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Epilepsy is a disease characterized by a recurrent predisposition to epileptic seizures. It is a disease with neurobiological, cognitive, psychological and social consequences. Epilepsy is a disease of the central nervous system that causes abnormal electrical discharges from neurons (brain cells), which can result in varied symptoms, the most common of which is a seizure.
Epileptic seizures can be classified into two types:
- Focal or partial crisis: occurs when the abnormal discharge of neurons is restricted to an area of the brain. Generally, the patient has no loss of consciousness and may or may not have motor jerks.
- Generalized crisis: occurs when the discharge spreads to the entire brain, causing loss of consciousness. Examples are the seizure crisis and the absence crisis.
Epileptic seizures can be classified into two types:
- Focal or partial crisis: occurs when the abnormal discharge of neurons is restricted to an area of the brain. Generally, the patient has no loss of consciousness and may or may not have motor jerks.
- Generalized crisis: occurs when the discharge spreads to the entire brain, causing loss of consciousness. Examples are the seizure crisis and the absence crisis.
Difference between epilepsy and seisure
Here, it is important to emphasize that epilepsy and seizure are not the same thing. A seizure is a type of epileptic seizure that progresses with motor jerks and, for the condition to be considered epilepsy, there must be a repetition of the seizures. Furthermore, not every epileptic seizure is a seizure.Unlike a seizure episode, an epileptic seizure is the transient occurrence of signs and symptoms caused by excessive or synchronous neuronal activity in the brain, with variable duration, usually from a few seconds to several minutes. According to the International League Against Epilepsy (ILAE), there are 2 types of definitions of epilepsy, one scientific and one operational. The operational definition suggests that the disease is characterized by:
- At least 2 unprovoked seizures - or two reflex seizures - which can occur within a period longer than 24 hours
- An unprovoked crisis – or reflex crisis – with an estimated occurrence of at least 60% of a new crisis. Structural changes in brain magnetic resonance imaging and/or electroencephalogram may suggest this recurrence.
- Diagnosis of an epileptic syndrome.
Epilepsy can have different causes. In children, for example, it is associated with neonatal anoxia and inborn problems with metabolism. In the elderly, cerebrovascular diseases, as well as brain tumors, are among the most frequent causes. Its causes can be grouped into 3 categories:
- Genetics: when epilepsy is a direct result of a known or presumed genetic problem, in which seizures are the main symptom of the disease.
- Structural/metabolic: when there is a distinct metabolic condition or disease associated with a substantial increased risk of developing epilepsy. Structural damage can come from stroke, trauma and infections.
- Unknown cause: it is a neutral way to designate that the nature of the underlying cause is still unknown; it may be a fundamental genetic defect, or it may be the consequence of a separate disorder not yet recognized. This represents a very significant percentage of cases.
In most cases, epilepsy is the result of small lesions in the brain. These scars have different origins (genetic predisposition, trauma during or after childbirth, malformations and even a stroke), but the consequence of them is similar: from time to time, neurons fire a bunch of electrical discharges that result in loss of sudden awareness and involuntary movements. However, in certain situations it is not possible to specify the cause of the problem – the gray matter seems to be fine, but the seizures persist.
As seizures are frightening, epilepsy is accompanied by prejudice and social stigma. Even for this reason, few people receive adequate treatment, which makes a good quality of life impossible. But it is not rare: according to the World Health Organization, up to 1% of the global population suffers from the disease.
As seizures are frightening, epilepsy is accompanied by prejudice and social stigma. Even for this reason, few people receive adequate treatment, which makes a good quality of life impossible. But it is not rare: according to the World Health Organization, up to 1% of the global population suffers from the disease.
Epilepsy and psychosocial consequences
Epilepsy is a condition associated with significant psychosocial consequences and the central factor is its stigmatizing nature. It is considered by >Ablon one of the chronic diseases with the highest level of stigma, and patients report stigma as one of the great difficulties they experience with epilepsy. The stigma in epilepsy starts with the origin of its name, as epilepsy is a word of Greek origin that means to be invaded, dominated or possessed. With that, we can have a magical, supernatural explanation, associated with possession by divine or evil spirits.Epilepsy occurs mainly in children, but it can affect all ages. The most frequent causes in adults are: head trauma, cerebrovascular accidents (CVA), tumors, vascular malformations, metabolic diseases, infectious brain diseases or heart disease. In children, the most common causes are genetic factors or diseases, problems with cerebral oxygenation during pregnancy or childbirth, brain malformations, infections/meningitis, and finally the so-called febrile seizures (resulting from high fever in younger children).
About a third of patients with epilepsy are resistant to the existing drug treatment, which is called “refractory epilepsy”, being important the research and development of new drugs.
Patients with refractory forms of epilepsy, that is, those who do not respond to different therapeutic schemes, suffer from all the consequences of a disabling chronic disease: in its social, psychological, personal, family aspects, among others. In these cases, their independence may be compromised, in addition to seeing other complications associated. The type of epilepsy and, consequently, the type of epileptic seizures may entail different risks, namely seizures with a fall or seizures with seizures, which can lead to the patient injuring himself during the event. In addition to crises, these patients may also have other comorbidities, including intellectual and learning difficulties, cognitive disorders, psychopathology and behavioral changes, with different repercussions on their daily life, which can often lead to discrimination and social exclusion, list the experts regarding the impact of refractory epilepsy.
The refractory epileptic syndromes
The refractory epileptic syndromes of childhood constitute a very polymorphic group both in their clinical manifestations and in the variability of their individual expression. Factors related to brain maturation and neuromodulation, as well as the effects of paroxysmal discharges on certain neuronal circuits in development are responsible for the different expressions of childhood epilepsies when compared to the adult epileptic population. Such factors point to the need for an early diagnosis in the delimitation of epileptic syndromes related to a worse prognosis. Thus, the concept of epileptic encephalopathies is centered on the fact that epileptic seizures themselves or even interictal discharges can be determinant in the development of cognitive and motor deficits associated with severe epilepsies, which is conceptually outlined as “negative brain plasticity”. In this sense, preventing and treating early-onset seizures can minimize the neuropsychological impact and sequelae associated with difficult-to-control epilepsies.To alleviate epileptic seizures and to combat refractory epilepsy, studies show that Cannabis sativa compounds, especially cannabinoids, can be an effective drug alternative, even to terpenes. The ability of Cannabidiol (CBD) to antagonize the psychotomimetic effects of ∆9-Tetrahydrocannabinol (∆9-THC) is recognized, raising the hypothesis that CBD may have anxiolytic properties, as well as an antipsychotic profile. A progressive body of evidence obtained from studies in both humans and animal models confirms the therapeutic potential of CBD in the treatment of symptoms of psychiatric disorders such as depression, anxiety and psychosis.
CBD has a wide therapeutic potential at the level of the central nervous system, showing great importance in the treatment of several neurological disorders. Furthermore, the recognized anticonvulsant effect of CBD is capable of significantly reducing seizures in drug-resistant epileptic patients, as well as preventing irreversible brain damage and preventing retrograde effects in the development of children and adolescents.
CBD treatment of refractory epilepsy
In the treatment of refractory epilepsy, CBD activity becomes an attractive therapeutic compound, which may act on the underlying epileptogenic process or even act on some disabling symptoms of the disease. Several pharmacological effects of CBD can act by inhibiting the reuptake mechanism and anandamide degradation. Because it is complex, the pharmacology of CBD can encompass direct and/or indirect interactions with receivers of various cell control systems.Several cannabinoids have anti-epileptic effects, but the most effective combinations with fewer side effects have not yet been determined. Recent studies indicate that pure cannabinoids are less effective than mixtures of cannabinoids (committal effect), including Cannabis sativa extracts with a broad spectrum of cannabinoids and terpenes.
Given this problem, the company Piauhy Labs intends to evaluate the effects of products derived from Cannabis sativa in the handling of status epilepticus in mice (also known as domestic rats), inducing the animals into an epileptic state, through the use of pilocarpine and kainic acid in animals treated with vehicle, Cannabis extracts with broad spectrum of cannabinoids and terpenes, and different proportions of cannabinoids and terpenes.
Therefore, the proposal is to compare the severity and duration of status epilepticus, induced by pilocarpine and kainic acid in animals treated with vehicle, cannabis extracts with broad spectrum of cannabinoids and terpenes, and different proportions of cannabinoids and terpenes. Dose-response curves will be used to estimate the ED50 required for each treatment. The ED50 is the dose of a drug that produces a desired pharmacological effect in 50% of the population studied (patients taking the drug). Electrophysiological (epileptiform discharges in a chemically induced animal model of status epilepticus) and biochemical (anti-inflammatory effects on microglia) studies will be conducted for treatments with the greatest anticonvulsant efficacy in the behavioral study.
Therefore, the proposal is to compare the severity and duration of status epilepticus, induced by pilocarpine and kainic acid in animals treated with vehicle, cannabis extracts with broad spectrum of cannabinoids and terpenes, and different proportions of cannabinoids and terpenes. Dose-response curves will be used to estimate the ED50 required for each treatment. The ED50 is the dose of a drug that produces a desired pharmacological effect in 50% of the population studied (patients taking the drug). Electrophysiological (epileptiform discharges in a chemically induced animal model of status epilepticus) and biochemical (anti-inflammatory effects on microglia) studies will be conducted for treatments with the greatest anticonvulsant efficacy in the behavioral study.
Additionally, the research and development carried out by Piauhy Labs aims to characterize and identify methods to obtain terpenes and other substances, in addition to cannabinoids, which have a safety and quality profile suitable to be included in medicines and preparations based on the plant of Cannabis for medicinal purposes, notably for the treatment of epilepsy.
As a result of the research and development processes, Piauhy Labs intends to create patents and originate intellectual property, with the ultimate objective of producing medicines based on the Cannabis plant.
References :
Ablon, J. The nature of stigma and medical conditions. Epilepsy Behav., 3(6S2):2-9, 2002.
Aicardi, J. Epileptic encephalopathies of early childhood. Curr. Opin. Neurol. Neurosurg., Jun; 5(3):344-8, 1992.
Berg A. T.; Levy, S. R.; Novotny, E. J. and Shinnar, S. Predictors of intractable epilepsy in childhood: a case-control study. Epilepsia, 37(1): 24-30, 1996. Bronen, R. A.; Fulbright, R. K.; SPENCER D. D. et al. Refractory epilepsy: comparison of MR imaging, CT, and histopathologic findings in 117 patients. Radiology, 201(1): 97-105, 1996. Comission on Epidemiology and Prognosis, International League Against Epilepsy. Guidelines for Epidemiologic Studies on Epilepsy. Epilepsia, 34(4): 592-596, 1993. Cowan, L. D.; Bodensteiner, J. B.; Leviton, A. and Doherty, L. Prevalence of the epilepsies in children and adolescents. Epilepsia, 30(1): 94-106, 1989. Dulac, O. Epileptic encephalopathy. Epilepsia, 42, Suppl 3:23-6, 2001. Kramer, U.; Nevo, Y.; Neufeld, M. Y.; Fatal, A.; Leitner, Y. and Harel, S. Epidemiology of epilepsy in childhood: a cohort of 440 consecutive patients. Pediatr. Neurol. 18: 46-50, 1998.
Moreira, F. A. and Guimarães, F. S. Cannabidiol inhibits the hyperlocomotion induced by psychotomimetic drugs in mice. European Journal of Pharmacology, 512, 199, 2005.
Moshé, S. L. Seizures in the developing brain. Neurology, 43 (Suppl. 5): S3- S7, 1993.
Pedrazzi, J. F. C.; Pereira, A. C. C. I.; Gomes, F. V.; Bel, E. D. Perfil antipsicótico do canabidiol. Revista da Faculdade de Medicina de Ribeirão Preto e do Hospital das Clínicas da FMRP, 47, 112, 2014.
Teixeira, P.; Li, M. L. Percepção de estigma na epilepsia. J. epilepsy clin. neurophysiol., 12 (4), 2006.
Zuardi, A. W.; Crippa, J. A.; Hallak, J. E. et al. A critical review of the antipsychotic effects of cannabidiol: 30 years of a translational investigation. Current Pharmaceutical Design, 18, 5131, 2021.
Ablon, J. The nature of stigma and medical conditions. Epilepsy Behav., 3(6S2):2-9, 2002.
Aicardi, J. Epileptic encephalopathies of early childhood. Curr. Opin. Neurol. Neurosurg., Jun; 5(3):344-8, 1992.
Berg A. T.; Levy, S. R.; Novotny, E. J. and Shinnar, S. Predictors of intractable epilepsy in childhood: a case-control study. Epilepsia, 37(1): 24-30, 1996. Bronen, R. A.; Fulbright, R. K.; SPENCER D. D. et al. Refractory epilepsy: comparison of MR imaging, CT, and histopathologic findings in 117 patients. Radiology, 201(1): 97-105, 1996. Comission on Epidemiology and Prognosis, International League Against Epilepsy. Guidelines for Epidemiologic Studies on Epilepsy. Epilepsia, 34(4): 592-596, 1993. Cowan, L. D.; Bodensteiner, J. B.; Leviton, A. and Doherty, L. Prevalence of the epilepsies in children and adolescents. Epilepsia, 30(1): 94-106, 1989. Dulac, O. Epileptic encephalopathy. Epilepsia, 42, Suppl 3:23-6, 2001. Kramer, U.; Nevo, Y.; Neufeld, M. Y.; Fatal, A.; Leitner, Y. and Harel, S. Epidemiology of epilepsy in childhood: a cohort of 440 consecutive patients. Pediatr. Neurol. 18: 46-50, 1998.
Moreira, F. A. and Guimarães, F. S. Cannabidiol inhibits the hyperlocomotion induced by psychotomimetic drugs in mice. European Journal of Pharmacology, 512, 199, 2005.
Moshé, S. L. Seizures in the developing brain. Neurology, 43 (Suppl. 5): S3- S7, 1993.
Pedrazzi, J. F. C.; Pereira, A. C. C. I.; Gomes, F. V.; Bel, E. D. Perfil antipsicótico do canabidiol. Revista da Faculdade de Medicina de Ribeirão Preto e do Hospital das Clínicas da FMRP, 47, 112, 2014.
Teixeira, P.; Li, M. L. Percepção de estigma na epilepsia. J. epilepsy clin. neurophysiol., 12 (4), 2006.
Zuardi, A. W.; Crippa, J. A.; Hallak, J. E. et al. A critical review of the antipsychotic effects of cannabidiol: 30 years of a translational investigation. Current Pharmaceutical Design, 18, 5131, 2021.
Epilepsy is a disease characterized by a recurrent predisposition to epileptic seizures. It is a disease with neurobiological, cognitive, psychological and social consequences. Epilepsy is a disease of the central nervous system that causes abnormal electrical discharges from neurons (brain cells), which can result in varied symptoms, the most common of which is a seizure.
