for genetic biomarkers to improve psychiatric treatment by predicting treatment response. It notes that while causes of psychiatric disorders are unclear, identifying genetic factors can help select the best treatments. Several studies are exploring candidate genes for conditions like depression. Ultimately, genetic testing may guide antidepressant selection in clinical practice, though social and ethical issues require consideration. Biomarkers could enhance psychiatry similarly to other fields by enabling personalized treatment.
This document discusses the potential for using genetic biomarkers to improve treatment for psychiatric disorders. It notes that while the causes of psychiatric disorders are still unclear, identifying genetic markers that predict treatment response could help tailor medication selection. The document outlines several studies that have identified candidate genes associated with response to antidepressants and other psychotropic drugs. It acknowledges limitations but argues that further research in pharmacogenetics, using larger, more standardized studies, could help incorporate genetic testing into clinical practice to select safer, more effective treatments for individual patients.
This document summarizes medication use patterns in the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort. It finds that 85% of ADNI patients took 4 or more daily medications (polypharmacy), and 22% took medications from Beer's list of potentially inappropriate drugs for elderly patients. Memantine treatment was associated with more severe Alzheimer's disease, while cholinesterase inhibitors were prescribed without difference by disease severity. Treatment also differed by gender, age, and education level in both mild cognitive impairment (MCI) and Alzheimer's disease (AD) groups.
Survival Outcomes Associated With 177lu-Dotatate Therapy in Advanced Stage Ge...semualkaira
Peptide receptor radionuclide therapy in gastroenteropancreatic neuroendocrine tumors (GEP-NETs) has been used
in the past two decades with a considerable prevalence of literature. However, due to the inherently indolent nature of GEP-NETs
it is critical to evaluate the patients for a longer duration to assess the sustainability of treatment, survival patterns, and observe
for late-side effects from treatment. The purpose of this study is
to give an overview of an 11-year experience from a single centre on 177Lu-DOTATATE peptide receptor radionuclide therapy
(177Lu-PRRT) in advanced stage GEP-NETs
Treatment resistant schizophrenia is defined as lack of satisfactory improvement despite trials of two antipsychotics for adequate duration and dose. Around 20-30% of schizophrenia patients are considered treatment resistant. Clozapine is currently the treatment of choice for such patients, though combination and augmentation strategies with other agents have limited evidence. Definitive treatment guidelines recommend establishing treatment resistance before trials of clozapine or other strategies for treatment resistant schizophrenia.
CBD and taurine show potential synergistic effects against Alzheimer's disease based on in vitro and previous studies. The current study aims to identify the synergistic mechanism of CBD and taurine in an Alzheimer's mouse model. It involves treating mice with CBD, taurine, and their combination, and assessing effects on behavior, biomarkers, and neuropathology. Preliminary experiments will screen doses of scopolamine for inducing Alzheimer's-like impairment and doses of CBD for effects on locomotion. Subsequent experiments will evaluate CBD and taurine treatments on scopolamine-induced impairment in the Y-maze and NOR tests.
This document provides an overview of multi-target drugs (MTDs) or designed multi-target ligands (DMLs) as a potential approach for treating Alzheimer's disease (AD). AD has a complex pathophysiology involving multiple factors. While previous drug candidates have targeted single factors, MTDs/DMLs aim to target multiple relevant factors simultaneously through a single compound in order to achieve synergistic effects. The document discusses advantages and limitations of the MTD/DML approach for AD treatment and provides recommendations for rational design of effective MTDs/DMLs, including consideration of physicochemical properties, pharmacokinetics, toxicity, and the blood-brain barrier. To date, clinical trials of MTDs
Treat to target in inflammatory diseases SMMI 2018SMMI2015
In conclusion, treat to target is a new paradigm that involves regular disease assessment, therapy adaptation, and consideration of patient factors. Integration into daily
Report Back from 2023 San Antonio Breast Cancer Symposium (SABCS)bkling
Curious about the latest information released about Early-Stage Breast Cancer at the annual San Antonio Breast Cancer Symposium? To help explain it all, we are thrilled to have Dr. Sherry Shen, medical oncologist and clinical investigator on the Breast Medicine Service at Memorial Sloan Kettering Cancer Center (MSK), as our presenter. Join us to hear about the different sessions and data that were presented at SABCS.
Hairy Cell Leukemia (HCL) is a rare subtype of B-cell chronic lymphoid leukemia which was first described by Bertha Bouroncle in 1958 [1]. The annual incidence of HCL is approximately 0.3 cases per 100,000 and the disease comprises 2-3% of all leukaemia?s in the Western world [2,3]...
This document summarizes recent advances in therapies for hairy cell leukemia (HCL). It discusses how purine nucleoside analogs like cladribine and pentostatin were previously the standard first-line treatment for HCL, achieving high response rates. However, many patients eventually relapse. The document then describes several promising new targeted therapies that are being studied for relapsed/refractory HCL, including the immunotoxin moxetumomab pasudotox, BRAF inhibitors like vemurafenib, and the BTK inhibitor ibrutinib. Ongoing clinical trials are evaluating these novel agents to determine their efficacy and safety in treating HCL.
Hairy Cell Leukemia (HCL) is a rare subtype of B-cell chronic lymphoid leukemia which was first described by Bertha Bouroncle in 1958 [1]. The annual incidence of HCL is approximately 0.3 cases per 100,000 and the disease comprises 2-3% of all leukaemia?s in the Western world [2,3]...
Hairy Cell Leukemia (HCL) is a rare subtype of B-cell chronic lymphoid leukemia which was first described by Bertha Bouroncle in 1958 [1]. The annual incidence of HCL is approximately 0.3 cases per 100,000 and the disease comprises 2-3% of all leukaemia?s in the Western world [2,3]...
Hairy Cell Leukemia (HCL) is a rare subtype of B-cell chronic lymphoid leukemia which was first described by Bertha Bouroncle in 1958 [1]. The annual incidence of HCL is approximately 0.3 cases per 100,000 and the disease comprises 2-3% of all leukaemia?s in the Western world
Hairy Cell Leukemia (HCL) is a rare subtype of B-cell chronic lymphoid leukemia which was first described by Bertha Bouroncle in 1958 [1]. The annual incidence of HCL is approximately 0.3 cases per 100,000 and the disease comprises 2-3% of all leukaemia?s in the Western world
Peptide Drug Conjugates (PDCs) Novel Targeted Therapeutics For Cancer.pdfDoriaFang
Peptide-drug conjugates (PDCs) are the next generation of targeted therapies after ADCs. PDCs has been developed as targeted therapeutic candidates for cancer, COVID-19, metabolic diseases, etc.
This randomized, double-blind, placebo-controlled crossover clinical trial studied the effects of coenzyme Q10 supplementation on oxidative stress and antioxidant enzyme activity in glazers occupationally exposed to cadmium. 40 male glazers were randomly assigned to receive either coenzyme Q10 (60 mg twice daily) or placebo for 2 months, with a 1-month washout period in between. The study measured markers of oxidative stress and antioxidant enzyme activity at baseline and after each treatment period. The results showed that coenzyme Q10 supplementation significantly reduced oxidative stress markers and improved antioxidant enzyme activity compared to placebo.
This document discusses the potential for genetic biomarkers to improve psychiatric treatment by predicting treatment response. It notes that while causes of psychiatric disorders are unclear, identifying genetic factors can help select the best treatments. Several studies are exploring candidate genes for conditions like depression. Ultimately, genetic testing may guide antidepressant selection in clinical practice, though social and ethical issues require consideration. Biomarkers could enhance psychiatry similarly to other fields by enabling personalized treatment.
This document discusses the potential for using genetic biomarkers to improve treatment for psychiatric disorders. It notes that while the causes of psychiatric disorders are still unclear, identifying genetic markers that predict treatment response could help tailor medication selection. The document outlines several studies that have identified candidate genes associated with response to antidepressants and other psychotropic drugs. It acknowledges limitations but argues that further research in pharmacogenetics, using larger, more standardized studies, could help incorporate genetic testing into clinical practice to select safer, more effective treatments for individual patients.
This document summarizes medication use patterns in the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort. It finds that 85% of ADNI patients took 4 or more daily medications (polypharmacy), and 22% took medications from Beer's list of potentially inappropriate drugs for elderly patients. Memantine treatment was associated with more severe Alzheimer's disease, while cholinesterase inhibitors were prescribed without difference by disease severity. Treatment also differed by gender, age, and education level in both mild cognitive impairment (MCI) and Alzheimer's disease (AD) groups.
Survival Outcomes Associated With 177lu-Dotatate Therapy in Advanced Stage Ge...semualkaira
Peptide receptor radionuclide therapy in gastroenteropancreatic neuroendocrine tumors (GEP-NETs) has been used
in the past two decades with a considerable prevalence of literature. However, due to the inherently indolent nature of GEP-NETs
it is critical to evaluate the patients for a longer duration to assess the sustainability of treatment, survival patterns, and observe
for late-side effects from treatment. The purpose of this study is
to give an overview of an 11-year experience from a single centre on 177Lu-DOTATATE peptide receptor radionuclide therapy
(177Lu-PRRT) in advanced stage GEP-NETs
Treatment resistant schizophrenia is defined as lack of satisfactory improvement despite trials of two antipsychotics for adequate duration and dose. Around 20-30% of schizophrenia patients are considered treatment resistant. Clozapine is currently the treatment of choice for such patients, though combination and augmentation strategies with other agents have limited evidence. Definitive treatment guidelines recommend establishing treatment resistance before trials of clozapine or other strategies for treatment resistant schizophrenia.
CBD and taurine show potential synergistic effects against Alzheimer's disease based on in vitro and previous studies. The current study aims to identify the synergistic mechanism of CBD and taurine in an Alzheimer's mouse model. It involves treating mice with CBD, taurine, and their combination, and assessing effects on behavior, biomarkers, and neuropathology. Preliminary experiments will screen doses of scopolamine for inducing Alzheimer's-like impairment and doses of CBD for effects on locomotion. Subsequent experiments will evaluate CBD and taurine treatments on scopolamine-induced impairment in the Y-maze and NOR tests.
This document provides an overview of multi-target drugs (MTDs) or designed multi-target ligands (DMLs) as a potential approach for treating Alzheimer's disease (AD). AD has a complex pathophysiology involving multiple factors. While previous drug candidates have targeted single factors, MTDs/DMLs aim to target multiple relevant factors simultaneously through a single compound in order to achieve synergistic effects. The document discusses advantages and limitations of the MTD/DML approach for AD treatment and provides recommendations for rational design of effective MTDs/DMLs, including consideration of physicochemical properties, pharmacokinetics, toxicity, and the blood-brain barrier. To date, clinical trials of MTDs
Treat to target in inflammatory diseases SMMI 2018SMMI2015
In conclusion, treat to target is a new paradigm that involves regular disease assessment, therapy adaptation, and consideration of patient factors. Integration into daily
Similar to A scoping review on cannabidiol therapy in tuberous sclerosis.pdf (20)
Muktapishti is a traditional Ayurvedic preparation made from Shoditha Mukta (Purified Pearl), is believed to help regulate thyroid function and reduce symptoms of hyperthyroidism due to its cooling and balancing properties. Clinical evidence on its efficacy remains limited, necessitating further research to validate its therapeutic benefits.
Adhd Medication Shortage Uk - trinexpharmacy.comreignlana06
The UK is currently facing a Adhd Medication Shortage Uk, which has left many patients and their families grappling with uncertainty and frustration. ADHD, or Attention Deficit Hyperactivity Disorder, is a chronic condition that requires consistent medication to manage effectively. This shortage has highlighted the critical role these medications play in the daily lives of those affected by ADHD. Contact : +1 (747) 209 – 3649 E-mail : sales@trinexpharmacy.com
Integrating Ayurveda into Parkinson’s Management: A Holistic ApproachAyurveda ForAll
Explore the benefits of combining Ayurveda with conventional Parkinson's treatments. Learn how a holistic approach can manage symptoms, enhance well-being, and balance body energies. Discover the steps to safely integrate Ayurvedic practices into your Parkinson’s care plan, including expert guidance on diet, herbal remedies, and lifestyle modifications.
Recomendações da OMS sobre cuidados maternos e neonatais para uma experiência pós-natal positiva.
Em consonância com os ODS – Objetivos do Desenvolvimento Sustentável e a Estratégia Global para a Saúde das Mulheres, Crianças e Adolescentes, e aplicando uma abordagem baseada nos direitos humanos, os esforços de cuidados pós-natais devem expandir-se para além da cobertura e da simples sobrevivência, de modo a incluir cuidados de qualidade.
Estas diretrizes visam melhorar a qualidade dos cuidados pós-natais essenciais e de rotina prestados às mulheres e aos recém-nascidos, com o objetivo final de melhorar a saúde e o bem-estar materno e neonatal.
Uma “experiência pós-natal positiva” é um resultado importante para todas as mulheres que dão à luz e para os seus recém-nascidos, estabelecendo as bases para a melhoria da saúde e do bem-estar a curto e longo prazo. Uma experiência pós-natal positiva é definida como aquela em que as mulheres, pessoas que gestam, os recém-nascidos, os casais, os pais, os cuidadores e as famílias recebem informação consistente, garantia e apoio de profissionais de saúde motivados; e onde um sistema de saúde flexível e com recursos reconheça as necessidades das mulheres e dos bebês e respeite o seu contexto cultural.
Estas diretrizes consolidadas apresentam algumas recomendações novas e já bem fundamentadas sobre cuidados pós-natais de rotina para mulheres e neonatos que recebem cuidados no pós-parto em unidades de saúde ou na comunidade, independentemente dos recursos disponíveis.
É fornecido um conjunto abrangente de recomendações para cuidados durante o período puerperal, com ênfase nos cuidados essenciais que todas as mulheres e recém-nascidos devem receber, e com a devida atenção à qualidade dos cuidados; isto é, a entrega e a experiência do cuidado recebido. Estas diretrizes atualizam e ampliam as recomendações da OMS de 2014 sobre cuidados pós-natais da mãe e do recém-nascido e complementam as atuais diretrizes da OMS sobre a gestão de complicações pós-natais.
O estabelecimento da amamentação e o manejo das principais intercorrências é contemplada.
Recomendamos muito.
Vamos discutir essas recomendações no nosso curso de pós-graduação em Aleitamento no Instituto Ciclos.
Esta publicação só está disponível em inglês até o momento.
Prof. Marcus Renato de Carvalho
www.agostodourado.com
Rasamanikya is a excellent preparation in the field of Rasashastra, it is used in various Kushtha Roga, Shwasa, Vicharchika, Bhagandara, Vatarakta, and Phiranga Roga. In this article Preparation& Comparative analytical profile for both Formulationon i.e Rasamanikya prepared by Kushmanda swarasa & Churnodhaka Shodita Haratala. The study aims to provide insights into the comparative efficacy and analytical aspects of these formulations for enhanced therapeutic outcomes.
ABDOMINAL TRAUMA in pediatrics part one.drhasanrajab
Abdominal trauma in pediatrics refers to injuries or damage to the abdominal organs in children. It can occur due to various causes such as falls, motor vehicle accidents, sports-related injuries, and physical abuse. Children are more vulnerable to abdominal trauma due to their unique anatomical and physiological characteristics. Signs and symptoms include abdominal pain, tenderness, distension, vomiting, and signs of shock. Diagnosis involves physical examination, imaging studies, and laboratory tests. Management depends on the severity and may involve conservative treatment or surgical intervention. Prevention is crucial in reducing the incidence of abdominal trauma in children.
These simplified slides by Dr. Sidra Arshad present an overview of the non-respiratory functions of the respiratory tract.
Learning objectives:
1. Enlist the non-respiratory functions of the respiratory tract
2. Briefly explain how these functions are carried out
3. Discuss the significance of dead space
4. Differentiate between minute ventilation and alveolar ventilation
5. Describe the cough and sneeze reflexes
Study Resources:
1. Chapter 39, Guyton and Hall Textbook of Medical Physiology, 14th edition
2. Chapter 34, Ganong’s Review of Medical Physiology, 26th edition
3. Chapter 17, Human Physiology by Lauralee Sherwood, 9th edition
4. Non-respiratory functions of the lungs https://academic.oup.com/bjaed/article/13/3/98/278874
TEST BANK For Community Health Nursing A Canadian Perspective, 5th Edition by...Donc Test
TEST BANK For Community Health Nursing A Canadian Perspective, 5th Edition by Stamler, Verified Chapters 1 - 33, Complete Newest Version Community Health Nursing A Canadian Perspective, 5th Edition by Stamler, Verified Chapters 1 - 33, Complete Newest Version Community Health Nursing A Canadian Perspective, 5th Edition by Stamler Community Health Nursing A Canadian Perspective, 5th Edition TEST BANK by Stamler Test Bank For Community Health Nursing A Canadian Perspective, 5th Edition Pdf Chapters Download Test Bank For Community Health Nursing A Canadian Perspective, 5th Edition Pdf Download Stuvia Test Bank For Community Health Nursing A Canadian Perspective, 5th Edition Study Guide Test Bank For Community Health Nursing A Canadian Perspective, 5th Edition Ebook Download Stuvia Test Bank For Community Health Nursing A Canadian Perspective, 5th Edition Questions and Answers Quizlet Test Bank For Community Health Nursing A Canadian Perspective, 5th Edition Studocu Test Bank For Community Health Nursing A Canadian Perspective, 5th Edition Quizlet Test Bank For Community Health Nursing A Canadian Perspective, 5th Edition Stuvia Community Health Nursing A Canadian Perspective, 5th Edition Pdf Chapters Download Community Health Nursing A Canadian Perspective, 5th Edition Pdf Download Course Hero Community Health Nursing A Canadian Perspective, 5th Edition Answers Quizlet Community Health Nursing A Canadian Perspective, 5th Edition Ebook Download Course hero Community Health Nursing A Canadian Perspective, 5th Edition Questions and Answers Community Health Nursing A Canadian Perspective, 5th Edition Studocu Community Health Nursing A Canadian Perspective, 5th Edition Quizlet Community Health Nursing A Canadian Perspective, 5th Edition Stuvia Community Health Nursing A Canadian Perspective, 5th Edition Test Bank Pdf Chapters Download Community Health Nursing A Canadian Perspective, 5th Edition Test Bank Pdf Download Stuvia Community Health Nursing A Canadian Perspective, 5th Edition Test Bank Study Guide Questions and Answers Community Health Nursing A Canadian Perspective, 5th Edition Test Bank Ebook Download Stuvia Community Health Nursing A Canadian Perspective, 5th Edition Test Bank Questions Quizlet Community Health Nursing A Canadian Perspective, 5th Edition Test Bank Studocu Community Health Nursing A Canadian Perspective, 5th Edition Test Bank Quizlet Community Health Nursing A Canadian Perspective, 5th Edition Test Bank Stuvia
micro teaching on communication m.sc nursing.pdfAnurag Sharma
Microteaching is a unique model of practice teaching. It is a viable instrument for the. desired change in the teaching behavior or the behavior potential which, in specified types of real. classroom situations, tends to facilitate the achievement of specified types of objectives.
A scoping review on cannabidiol therapy in tuberous sclerosis.pdf
1. Review
A scoping review on cannabidiol therapy in tuberous sclerosis: Current
evidence and perspectives for future development
Debopam Samanta ⇑
Child Neurology Section, Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR, United States
a r t i c l e i n f o
Article history:
Received 10 December 2021
Revised 6 January 2022
Accepted 14 January 2022
Available online 9 February 2022
Keywords:
Cannabis
CBD
Epilepsy
mTOR
Vigabatrin
a b s t r a c t
Cannabidiol (CBD) has recently been approved as an add-on therapy by various regulatory agencies for
tuberous sclerosis complex (TSC)-associated seizures based on its short-term efficacy and safety in a piv-
otal randomized controlled trial. However, critical information about which patients with TSC and seizure
types respond best to CBD (clinical, electrophysiological, and genetic predictors of responsiveness), when
to use CBD in the treatment algorithm, and how CBD can be combined with other antiseizure medications
(ASMs) in the form of a rational polypharmacy therapy is still lacking. In general, there is a limited in-
depth critical review of CBD for the treatment of TSC to facilitate its optimal use in a clinical context.
Here, we utilized a scoping review approach to report the current evidence of efficacy and safety of
pharmaceutical-grade CBD in patients with TSC, including relevant mechanism of action and drug–drug
interactions with other ASMs. We also discussed emerging information about CBD’s long-term efficacy
and safety data in patients with TSC. Finally, we discussed some critical unanswered questions in several
domains related to effective clinical management of TSC using CBD, including barriers to early and
aggressive treatment in infants, difficulty with universal access to CBD, a lack of studies to understand
CBD’s impact on seizure severity and specific seizure types, insufficient exploration of CBD in TSC-
related cognitive and behavioral issues, and the need for more research into CBD’s effects on various
biomarkers.
Ó 2022 Elsevier Inc. All rights reserved.
1. Introduction
Tuberous sclerosis complex (TSC) is an autosomal dominant
neurocutaneous disorder due to pathogenic variants in TSC1
orTSC2 genes with secondary hyperactivation of the mechanistic
target of rapamycin (mTOR) pathway and development of hamar-
tomas in the brain and other parts of the body [1]. Epilepsy is
another key feature of TSC and is present in 85–90% of patients
[2]. Unfortunately, approximately 65% of patients with TSC with
epilepsy have treatment-refractory epilepsy (TRE), about double
compared to the general population with epilepsy [3,4]. In addi-
tion, most patients develop epilepsy in the first two years of life,
which is associated with a higher risk of intellectual disability
and autism, further highlighting the importance of potential pre-
vention of epilepsy, evidence-based early treatment, and search
for better, safer treatment options for epilepsy [5].
Despite the utilization of cannabis for the treatment of epilepsy
since antiquity, only over the last decade, focused research in
cannabis-based therapies has gained momentum [6–9]. Highly
purified cannabidiol (CBD) formulation, the principal nonpsy-
choactive constituent of the Cannabis sativa plant, had been used
in clinical trials to mitigate the concern related to inconsistency
of the unregulated crude CBD extracts (artisanal CBD) [10]. Follow-
ing 4 phase III, randomized controlled trials (RCTs) of CBD in the
treatment of Lennox–Gastaut (LGS) and Dravet syndromes (DS), a
pharmaceutical-grade product (EpidiolexÒ
/ EpidyolexÒ
) was
approved by the US Food and Drug Administration (FDA) in 2018
and by the European Medicines Agency (EMA) in 2019 for the
treatment of seizures associated with patients with DS and LGS
aged 2 years [7,9–11]. In 2020, based on another RCT in TSC, this
formulation has also been approved for treating seizures associ-
ated with TSC in patients one year of age and older by the FDA
and in 2 years old by the EMA [14]. Although clinical evidence
about CBD treatment in patients with DS and LGS has been exten-
sively reviewed, there is a limited in-depth critical appraisal of CBD
for treatment of TSC that may facilitate the optimal clinical use and
foster future research of CBD for this indication. Here, we summa-
rized the currently available body of knowledge about the use of
pharmaceutical-grade CBD in patients with TSC, including relevant
mechanism of action, efficacy and safety data, relevant drug–drug
interactions with other antiseizure medications (ASMs), and finally
https://doi.org/10.1016/j.yebeh.2022.108577
1525-5050/Ó 2022 Elsevier Inc. All rights reserved.
⇑ Address: 1 Children’s Way, Little Rock, AR 72202, United States.
E-mail address: dsamanta@uams.edu
Epilepsy Behavior 128 (2022) 108577
Contents lists available at ScienceDirect
Epilepsy Behavior
journal homepage: www.elsevier.com/locate/yebeh
2. offered some suggestions for future development and research to
understand the role of CBD in the patients with TSC.
2. Methods
Based on our research question of the role of CBD treatment in
patients with TSC, we identified relevant articles by searching
PubMed, Google Scholar, and ClinicalTrials.gov. Additional studies
were identified by searching bibliographies of included studies
and other relevant review articles. The first search was done on
July 18, 2021, and the last on November 16, 2021. We imple-
mented several inclusion and exclusion criteria to identify relevant
papers (Table 1). We found two primary types of studies: open-
label studies from the expanded access programs (12 months
follow-up, 5-year follow-up, efficacy and safety of CBD therapy
with or without clobazam, the efficacy of CBD against epileptic
spasms) and one pivotal RCT (16 weeks efficacy and safety, efficacy
in patients with or without a history of spasms, and multiple
interim analysis of open-label extension) [14–23]. Many of these
studies are still available in abstract form only [15,20–22]. Addi-
tional two studies were identified from the ClinicalTrials.gov.
One study evaluates the safety, pharmacokinetics, and exploratory
efficacy of CBD in infants with TSC (NCT04485104), and the other
study evaluates CBD’s long-term potential of chronic liver injury
(NCT05044819). One unrelated case series explored laboratory
and adverse effects of concomitant CBD and mTOR inhibitor ther-
apy [24]. We did not find any study that specifically assessed CBD’s
impact on TSC-associated cognitive and behavioral issues (includ-
ing symptoms associated with autism) despite these symptoms
being the greatest concern to families. Similarly, CBD’s effect is
yet to be explored as a preventive therapy or mediator to various
epilepsy biomarkers in TSC.
2.1. Mechanism of action
The antiseizure mechanism of action of CBD is unresolved but
likely independent of its action on the endocannabinoid system
[24,25]. Several antiseizure mechanisms have been hypothesized,
with few identified as most relevant [26–31]. (Table 2) Specifically
for antiseizure action in TSC, facilitation of gamma-aminobutyric
acid (GABA)ergic neurotransmission and activation of mTOR intra-
cellular protein pathway may be most suitable for further investi-
gation. Gobira et al. showed an anticonvulsant effect of CBD in
cocaine-induced seizure-model in mice, which they suggested
mediated by mTOR activation as the anticonvulsant effect subsided
following pre-treatment of the mTOR inhibitor rapamycin [32].
Similarly, Gugliandolo et al. demonstrated protective effects of
CBD following activation of ERK and AKT/mTOR pathways in an
Table 1
Search Strategies.
Factors Inclusion criteria Exclusion criteria
Population Patients with TSC(2 patients with TSC if it is a part of a heterogeneous cohort and specific
outcome was known for patients with TSC)
Healthy volunteers or patients without diagnosis of
TSC
Intervention Pharmaceutical grade CBD Artisanal CBD
Outcomes CBD’s efficacy against seizures (short-and long-term), cognitive and behavioral issues, and
autism-related symptoms. Short-and long-term safety data
Outcomes for patients with TSC were not able to be
isolated from the general outcomes.
Publication
types
Published manuscripts (randomized clinical trial, non-randomized retrospective or prospective
studies), meeting abstracts, ongoing clinical trials (only to assess future prospect)
Single-case case report
No date filter was applied Non-English articles
TSC: Tuberous Sclerosis Complex.
CBD: Cannabidiol.
Table 2
Most relevant mechanisms for cannabidiol’s antiseizure and neuroprotective activity.
Pharmacological action Potential mechanism
Antagonism of G protein-coupled receptor 55 (GPR55) Activation of GPR55 triggers a sequence of events resulting in intracellular Ca2+
release from intracellular
stores, and consequent modulation of neurotransmitter release and neuronal excitability. As a GPR55
antagonist, CBD restores inhibitory neurotransmission in the hippocampal dentate gyrus and reduces
GPR55-mediated increase of miniature excitatory postsynaptic current frequency in the hippocampus.
Desensitization of transient receptor potential vanilloid
type 1 (TRPV1) channels
TRPV1 channels are widely expressed in the brain and modulate intracellular Ca2+
concentration. CBD acts
as an agonist of TRPV1 and subsequently causes rapid desensitization.
Potent inhibition of the equilibrative nucleoside
transporter (ENT1)
In the brain, adenosine is considered to act as an endogenous anticonvulsant and seizure terminator. CBD
causes concentration-dependent inhibition of adenosine uptake and elevation of extracellular adenosine
concentration by inhibiting ENT1.
Potentiation of c-amino-butyric acid (GABA)
transmission,
CBD is a positive allosteric modulator at GABAA receptors
Inhibition of nitric oxide production and inducible nitric
oxide synthase protein expression
Modulation of the oxidative stress as nitric oxide-synthesized in response to inflammatory stimuli
Inverse agonist effects at the cannabinoid receptor CB2 Reduction of neuroinflammation by preventing migration of immune cells and, therefore, reducing
numbers of reactive astrocytes and activated microglia
Increase hippocampal mRNA expression of brain-derived
neurotrophic factor (BDNF)
BDNF promotes neurogenesis and is critical for learning and memory
Action on serotonin receptor 5-HT1A Specific mechanism not known but may have mood modulating effects, the activation of 5HT1 receptors in
the hippocampus causes an increase in neurotransmission; in contrast, in raphe nuclei, activation of 5-
HT1A receptors produces the inhibition of serotonergic neurons
Increases synaptic levels of noradrenaline Specific mechanism not known but may have mood modulating effects
D. Samanta Epilepsy Behavior 128 (2022) 108577
2
3. in-vitro cell model [33]. Serra et al. also showed that CBD selec-
tively modulates levels of phosphorylated rpS6 and suppresses
mTOR activity in the tsc2 / zebrafish larval brain [34]. In addi-
tion to the overactivation of mTOR, epileptogenesis in TSC might
be caused by a decreased number of GABA receptors in dysplastic
neurons of cortical tubers, causing reduced inhibition. CBD’s
increasing GABAergic activity may compensate for this reduced
inhibition. Several additional mechanisms (neuroprotective and
anti-inflammatory effects, and serotonergic and dopaminergic
activities) of CBD have been postulated that may mitigate cognitive
and behavioral challenges. However, further animal and human
data are needed to fully understand CBD’s effects on neuropsychi-
atric functions.
2.2. Clinical efficacy (Table 3)
Clinical efficacy of 99% pure CBD extract in DRE with TSC was
first reported in 2016 from an open-label, expanded-access pro-
gram (EAP) in 18 patients [18]. In that study, weekly median sei-
zure frequency decreased by half after three months of
treatment, and 38.9–50% of patients had 50% seizure reduction
throughout the treatment course over one year. Better efficacy
was noted in patients receiving concurrent clobazam. Although
the frequency of every seizure type was reduced and many
patients experienced seizure freedom from one or more of their
seizure types, complete seizure freedom from all seizure types
was not noted (2 patients had 90% and four patients had 80% sei-
zure reduction). Among seizure types, epileptic spasms responded
very well to CBD. The doses of CBD and concomitant ASMs were
inconsistent between patients and across time in this uncontrolled
study.
Subsequently, a double-blind, placebo-controlled randomized
clinical trial (GWPCARE6) was conducted in 2016–2019 at 46 sites
from the United States and Europe [14]. Total 224 patients with
TSC with TRE (aged 1–65 years) were randomized to CBD [25 mg/
kg/day (CBD25) or 50 mg/kg/day (CBD50)] or a matched placebo
for 16 weeks. During four weeks of the baseline period, these
patients had 8 TSC-associated seizures (absence, myoclonic, focal
sensory seizures, and infantile/epileptic spasms were excluded).
Compared to 4 prior phase III trials of CBD in the treatment of
LGS and DS, this trial included patients younger than two years
old and used a higher dosage of CBD with an accelerated titration.
Patients in the CBD25 and 50 groups had 48.6% and 47.5% reduc-
tion of seizures, respectively, compared to a 26.5% reduction in
the placebo group during the treatment period. Additionally, 36%
and 40% of CBD25 and CBD50 patients had 50% seizure reduction
during the treatment period compared to 22% in the placebo group.
Approximately 17% in the CBD groups had 75% reduction in sei-
zures than none in the placebo group. However, seizure freedom
was rare (only six patients were seizure-free during the mainte-
nance period), similar to what was observed in the previous
expanded access study. A post hoc analysis showed that the onset
of clinical efficacy occurred within the first two weeks, with differ-
ences in seizure reduction between CBD and placebo emerging on
Day 6 (when titration reached 15 mg/kg/d) [35]. It became nomi-
nally significant (p 0.05) by Day 11–12. Further evidence toward
an independent antiseizure effect of CBD has emerged from this
RCT as only 27% of the 224 patients enrolled in this trial received
clobazam comedication compared to 4 previous RCTs in DS and
LGS (47%–68% of patients allocated to CBD treatment in these trials
were receiving clobazam) [6,7,12–14]. Despite concerns associated
with post hoc subgroup analysis, a positive treatment effect was
evident in the subgroup of patients treated without concomitant
clobazam in this trial [14]. Another post hoc analysis showed that
CBD reduced TSC-associated seizures regardless of the previous
history of infantile spasms [21].
Despite Class I evidence of CBD’s efficacy against TSC-associated
seizures over a short period (weeks to months), clinicians have fur-
ther interest in knowing if this efficacy extends beyond such a
‘‘honeymoon period.” Of the 18 patients with TSC enrolled in the
Massachusetts General Hospital’s open-label EAP, 13 had analyz-
able follow-up data to appraise efficacy after year 1 (for a treat-
ment period of up to 60 months; median = 45.5 months) [23].
Effectiveness of CBD showed improvement over time with ten
patients (76.9%) having 50% reduction in total seizure frequency
compared to five (38.5%) patients at year 1, including four subjects
(30.8%) with 90% reduction compared to 2 patients (15.4%) at
year 1. Most participants were able to reduce the dose of at least
one concurrent ASM, but were unable to completely wean off.
Another open-label study from the EAP at 35 US epilepsy centers
reported sustained long-term efficacy (through 192 weeks) of
CBD in 34 patients with TSC, with similar responder rates for all
seizure types [20]. Median percentage reduction in seizure fre-
quency during the first 48 weeks ranged from 48–55% for convul-
sive, 61–75% for focal, and 44–56% for total seizures. After
completing the RCT, 199 of 201 patients entered the open-label
extension phase. Long-term analysis showed that seizure-
reduction was maintained through 48 weeks, with median per-
centage reductions in seizure frequency (12-week windows over
48 weeks) being 54–68% [15]. Seizure responder rates (50%,
75%, and 100% reduction) were maintained up to 48 weeks, rang-
ing from 53–61%, 29–45%, and 6–11% across 12-week visit win-
dows. The second interim analysis through 72 weeks
demonstrated median 53%–75% seizure reductions [22]. Seizure
responder rates at 50%, 75%, and 100% were maintained, rang-
ing from 52%–63%, 29%–51%, and 6%–19%, respectively, across
12-week windows.
Due to the high incidence of epileptic spasms associated with
TSC, particular interest has been to evaluate CBD’s efficacy against
spasms [36]. Some individuals with TSC suffer infantile spasms
that last until later childhood, have a recurrence of infantile
spasms at a later age after an initial remission, or develop de novo
spasms beyond the age of two. Specific criteria for determining the
clinical efficacy of epileptic spasms occurring in older children and
adults have not been defined, in contrast to a two-week response
rate of complete remission of spasms and hypsarrhythmia in
infants. Gradual reduction of spasms in older children and adults
may occur with CBD therapy; one open-label study showed all
patients had 50% reduction in spasms.[23] Herlopian et al. also
evaluated the efficacy of CBD in 9 patients (3 patients with TSC:
3–13 years of age with spasm onset at 4–16 months of age) with
refractory epileptic spasms [17]. Progressive reduction of spasm
frequency was noted in all three patients, and all of them were
spasm free at one year. Additionally, two patients, who had EEG
studies, also had resolution of hypsarrhythmia. Despite excellent
response against spasms over a longer period, acute efficacy in
younger patients with or without TSC diagnosis is unsatisfactory.
In a phase 2, multi-center clinical trial (NCT02551731) 9 children
with intractable infantile spasms (6 months to 36 months) were
treated with 20 mg/kg/day or 40 mg/kg/day of CBD. No patients
had complete resolution of spasms and hypsarrhythmia in
2 weeks. The two-week response rate was similarly poor in
another refractory infantile spasm study (median age = 23 months
and median spasm duration of 6 months and median six prior
treatment failures) using synthetic pharmaceutical grade CBD, in
which only 1 out of 9 patients (one patient with TSC who did not
show response) had clinical and electrographic response [37].
TSC is associated with a wide range of cognitive-behavioral (ag-
gressive behaviors, autism spectrum disorder (ASD), and psychi-
atric manifestations, collectively known as TSC-Associated
Neuropsychiatric Disorders (TAND). Approximately 50% of patients
with TSC have a cognitive impairment, and 50% of patients with
D. Samanta Epilepsy Behavior 128 (2022) 108577
3
4. Table 3
Cannabidiol in the treatment of TSC-associated seizures.
Study AAN Classification of Evidence
and
N Study length Efficacy Safety Cognitive, behavioral, and subjective
changes
Design
Thiele, 2021 Class I 224 patients
randomized; 75 to
CBD25, 73 to CBD50,
and 76 to placebo,
with 201 completing
treatment
16 weeks Seizure* reduction from baseline:
48.6% (95% CI, 40.4–55.8%) for the
CBD25 group, 47.5% (95% CI, 39.0–
54.8%) for the CBD50 group, and
26.5% (95% CI, 14.9–36.5%) for the
placebo group; the percentage
reduction from placebo was 30.1%
(95% CI, 13.9–43.3%; P 0.001) for
the CBD25 group and 28.5% (95% CI,
11.9–42.0%; nominal P = 0.002) for
the CBD50 group. 50% seizure
responders: 27 of 75 patients (36%) in
the CBD25 group, 29 of 73 patients
(40%) in the CBD50 group, and 17 of
76 patients (22%) in the placebo
group. 25 patients (16.9%) taking CBD
had at least a 75% reduction in
seizures, vs none taking placebo. 4
patients in the CBD25 group, 2 in the
CBD50 group, and none in the
placebo group were seizure free
during the maintenance period.
The most common adverse events
were diarrhea (placebo group, 19
[25%]; CBD25 group, 23 [31%]; CBD50
group, 41 [56%]) and somnolence
(placebo group, 7 [9%]; CBD25 group,
10 [13%]; CBD50 group, 19 [26%]).
Eight patients in CBD25 group, 10 in
CBD50 group, and 2 in the placebo
group discontinued treatment
because of adverse events. Twenty-
eight patients taking CBD (18.9%) had
elevated liver transaminase.
48 of 70 patients (69%) in the CBD25
group, 43 of 69 patients (62%) in the
CBD50 group, and 30 of 76 patients
(39%) in the placebo group reported
improvement from baseline in
overall condition, according to the
participants’ or caregivers’ global
impression of change.
RCT(GWPCARE6)
Hess, 2016 Class IV 18 12 months Median weekly seizure frequency
decreased from 22.0 to 13.3 in
3 months with a change in total
weekly seizure frequency of 48.8%.
The 50% responder rates over the
course of the study were 50%, 50%,
38.9%, 50%, and 50% after 2, 3, 6, 9,
and 12 months of treatment. In
patients taking clobazam
concurrently with CBD (n = 12), the
responder rate after 3 months of
treatment was 58.3%, compared to
33.3% in patients not taking clobazam
(n = 6). 75% and 100% responder rate
in 4 patients with refractory epileptic
spasms after 3 and 6 months of
treatment, respectively
Twelve (66.7%) of 18 patients
experienced adverse events; the most
common adverse events were
drowsiness (n = 8, 44.4%), ataxia
(n = 5, 27.8%), and diarrhea (n = 4,
22.2%).
Parents of patients reported cognitive
gains in 85.7% of cases with baseline
global developmental delays and
behavioral improvements in 66.7% of
cases with baseline behavioral
problems. These improvements were
irrespective of seizure control.
EAP in patients with TSC-
associated TRE
Patel, 2021 Class IV TSC (n = 13; total
n = 54)
Up to 60 months
(median = 45.5 months)
10 subjects (76.9%) had a greater
than 50% reduction in overall seizure
frequency compared to baseline,
including four subjects (30.8%) with
greater than 90% reduction. This
represented an improvement from
the Year 1 follow-up visit data, when
five subjects (38.5%) had a greater
than 50% reduction in overall seizure
frequency compared to baseline,
including two subjects (15.4%) with
greater than 90% reduction. 80%. All
subjects with spasms (100%) and four
of five subjects with absence seizures
(80%) had 50% seizure reduction.
133 adverse reactions (related to the
study drug) were reported; none of
them severe: drowsiness (n = 44),
diarrhea (n = 22), ataxia (n = 15),
reversible elevated liver function
tests (LFTs) (n = 9; all patients also on
valproic acid), and irritability (n = 8),
fatigue (n = 4), loose stool (n = 3), and
appetite suppression (n = 3). 49
adverse reactions were deemed to be
related to an interaction between
CBD and clobazam, and CBD dose was
reduced in 15 patients
Retrospective review of EAP
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4
5. Table 3 (continued)
Study AAN Classification of Evidence
and
N Study length Efficacy Safety Cognitive, behavioral, and subjective
changes
Design
Savage, 2020 Class IV TSC (n = 17; total
n = 47)
12 months Mean reduction in weekly seizure
frequency was greater at the best
point of seizure control [58.5% (CLB-
On), 49.5% (CLB-Off)] within the first
year than at two months of treatment
[: 26.8% (CLB-On), 26.2% (CLB-Off)]
with CBD, regardless of concomitant
CLB usage. There was a significantly
greater responder rate for subjects
taking CBD and CLB than those taking
CBD without CLB only at the point of
best seizure control within the first
year of CBD treatment (p = 0.0240)
[Responder rate: 50.0% (CLB-On),
26.7% (CLB-Off) at M2; 71.9% (CLB-
On), 33.3% (CLB-Off) at the best point
of seizure control within the first
year. Seizure freedom: 3.1% (CLB-On),
0% (CLB Off) at M2; 6.3% (CLB-On), 0%
(CLB-Off) at the best point of seizure
control within the first year. (all
p 0.05).
Most common AEs: diarrhea,
somnolence, fatigue; increased
serum aminotransferases in patients
taking concomitant valproate.
Somnolence, ataxia, irritability, and
urinary retention were common in
the setting of concomitant CLB use
and typically resolved after dose
adjustments to either CLB or CBD.
Retrospective review of EAP to
evaluate the efficacy of CBD with
or without concomitant clobazam
treatment
Ebrahimi-
Fakhari,
2020
Class IV 25 patients with TSC
treated with CBD
and a mechanistic
target of rapamycin
inhibitor (18
everolimus and 7
sirolimus)
Laboratory and adverse
events were reviewed
before and after
initiation of CBD
Adverse events (diarrhea,
drowsiness, increased and severe
mouth sores, increased acne, ankle
swelling, sinusitis, abdominal pain,
mild elevation of transaminases;
none severe) occurred in 10 of 25
patients (40%). Median change from
baseline level was +9.8 ng/mL for
everolimus and +5.1 ng/mL for
sirolimus. No treatment
discontinuation was required.
Retrospective study
Herlopian,
2020.
Class IV TSC (n = 3; total
n = 9) with
refractory epileptic
spasms
12 months Reduction in epileptic spasm
frequency: 15.1–98.8% (week 2), 3.7–
94.2% (M1), 58.3–100% (M2),49.1–
100% (M3), 80.2–100% (M6), 85.8–
100% (M9), 100% (M12)
Drowsiness, ataxia, appetite loss,
agitation
One patient had marked
improvement in cognition, social and
language, and motor skills
Retrospective Resolution of hypsarrhythmia: 2/2
Geffrey, 2015 Class IV TSC (n = 2; total
n = 13) epilepsy
concomitantly
taking CLB and CBD
8 weeks Seizure frequency reduction: 58–93%
(week 8)
One with no side effects but the other
individual had irritability.
Norclobazam (nCLB), the active
metabolite of clobazam (CLB),
increased substantially in both
patients
EAP, investigational new drug
(IND) trial
(continued on next page)
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5
6. Table 3 (continued)
Study AAN Classification of Evidence
and
N Study length Efficacy Safety Cognitive, behavioral, and subjective
changes
Design
Thiele, 2020 Class IV 199 patients with
TSC
median treatment
time: 267 days (range,
18–910)
Median percentage reductions in
seizure frequency (12-week windows
over 48 weeks) were 54–68%. Seizure
responder rates (50%, 75%, and
100% reduction) were maintained up
to 48 weeks, ranging from 53–61%,
29–45%, and 6–11% across 12- week
visit windows.
AE incidence was 93%; serious AE
incidence: 15%; 6% discontinued due
to AEs. There was 1 death deemed
unrelated to treatment by the
investigator. Most common AEs
(20%): diarrhea (42%), seizure (22%),
decreased appetite (20%). Elevated
ALT/AST 3 ULN were reported in
17 (8.5%) patients; 12 were on
concomitant valproate.
Improvement in S/CGIC was reported
by 87% of patients/caregivers at week
26, with 53% reporting much/very
much improvement
An interim analysis of the OLE of
phase 3 randomized controlled
trial (RCT) GWPCARE6
Wheless,
2021
Class IV At this analysis of
199 patients with
TSC, 12% of patients
completed
treatment, 31% were
withdrawn, and 57%
were ongoing.
OLE median (range)
treatment time: 372
(18–1127) days
Median percentage reductions in
TSC-associated seizures (12-week
windows through 72 weeks): 53%–
75%. Seizure reductions were 54%–
80% for patients with a modal dose
25 mg/kg/day (n = 145). 50%,
75%, and 100% responder rates were
maintained up to 72 weeks, ranging
from 52%–63%, 29%–51%, and 6%–
19%, across 12-week windows.
AE incidence: 94%; serious AE
incidence: 26%; 8% discontinued due
to AE(s). Most common AEs: diarrhea
(45%), seizure (28%), decreased
appetite (23%), pyrexia (21%), and
vomiting (20%). ALT/AST 3 ULN
occurred in 17 (9%) patients; 12 on
concomitant valproate No patient
met Hy’s law criteria. There was 1
death due to cardiopulmonary
failure, deemed not treatment-
related by the investigator.
Improvement on S/CGIC was
reported by 85% and 89% of
subjects/caregivers at 26 and
52 weeks.
2nd interim analysis of an OLE
trial (GWPCARE6)
Weinstock,
2021
Class IV TSC (n = 34;
total = 892)
Long-term efficacy (up
to 192 weeks) and
safety (up to
233 weeks)
Median % reduction in seizure
frequency during the first 48 weeks
ranged from 48–55% for convulsive,
61–75% for focal, and 44–56% for
total seizures; and the overall pattern
of response was maintained through
192 weeks. Similarly, responder rates
(50%) were maintained through
192 weeks
AEs in 94% of patients and serious
AEs in 47%; no deaths; somnolence
(32%), diarrhea (29%), convulsion
(18%), and vomiting (18%). Liver-
related AEs occurred in 1 patient
(3%).
EAP from 35 US epilepsy centers
(January 2014 through January
2019)
Saneto, 2021 Class IV 138/224 (62%)
patients had IS
history.
16 weeks CBD reduced TSC-associated seizures
vs placebo regardless of IS history
(interaction p-value: 0.803 for
CBD25, 0.561 for CBD50). Percentage
reduction in seizures: for patients
with IS history: 45% for CBD25, 43%
for CBD50, and 23% for placebo; for
patients without IS history: 54% for
CBD25, 55% for CBD50, and 32% for
placebo.
AE incidence: 93% for CBD25, 100%
for CBD50, and 95% for placebo. 8
patients (11%) on CBD25, 10 (14%) on
CBD50, and 2 (3%) on placebo
discontinued treatment due to AE(s).
Most common AEs: diarrhea and
somnolence, occurring more
frequently with CBD than placebo.
ALT/AST elevations (3 ULN): 9
(12%) patients on CBD25, 19 (26%) on
CBD50, none on placebo; 79% were
on concomitant valproate.
Post hoc analysis of a phase 3
randomized controlled trial (RCT:
GWPCARE6)to compare response
to CBD in patients with TSC and
treatment-resistant epilepsy with
and without history of infantile
spasms.
TRE: Treatment-resistant epilepsy; EAP: Expanded access program; RCT Randomized Clinical Trial; TSC Tuberous sclerosis complex; CBD25: oral cannabidiol at 25 mg/kg/day; CBD50: oral cannabidiol at 50 mg/kg/day; OLE- Open-
label extension; M- Month; AE- Adverse event; S/CGIC Subject/caregiver global impression of change.
*TSC-associated seizures: countable focal motor seizures without impairment of awareness, focal seizures with impairment of awareness, focal seizures evolving to bilateral motor seizures, and generalized seizures (tonic-clonic,
tonic, clonic, or atonic). This study excluded absence, myoclonic, and focal sensory seizures and infantile/epileptic spasms in the primary outcome.
D.
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7. TSC have behavioral difficulties [38,39]. Many of these patients
require pharmacological management of psychiatric symptoms.
CBD’s role in the serotonergic/dopaminergic pathway leads to fur-
ther hope in mitigating cognitive and behavioral challenges
[40,41]. Hess et al. reported that 12 (85.7%) of 14 patients had
improved cognitive function (improved alertness, verbal commu-
nication, vocalizations, cognitive ability, and initiation of emo-
tional and physical connections), and in 6 (66.7%) patients had
behavioral improvements during treatment with CBD [18]. These
changes were independent of seizure control. However, in the piv-
otal RCT statistically significant treatment difference was not noted
in the Quality of Life (evaluated by QOLCE and QOLIE-31-P scores)
scores in CBD groups [14]. On the other hand, the Physician Global
Impression of Change scale showed a statistically significant differ-
ence in the CBD group compared to placebo.
2.3. Safety (Table 3)
From the first reported study by Hess et al., CBD demonstrated
excellent safety and tolerability profile; however, several mild-to-
moderate but primarily dose-dependent transient adverse effects
(AE; diarrhea, sedation, and decreased appetite) were observed
[18]. Notably, previous studies reported increased sedation and
the possibility of increased respiratory secretions in patients with
concomitant clobazam treatment [7]. In the TSC RCT, 29–53% of
patients had somnolence with clobazam therapy compared to 9–
17% without clobazam [14]. Additionally, 90% of patients with
TSC had adverse effects (AE), with onset during the first two weeks
of treatment in 2/3rd of the patients. However, AE resolved within
one month in 27% of patients and 51% within 16 weeks of treat-
ment. Most frequent AEs (diarrhea, sedation, decreased appetite)
were resolved in 69–88% of patients. Importantly, the RCT showed
transient liver enzyme elevation (noted in 18.9% of patients and
26% of patients with 50 mg/kg/d) as another potential significant
side effect; approximately 80% of patients received concomitant
valproate [14]. The enzyme elevation happened most frequently
within the first month of commencing therapy and resolved spon-
taneously, either after treatment withdrawal (apart from rash, the
enzyme elevation was one of the most prevalent reasons for CBD
termination) or by CBD/other ASM dose reduction. However, fortu-
nately, none of the patients met Hy’s law criteria (liver enzyme ele-
vation 3 upper limit of normal and total bilirubin 2 upper
limit of normal) of drug-induced liver injury [42]. Regarding
long-term safety, multiple interim analyses (median treatment
period of 267 days and 372 days) of the open-label extension phase
demonstrated a favorable safety profile [15,22].
In general, the safety profile of the 25 mg/kg/day dosage in the
pivotal TSC RCT was similar to the highest dosage (20 mg/kg/day)
used in prior trials; however, dosages 25 mg/kg/day were associ-
ated with higher incidences of adverse events with half of the
patients randomized to 50 mg/kg/day unable to reach or maintain
that dosage [14]. The FDA authorized CBD for TSC with the follow-
ing regimen based on the more negative effects in the CBD 50
group: Starting at 2.5 mg/kg twice daily, increase by 2.5 mg/kg
twice daily every other day to weekly intervals until reaching a
maximum maintenance dose of 12.5 mg/kg twice daily. On the
other hand, slow titration can increase tolerance while maintaining
efficacy [43].
2.4. Drug–drug interactions with antiseizure medications
As most patients with TSC are on ASM polytherapy, drug–drug
interactions between CBD and other ASMs are essential considera-
tions in clinical practice. CBD is a potent inhibitor of the cyto-
chrome (CYP) p450 oxidase system (CYP2C19, CYP2D6, CYP3A4,
and CYP2C9) with several significant interactions with other ASMs.
The most clinically relevant pharmacokinetic interaction is with
clobazam, which is metabolized by cytochrome P450 (CYP)3A4
and CYP2C19 to its active metabolite N-methylclobazam (N-CLB)
that then further metabolized by CYP2C19. Being a potent inhibitor
of CYP2C19, CBD significantly increases the N-CLB level with supra
additive efficacy and toxicity potential [44]. Additionally, clobazam
increases the active metabolite of CBD, 7-hydroxy-cannabidiol,
without a significant increase in CBD [45]. The bidirectional solid
drug–drug interactions and superior seizure outcomes in patients
with concomitant clobazam and CBD treatment raised some doubt
about the independent antiseizure effect of CBD [45,46]. Although
previous meta-analyses provided evidence that CBD does have
independent antiseizure effects, the EMA had previously restricted
approved indications to patients comedicated with clobazam [45].
CBD also increases trough levels of mTOR inhibitors (everolimus
and sirolimus) by 2–3 fold due to inhibition of metabolism by
CYP3A4 [24,47]. This may result in clinical toxicities. A clinically
non-significant increase in levels of rufinamide, topiramate, zon-
isamide, and eslicarbazepine has been seen with CBD treatment
[48,49]. In a few patients, increased brivaracetam blood concentra-
tion was noted with concomitant CBD with self-limiting side
effects [50]. On the other hand, level of several ASMs (valproate,
levetiracetam, phenobarbital, clonazepam, phenytoin, carba-
mazepine, lamotrigine, oxcarbazepine, ethosuximide, vigabatrin,
ezogabine, pregabalin, perampanel, and lacosamide) shows no sig-
nificant change with concurrent CBD thereapy [48]. In addition,
CBD is metabolized in the liver by cytochrome P450 enzymes,
and CBD bioavailability can be increased or decreased by exposure
to ASM with potent enzyme inhibitors or inducer properties,
respectively [10]. Lastly, although significant pharmacokinetic
interaction doesnot occur between valproate and CBD, liver
enzyme elevation occurs at a much higher rate for patients taking
concomitant VPA [14].
2.5. Knowledge gaps and future research
Despite the existence of Class I evidence of CBD’s short-term
efficacy and safety in TSC-related seizures, several obstacles
remain in the way of its optimal use. Some of these are due to a
lack of access, as pharmaceutical-grade CBD is not recommended
for use in infants, is expensive, and frequently requires insurance
authorization. Some of the barriers, however, are related to knowl-
edge gaps, such as which patients with TSC and seizure types
respond best to CBD (clinical, electrophysiological, and genetic pre-
dictors of responsiveness), when to use CBD in the treatment algo-
rithm, what are the cognitive and behavioral effects of CBD in
patients with TSC, what is the scope of presymptomatic CBD treat-
ment, and how CBD can be combined with other ASMs in the form
of a rational polypharmacy therapy. The following section covers
the major roadblocks as well as some potential future projects to
help overcome them (Table 4).
2.6. Early and aggressive treatment
Most infants with TSC will experience their first seizure before
age one year, and aggressive seizure control in infancy is associated
with better long-term neurological outcomes. However, most TSC-
specific approved ASMs are not specifically evaluated and
approved for focal seizures for infants with TSC: CBD has been
approved after age one year, and everolimus and vigabatrin after
age 2. Antiseizure medications (for example, levetiracetam)
approved for infants have low-quality evidence of efficacy against
TSC [51]. An ongoing trial evaluating the safety, pharmacokinetics,
and efficacy of CBD in infants with TSC may help fill that critical
gap.
D. Samanta Epilepsy Behavior 128 (2022) 108577
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8. In addition, the comparative effectiveness of CBD needs to be
evaluated to other potentially useful nonpharmacologic treat-
ments for TSC, particularly epilepsy surgery, which had been used
in less than 10% of patients but has a much higher seizure-
responder rate [52–54]. There is no consensus guideline to facili-
tate medication choice that might assist clinicians in choosing a
particular ASM in TSC based on age, seizure type, comedications,
and associated neuropsychiatric comorbidities. TSC-associated sei-
zures are typically treated with a variety of ASMs, often in combi-
nation [3,4,52,55]. Management and treatment decisions can be
challenging due to the multiple seizure types and comorbidities
associated with TSC. There are no large-scale direct comparison
studies between ASMs that promote evidence-based ASM selec-
tion. Indirect comparisons of various clinical trials on ASMs may
provide some helpful information but are confounded by diverse
trial designs and differences in patient populations and intractabil-
ity of seizures. A panel of European experts in 2012 recommended
vigabatrin as the first-line treatment for focal seizures before the
age of 1 year and ASMs enhancing GABAergic inhibition in patients
after the age of 1 [55]. Vigabatrin was the most commonly used
ASM with increasing use in recent times and a clear shift after
the 1990s in the TOSCA(TuberOus SClerosis registry to increase
disease Awareness) registry that reflects real-world treatment pat-
terns from 31 countries from Europe, Australia, Asia, Eurasia, and
Africa [56]. Although increasing use of vigabatrin improved the
outcome of infantile spasms, the outcome of focal seizure did not
change (56–64% response rate) since the 1960s despite the avail-
ability of multiple new ASMs, including mTOR inhibitor therapy
(17–18% of patients in the registry received this in later years)
[52]. Clinical studies of CBD in TSC so far suggested a low rate of
complete seizure freedom. Additionally, no particular clinical (his-
tory of spasms vs. not), neurophysiological, or genetic biomarkers
in TSC has been identified that might predict favorable treatment
response from CBD. In this scenario, a rational polypharmacy
approach may be evaluated to test combinations of two ASMs
(CBD with clobazam or everolimus) with a different mechanism
of action causing supra additive or synergistic antiseizure effect
[57,58]. Combination therapy is particularly relevant for CBD as
none of the pivotal trials had adequate power to detect differences
in seizure outcomes between subgroups on or off clobazam
comedication. Combination therapy using CBD and vigabatrin also
can be evaluated due to a lack of significant pharmacokinetic inter-
action, posing less risk of excessive toxicity. In contrast, combina-
tion treatment with valproate can be problematic due to the high
risk of liver enzyme elevation. Still, CBD’s effect on weight loss
(3–31%) and decreased appetite (16–31%) can mitigate valproate-
induced weight gain [14].
Further research is also needed regarding the combined effect of
CBD and the ketogenic diet, which by itself is a very potent treat-
ment option for TSC-associated seizures [59]. However, combina-
tion therapy using the ketogenic diet, CBD, and everolimus may
need greater vigilance of potential adverse effects, such as lipid ele-
vation and insulin resistance. Until the availability of high-quality
evidence for ASM selection, a critical starting point for personal-
ized treatment for TSC management can be international experts
and patient advocacy groups coming together and leveraging data
from the existing research studies to formulate a data-driven algo-
rithm for guiding selection among various ASMs, including CBD
[60].
2.7. Seizure response
Patients with TSC with intractable epilepsy are frequently
younger, on polytherapy, have high-frequency seizures, and have
associated intellectual impairment [4]. Therefore, they are at high
risk of paradoxical seizure worsening from ASMs [61]. Nineteen
to 23% of patients in the pivotal trial showed seizure worsening
in the CBD groups, but it is unclear which patients are at high risk.
Table 4
Optimizing the use of cannabidiol in patients with tuberous sclerosis complex.
Topic Barriers to optimum use Future Perspectives
Early and aggressive treatment CBD is approved in children 1-year-
old
An ongoing trial is evaluating the safety, pharmacokinetics, and efficacy of CBD in
infants with TSC
Lack of high-quality comparative effec-
tiveness data among existing ASMs
A systematic evidence review on interventions for infantile epilepsy
No consensus guideline to facilitate
medication choice
Evidence-based international clinical guideline to manage TSC-associated seizures
that might assist clinicians in choosing particular ASM in TSC, based on age, seizure
type, co-medications, and associated neuropsychiatric comorbidities
Indirect comparisons of various ASMs
from diverse clinical trials are
challenging
Rational polypharmacy (combination of CBD and clobazam, everolimus, or
vigabatrin)
Excessive toxicity with aggressive
therapy
Greater vigilance of potential adverse effects
Access The pharmaceutical-grade CBD is
expensive
Copay assistance
Step therapy (trying less expensive
treatment first)
Patient advocacy groups are working on policy issues
Delay related to insurance preapproval
Seizure response Reduction of seizure severity is
unknown
TSC specific studies to assess changes in seizure severity
Seizure-type specific response Controlled studies using video-EEG to evaluate efficacy against specific seizures,
particularly epileptic spasms and absence seizures
Seizure worsening effect
Cognitive and behavioral
effects of CBD in patients
with TSC
Effect on TAND (Tuberous sclerosis
associated neuropsychiatric disorders)
Clinical trials with standardized neurocognitive assessments to evaluate the cogni-
tive and behavioral impact
Specific effects on autism Clinical trials with specific tools to measure CBD’s impact on associated and core
symptoms of autism
Use of surrogate markers to evaluate acute effects of CBD therapy: electrophysiolog-
ical, functional neuroimaging markers, and molecular biomarkers
Presymptomatic treatment The effects of CBD on the interictal EEG Analysis safety, pharmacokinetics, and Efficacy in infants with TSC
D. Samanta Epilepsy Behavior 128 (2022) 108577
8
9. Although it might be challenging to differentiate seizure worsening
from the natural fluctuation of seizure occurrence, further investi-
gation is necessary to explore if CBD may preferentially worsen any
particular seizure type in TSC.
Despite CBD’s potential broad effectiveness against a wide vari-
ety of seizures, differential efficacy toward different seizure types
(focal vs. generalized) needs further exploration as the pivotal
RCT included both focal and generalized seizures(more patients
had focal seizures as these are the predominant seizure type in
TSC) [14]. However, CBD demonstrated effectiveness in reducing
generalized interictal epileptiform discharges in an absence seizure
rat model [62]. Open-label clinical studies also suggested CBD’s
preferential effect on generalized seizures, such as epileptic
spasms and absence seizures (80–100% seizure responder rates).
Notably, these seizures were excluded from the primary outcome
of the RCT due to difficulty in counting these seizures [23]. Future
controlled studies using video-EEG are necessary to explore CBD’s
efficacy against these difficult-to-count seizures. An open-label
study suggested that CBD might be less effective at controlling
tonic-clonic seizures, atonic seizures, and focal seizures with
evolving components [23]. Additionally, one of the pivotal LGS tri-
als suggested CBD can also worsen drop seizures in a small subset
of patients [6].
2.8. Access
The pharmaceutical-grade CBD is expensive and timely, afford-
able, and consistent access is challenging. Besides high out-of-
pocket costs, many patients are required to try multiple other
ASMs and check whether their seizures fail multiple other ASMs
before receiving approval of CBD from the payors. The prior autho-
rization process also can delay the access of CBD. Copay assistance
(Epidiolex copay savings program) can be helpful for some fami-
lies. Additionally, several patient advocacy groups such as the Epi-
lepsy Foundation engages on many policy issues to facilitate
patients’ access to prescription medications.
2.9. Seizure severity
Despite the approval and availability of many ASMs over the
past three decades, the seizure freedom rate in TSC-associated
focal seizures has not improved [52]. Unfortunately, CBD may
not have any significant advantage over existing ASMs in this
regard. Reduction of seizure severity in TSC due to CBD can be an
essential metric to evaluate and, unfortunately, understudied. Sza-
flarski et al. showed CBD’s impact in reducing seizure severity in
the short term that persisted over two years [63]. However, Gaston
et al. demonstrated that at the 1-year time point, seizure severity
reduction was significantly greater in adults than in children
[64]. TSC-specific studies are critically needed to justify its use over
other ASMs as aggressive seizure reduction should be balanced
with optimization of learning, behavior, and overall quality of life.
2.10. Cognitive and behavioral effects of CBD in patients with TSC
Preferential use of CBD may be accounted for due to its favor-
able cognitive and behavioral effects compared to some other
broad-spectrum ASMs, such as levetiracetam, valproate, topira-
mate. Compared to THC (a partial agonist to the endocannabinoid
receptor CB1, which shows a high density in the medial–temporal,
prefrontal, and anterior cingulate cortex, brain regions critical for
cognitive processes), CBD has a lower affinity for the cannabinoid
receptors and potentially has less cognition impairing effects
[31]. Extensive studies in animals, healthy subjects, and patients
with various diseases showed it might have an anxiolytic impact
and positively influence frontal lobe-mediated functions (decision
making, working memory, reward learning, and emotion regula-
tion) [65–69]. Cannabidiol also showed improvement in the Global
Impression of Change measures in previous RCTs involving TRE
[14]. Anderson et al. reported the effect of CBD on quality of life,
behavior, and sleep in 35 children (only 1 patient with TSC was
in the cohort) with TRE in a prospective open-label EAP with signif-
icant improvement in irritability, hyperactivity, cognition, behav-
ioral function, general health, and sleep duration over 12 months
[70]. Metternich et al. reported substantial improvement in selec-
tive attention and caregiver-rated behavioral measure in a cohort
of 39 patients with TRE treated with three months of CBD [71].
These patients were tested with standardized neuropsychological
tests on memory, executive functions, and attention. However,
clinical trials with standardized neurocognitive assessments are
critically necessary to evaluate the cognitive and behavioral impact
of CBD in patients with TSC. Protocol development can utilize other
similar clinical studies (EPI-COG study for LGS or study to assess
cognitive impairments patients with Sturge Weber syndrome) to
estimate the impact of CBD on cognitive function.
Rigorous prospective studies showed a 40–50% autism preva-
lence rate in TSC [5]. Dysfunctional GABAergic neurotransmission
and reduced GABAA and GABAB subunit expression may be possi-
ble factors in the development of autism [72]. Researches also sug-
gested the direct role of mTOR hyperactivation in causing autism
due to abnormal neuronal migration, differentiation, and axonal
and dendritic development [73,74]. For many patients with TSC,
autism is the primary driver of poor quality of life rather than sei-
zures [5]. Additionally, there is a lack of treatment options for aut-
ism. Although risperidone and aripiprazole are FDA approved for
autism-associated irritability, aggressiveness, and self-injurious
behavior, these medications frequently cause side effects and do
not improve communication and social interaction [75,76].
Cannabidiol, an effector on GABAergic and mTOR function, has
been evaluated in patients with autism, with improvement in
symptoms such as behavioral challenges, insomnia, and hyperac-
tivity. Additionally, CBD’s 5HT1a agonist activity may diminish
symptoms of depression, anxiety, and cognitive impairments, and
its dopaminergic effects may mitigate psychosis [41]. So far, CBD’s
effect on autism has been evaluated in heterogeneous populations
with improvement in caregiver global impression, parental stress,
problem behaviors, anxiety, hyperactivity, and sleep disturbances;
however, patients with TSC and autism should be specifically eval-
uated [77–82]. The added benefit of clinical studies in TSC is the
potential earlier identification of autism(abnormal visual or fine
motor behavior may be evident by six months of age) and the sub-
sequent possibility of prompt intervention in this high-risk popu-
lation [83]. Cannabidiol clinical trials should use specific tools to
measure changes in ASD-associated symptoms and ASD core
symptoms (repetitive behaviors, stereotypies, and socio-
communication impairments). As these symptomatic improve-
ments may happen over a longer time frame, neuroimaging mark-
ers (magnetic resonance spectroscopy for cortical/subcortical
glutamate/GABA concentration, functional MRI to evaluate the
fractional amplitude of low-frequency fluctuations and functional
connectivity, and alpha-methyl-tryptophan hotspots in the posi-
tron emission tomography scan) can be used as surrogate markers
to assess acute effects of cannabinoids [84,85]. Besides electro-
physiological and functional neuroimaging biomarkers, CBD’s
impact on molecular biomarkers(mTOR activation) needs further
evaluation, which may open up a precision medicine approach to
target seizures, developmental impairments, and other
comorbidities.
D. Samanta Epilepsy Behavior 128 (2022) 108577
9
10. 2.11. Presymptomatic treatment
Presymptomatic diagnosis with EEG and early preventive ther-
apy with vigabatrin is getting momentum with the possibility of
delaying the onset of epilepsy, lessening the risk of severe epilepsy,
and possibly causing better cognitive outcomes [86–88]. However,
vigabatrin is associated with retinal toxicity – a common concern
regarding its long-term use among parents and clinicians [89].
Other potential therapeutic agents, mTOR inhibitors such as siroli-
mus and everolimus, have failed to improve cognition and behav-
ior in TSC in many studies [90]. Although several preventive
clinical trials using vigabatrin and mTOR inhibitors are underway
or getting planned, early treatment with CBD may be evaluated
due to its better safety profile and approved indication in infants
as young as one-year old. Although an ongoing trial is evaluating
CBD’s safety, pharmacokinetics, and efficacy in infants with TSC-
associated seizures, no comparable preventive clinical trials using
CBD are under development. However, if the safety of the CBD in
infants can be confirmed, further exploration as a preventive ther-
apy may be considered. Another relevant aspect is the evaluation
of CBD’s effects on interictal EEG, as EEG has been shown to be a
useful biomarker in individuals with TSC, with interictal discharges
emerging before seizure onset. Klotz et al. demonstrated that CBD
reduced the frequency of interictal epileptiform discharges (IEDs)
at three months compared to baseline (19.6 ± 19.5 vs. 36.8 ± 27.2,
respectively; p 0.0001) in 35 children with TRE [91]. A higher
IED rate at the beginning, as for patients with LGS, was negatively
correlated with IED reduction during treatment and thus suggested
potentially more significant benefits with early use(possibly before
the onset of seizures) when patients have fewer and spatially
restricted epileptiform discharges.
3. Conclusion
Despite the availability of Class I evidence of CBD’s short-term
efficacy against TSC-associated seizures, crucial information is still
missing regarding clinical, electrophysiological, and genetic predic-
tors of CBD responsiveness, CBD’s position in the rapidly changing
treatment algorithm, and its utility as a rational polypharmacy
therapy. Observational studies to evaluate sustained efficacy and
safety should be interpreted with caution due to several potential
biases. Further research is needed to understand its effect on TAND
and its potential utility as a preventive therapy in TSC. Finally, clin-
icians should avoid two contrasting pitfalls when considering CBD
therapy for TSC-associated seizures. First, the low probability of
sustained seizure freedom with CBD may not outweigh its favor-
able safety profile and seizure reduction potential. Thus, a lower
seizure-freedom rate should not deter physicians from using CBD
when better options are not available. However, tailored surgical
resection of epileptogenic foci may stop seizures in 25–90% of
patients [92]. Although comprehensive presurgical assessment is
necessary due to multifocal lesions, localized seizure onset zone
can still be identified in a large number of patients, leading to a
remarkable impact on the quality of life following early and suc-
cessful surgical intervention [18]. Thus, overzealous use of CBD
should be avoided when timely referral for epilepsy surgery and
curative surgical treatment is accessible and feasible.
Funding
The author received no financial support for the research,
authorship, and/or publication of this article.
Declaration of Competing Interest
The authors declare that they have no known competing finan-
cial interests or personal relationships that could have appeared
to influence the work reported in this paper.
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