|Year : 2016 | Volume
| Issue : 1 | Page : 3-11
The impact of epilepsy on the manifestation of anxiety disorder
Alina Arulsamy, Mohd Farooq Shaikh
Jeffrey Cheah School of Medicine and Health Sciences, Monash University Malaysia, Selangor, Malaysia
|Date of Submission||03-Jun-2015|
|Date of Acceptance||07-Aug-2015|
|Date of Web Publication||12-Jan-2016|
Mohd Farooq Shaikh
Jeffrey Cheah School of Medicine and Health Sciences, Monash University Malaysia, Bandar Sunway 46150, Selangor
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Epilepsy affects the neuronal activity of our brain and leads to the development of behavioral disorders such as depression and anxiety. Epilepsy-induced anxiety is a debilitating disorder that burdens almost 45% of the global population and has a severe impact on the quality of life led by the patients. This disorder affects men, women, children, families, and even society at large. Although there is no clear pathophysiological pathway for the manifestation of anxiety in epilepsy patients, there are many theories proposed by researchers that include neurological and psychological pathways. Based on this knowledge, pharmacological treatments are constantly being discovered to help patients with their disorder. Nonpharmacological treatments (such as psychotherapy) are strongly encouraged as first-line treatment, more so than reliance on medication due to the high possibility of adverse effects associated with the latter. Nevertheless, comprehensive diagnosis of the disorder is needed prior to treatment in order to avoid false negatives or positives. In conclusion, the quality of life of epilepsy patients with anxiety can only be improved once full understanding of the disorder is achieved through research.
Keywords: Animal models, antiepileptics, mood disorders, pathophysiology, seizure
|How to cite this article:|
Arulsamy A, Shaikh MF. The impact of epilepsy on the manifestation of anxiety disorder. Int J Nutr Pharmacol Neurol Dis 2016;6:3-11
|How to cite this URL:|
Arulsamy A, Shaikh MF. The impact of epilepsy on the manifestation of anxiety disorder. Int J Nutr Pharmacol Neurol Dis [serial online] 2016 [cited 2022 Dec 6];6:3-11. Available from: https://www.ijnpnd.com/text.asp?2016/6/1/3/173783
| Introduction|| |
The brain is responsible for almost all the functions of our body, from moving to reacting, to the management of bodily functions. We are connected to our surroundings through the neuronal activity of organized and systematic electrical messages sent to and from the brain. Epilepsy occurs when these messages become disorganized due to sudden, intense outbursts of electrical impulse that lead to the development of seizures. The cause of the sudden outbursts is often unclear, but approximately 20–40% of brain tumor patients are often diagnosed with the onset of seizures., Epilepsy is commonly diagnosed through a combination of electroencephalographic (EEG) testing of brain wave activity and a comprehensive evaluation of the patient&'s condition by an expert epilepsy specialist. Patients are diagnosed with epilepsy only when they have exhibited recurrent seizure episodes, as many who experience a seizure attack only once in their life do not develop epilepsy. After diagnosis, patients are classified according to the type of seizures they exhibit before treatment is given to them. If not managed well, epilepsy may lead to other detrimental problems.
Epilepsy can cause a wide range of neurological disorders and psychological disorders, the latter most commonly being mood disorders such as depression and anxiety. Although extensive studies on epilepsy-induced depression have been performed, the manifestations of anxiety disorder among epilepsy patients are yet to be fully understood. Anxiety disorder is an excessively uneasy feeling or worry about uncertainties in life that may or may not be realistic. Patients, whether epileptic or nonepileptic diagnosed with anxiety disorder, show signs of anxiousness, tension, insomnia, and even cardiovascular symptoms. Anxiety disorder can be classified in relation to epilepsy, such as preictal, ictal, interictal, and postictal anxiety. Preictal anxiety refers to anxiety symptoms that increase before the onset of a seizure attack and can serve as a determinant of possible future seizure attacks., Ictal anxiety is the most common type, especially among temporal lobe epilepsy (TLE) patients, where anxiety symptoms are seen as simple, partial seizures that can result in hallucinations. Interictal anxiety has no temporal relationship with seizures and thus develops into clinical anxiety symptoms. Postictal anxiety denotes anxiety symptoms that last from hours to days after seizure attacks.,
As anxiety disorders among epilepsy patients further burden them and diminish their ability to lead a normal life, a better understanding of the relationship between the two is the key to possible effective treatment options in the future. This article reviews the prevalence, the pathophysiology, and the medical interventions of anxiety among epilepsy patients.
| Prevalence in Population|| |
Mood disorders have long been established to be associated as a secondary effect of epilepsy. Although much research has been done on the prevalence of depression in epilepsy patients, studies on the prevalence of anxiety among patients with epilepsy are still ongoing. Anxiety disorders are clinically significant comorbid disorders in epilepsy patients and are rising in frequency. In the late 80s and the 90s, the prevalence of anxiety disorders among epilepsy patients regardless of the type of epilepsy was 14–25%, based on community studies,, and 16–25% in hospital-based studies., This trend has continued in the 21st century with the global prevalence rate [Figure 1] of 5–45%; the United States has the highest prevalence rate of 45%, followed by Canada, the United Kingdom, and Germany with 22.8%, 15%, and 5.8%, respectively.,,
|Figure 1: The global prevalence rate of epilepsy-induced anxiety disorders|
Click here to view
Recent studies have been more focused on the types of epilepsy, that is, TLE, frontal lobe epilepsy (FLE), or generalized epilepsy (GE), in relation to the manifestation of anxiety disorders among them. The prevalence of anxiety disorders among TLE patients is high, at 18%, while it has also been reported that FLE or extratemporal epilepsy patients have higher anxiety scores than GE patients., Anxiety disorder has the highest prevalence among TLE patients compared to other types of epilepsy due to the dysfunction of the limbic system, found specifically in the temporal lobe, that regulates emotion and mood disorders., Anxiety disorders can be classified as panic disorder, generalized anxiety disorder (GAD), obsessive-compulsive disorder (OCD), and phobias. In a recent study by Brandt et al. (2010) involving 97 epilepsy outpatients, 19 patients were diagnosed with anxiety, and among them social phobias were of the highest prevalence (7.2%), followed by panic disorder (5.1%), GAD (3.1%), and OCD (1%). Although this study does not represent the overall population, it provides a good indication of the type of anxiety that might be of high prevalence in communities with epilepsy, thus allowing more targeted research in treating the same.
| Impact on Individual, Family, and Society|| |
Fear of social unacceptance, shame, and low self-esteem are some of the negative impacts of epilepsy on patients. Epilepsy patients are unable to control or hide their epileptic episodes, thus they constantly feel ashamed or fearful of experiencing an episode, especially in the presence of others. Self-reports by epilepsy patients reinforce these statements. However, most epilepsy patients tend to lead a close-to-normal life, participating in school, work, and social events. Nevertheless, constant fear of an epileptic episode and its aftermath could lead to the development of anxiety among these epilepsy patients. Some patients predispose themselves to developing anxiety by overestimating the risk of an epileptic episode and concurrently underestimating their ability to handle the same., Once anxiety develops in these epilepsy patients, their quality of life is further reduced. Fearing the physical and mental harm of an epileptic episode (an unpredictable seizure attack) as well as the shame it brings to themselves and their loved ones can cause them to isolate themselves and avoid social interactions as much as possible, a condition known as “seizure phobia,” thus leaving them in a life of solitude. This eventually affects their emotions and makes them more susceptible to depression as a result of their inability to socialize with people. Those most severely affected by epilepsy are women, which increases their risk of developing anxiety. This is because epileptic episodes in women may disrupt their sexual development, fertility, and pregnancy, which increases their worry and concern about the future, especially for women who are already pregnant or at a childbearing age. Similarly, fertility and sexual function in men are also affected by epilepsy, leading to concerns about fathering a child, which causes the development of anxiety. Children with epilepsy may manifest anxiety very easily due to the stress of growing up and lack of knowledge about dealing with the situation. About 40% of epileptic children suffer from anxiety disorder. Anxiety in epileptic children may retard their normal growth as they are more susceptible to the negative impact associated therewith. This is due to their lack of communication skills—they are unable to seek help from others. This manifests in their behavior in the form of outbursts of anger, aggressiveness, or phobias toward school and social events. Moreover, epilepsy patients are at a higher risk of developing brain damage if the seizures are powerful and frequent, or as a result of side effects of antiepileptic drugs (AEDs). Thus, when anxiety develops in these patients, further brain damage could result as they would need to medicate themselves with other antipsychotic drugs—anxiolytic drugs, which could have their own damaging potential on brain cells as a result of their side effects, or as a result of a negative reaction with their AEDs.
Epilepsy also impacts the families of epilepsy patients. Family members of epilepsy patients can also have the tendency to develop anxiety even if they do not suffer from epilepsy themselves. Parents are affected when their children have epilepsy, or anxiety, or anxiety associated with epilepsy. Parents often think that their epileptic child is abnormal and therefore tend to show negative attitudes toward them, either by being overprotective and thus hindering them from living a normal life like other children of the same age, or by being ignorant about the extra care that is needed for these children with epilepsy. These parents may manifest a disorder known as generalized parental anxiety due to their overprotective parenting, which impedes their children from being independent., Recent research has also reported that maternal anxiety about epilepsy can lead to further development of anxiety in epileptic children as they feel that they are burdening their parents, and this is particularly due to the lack of interaction between the parents and the children. However, this research was only done on mothers; the role of fathers in the social development of epileptic children should also be investigated. When an epileptic family member develops anxiety, he/she tends to set off a chain of anxiety reactions among the other members of the family., A study also reported that siblings of epileptic children feel envy and anger toward their epileptic siblings due to the increased attention they receive from everyone else, especially their parents. An epilepsy patient with anxiety will often be aggressive, moody, or emotionally detached due to his/her constant worrying, and battle with epileptic episodes; this will take a toll on those surrounding him/him, and lead to such problems as higher divorce rates and abandoned children.
Anxiety in epilepsy patients has little impact on society in general. Unless someone is close to the patient, most individuals in the community usually do not concern themselves with understanding epilepsy or the epilepsy patient. One of the communities that might be affected by epilepsy patients with anxieties is the workplace of the patients, as the loss of focus and determination in epileptic employees due to their struggle with the disorder or struggle in being accepted by fellow coworkers might cause a decrease in production value, affecting the company&'s outcome. Most coworkers tend to avoid an epileptic coworker due to feelings of discomfort about providing the appropriate first aid during an epileptic episode. School communities might also be affected—the normal learning curve of other children might be disturbed by the epileptic children in their class as witnessing an epileptic episode of a classmate can be traumatizing, especially when they are unable to understand the situation at such a young age.
| Risk and Pathophysiology|| |
As mentioned earlier, epilepsy is the sudden, abnormal brain activity that usually results in brief to prolonged seizures. Anxiety, on the other hand, is a mood disorder that is caused by an increased, unrealistic awareness to perceived risk and dangers. Despite the prevalence of anxiety among epilepsy patients, there is no clear or definite cause or pathophysiology for the development of anxiety in epilepsy patients. Nevertheless, many theories have been raised through extensive research on the possible risk factors and mechanisms of genesis that could be involved in the development of anxiety among epilepsy patients.
First, anxiety may be caused by physiological reactions. Fear (awareness to realistic risks), although having a slightly different definition from anxiety, is the main physiological reaction that often leads to the development of anxiety in people. Epilepsy patients tend to have an increased fear and anxiety of seizure episodes. The inability to predict the occurrence of their seizure attacks frightens epileptic individuals and leaves them with a sense of vulnerability.,, Besides, their doubtfulness in managing their seizure attacks also causes them to develop anxiety due to the exaggerated worry about the consequences of an uncontrollable and unpredictable epileptic episode. Confidence in facing the seizure attacks will reduce the fear and therefore prevent the development of anxiety.
Epilepsy patients who developed epilepsy at a later stage in life (adulthood) would be more likely to develop anxiety than those diagnosed with epilepsy at earlier stages of life, as understanding and learning to accept their disorder early on enables them to manage their disorder better and therefore gives them more confidence in facing the seizure attacks. However, when observing the relationship between age of onset of epilepsy and the development of anxiety directly without taking into account the individual&'s managing skills, it was observed that there was no strong correlation between age of onset and anxiety. For example, if an epilepsy patient who has developed epilepsy in childhood is told by people around him/her that he/she has an incurable and unmanageable disorder, that epileptic child may not understand his/her disorder properly and will thus fear it, believing that he/she is a lost cause. Meanwhile, an epilepsy patient who has developed epilepsy at a later stage of life may receive proper guidance from the people around him/her and thus be less likely develop anxiety, as he/she would understand the disorder better and believe that with good managing skills, he/she can lead a normal life.
It was once assumed that seizure frequency might play a part in the development of anxiety—that the more seizure attacks someone experiences (recurrent seizures), the less likely he/she will be to develop anxiety, due to experience and knowledge about his/her attacks. Another study also showed that there was a positive association between higher frequency of seizures and the development of mood disorders through different anxiety and depression scales, but this research did not investigate the direct correlation between seizure frequency and the type of anxiety that manifests in epilepsy patients, and thus the positive association could be related more to depression than to anxiety. More research needs to be done to strongly conclude that there is a direct association between seizure frequency and anxiety.
Anxiety is also manifested in epilepsy patients who have suffered a traumatic experience as a consequence of a seizure attack. Some epilepsy patients have reported that seizure attacks have damaged certain brain areas, such as the amygdala, which may lead to the development of behavioral disturbances such as paroxysmal anxiety.,,,,,, Surgery can also cause the development of anxiety, especially major surgeries involving the brain in treating epilepsy. It has been reported that epilepsy patients developed a higher frequency of anxiety or new onset of anxiety after undergoing surgery where their seizure frequency is reduced., Moreover, if the patient has a history of anxiety preoperative to epilepsy surgery, that patient is at a higher risk of developing postoperative anxiety.
Anxiety could also manifest in epilepsy patients as a result of changes in the physiology of the brain [Figure 2]. The following are the theories offering explanations of the pathophysiology of anxiety at a molecular level. First, as a direct cause or effect from epileptic firing in the brain, some parts of the brain such as the amygdala (the center for fear experiences) might undergo modifications in physiological structure and function, which could result in the manifestation of other disorders. Magnetic resonance imaging (MRI) on epilepsy patients has demonstrated the strong association between anxiety and abnormalities in the amygdala whereby a reduced volume of the amygdala caused by seizures resulted in the development of ictal anxiety.,, Besides the amygdala, changes in the structure and function of the hippocampus could also lead to anxiety. This is because the hippocampus is involved in re-experiencing of fear  and thus abnormalities in the hippocampus could cause a patient to develop anxiety by constantly triggering a particular fear and so cause a patient to develop anxiety. Lesions in any part of the brain could also cause anxiety or lead to the development of other disorders. Lesions caused by seizures may advance/develop on either side of the temporal lobe: Those with lesions found on the left side of the temporal lobe have been reported to have/experience higher levels of anxiety., Although studies are inconclusive, lesions affecting a certain hemisphere, either left or right, could also play a part in determining the manifestation of physiological disorders. Some studies have shown that patients with left hemisphere lesions have higher reports of depression than those with right hemisphere lesions., Similar reasoning may also be seen regarding the development of anxiety, through further research. Besides structural changes in the brain, the imbalance of neurotransmitters in epilepsy may cause anxiety. The key neurotransmitters involved in anxiety include γ-Aminobutyric acid (GABA), serotonin, dopamine, and noradrenaline. It is very much evident from the literature that GABAA receptors, involved in regulating excitability, and GABA, an inhibitory neurotransmitter play a key role not only in the pathophysiology of epilepsy but also in the development of epilepsy. Furthermore, the GABAA antagonist has been reported to cause convulsions in patients, whereas increased levels of GABA have ameliorated the levels of anxiety in patients.,,, Serotonin receptors with altered binding function have also been shown to have a strong correlation with epilepsy and anxiety.,,, Recently, the calcium channels that control the release of neurotransmitters at the synapse have been proposed to be involved in the genesis of anxiety in epilepsy patients. The α2δ subunit of the calcium channel was hypothesized to be involved in managing abnormal neuronal firing, which in turn helps manage epilepsy and anxiety.
|Figure 2: The changes in structural physiology of the brain caused by recurrent seizures|
Click here to view
Another theory states that epilepsy patients could develop anxiety due to AEDs. Although most AEDs have anxiolytic properties as well, some tend to potentiate anxiety instead of resolving it. This could be due to the side effects of the antiepileptic itself. It is well known that AEDs, although working effectively in managing epilepsy, have been reported to cause adverse psychiatric effects. There have been reports suggesting the role of AEDs in causing or sometimes exaggerating anxiety., However, there is no evidence to suggest that being medicated solely with one type of AED can cause anxiety, as most epilepsy patients are usually on a multiple medication regimen, and thus interaction between the AEDs or with other drugs could have resulted in the anxiety reported among epilepsy patients. Besides, withdrawal from long-term dependence on AEDs could also result in the development of anxiety as well as increase seizures  in patients. This could be due to fear of seizure recurrence after AED withdrawal and lack of confidence in managing it. It could also be due to some molecular changes in the neuronal circuit of the brain caused by the AED. Thus withdrawal causes severe seizures and even psychological changes such as anxiety and depression.
Patients with epilepsy may develop anxiety due to other causes as well, such as lack of education and gender differences. Lack of knowledge of matters related to epilepsy can cause one to worry and fear it, and thus anxiety is developed in the long run. Gender has been reported to play a role in the development of anxiety in epilepsy patients, with male patients with TLE being more vulnerable to mood disorders than female patients., However, female epilepsy patients have been reported to have a higher rate of death due to anxiety than males, and this could be due to hormonal differences between the genders. Racial differences may be implicated as a cause for the development of anxiety among epilepsy patients but studies on this factor are very limited, and thus a causative correlation is yet to be found.
| Tools of Diagnosis|| |
Before initiating treatment, a comprehensive diagnosis of the patient&'s condition needs to be evaluated first so that the treatment will be more effective and have potentially less side effects. The diagnosis process comprises various methods, including assessment of the patient&'s history and medical background, psychiatric evaluation by a professional psychiatrist, and physical examination of brain and body. Although epilepsy and anxiety are disorders of the brain, laboratory tests on the body should also be conducted to rule out other possible medical conditions that might interact with or cause the disorders. Further diagnosis of the disorders can also be done using EEG and brain imaging technology in order to avoid any misdiagnosis. Once a clear diagnosis is made, medical interventions can begin.
| Possible Interventions to Treat Epilepsy-Induced Anxiety|| |
Treatments for epilepsy patients with anxiety can be divided into nonpharmacological treatments such as lifestyle changes or cognitive behavioral therapy (CBT) and pharmacological treatments such as medications.
As a preventive measure against the development of anxiety in epilepsy patients, nonpharmacological methods can be applied. As mentioned previously, comprehensive knowledge on epilepsy is the key for managing the disorder as well as preventing the occurrence of anxiety and panic. Psychoeducational methods such as seminars on epilepsy and self-help groups for epilepsy patients can effectively help epilepsy patients to embrace and cope with their disorder in a positive manner, hence eliminating the risk of feeling anxious, depressed, or vulnerable., Educational programs on epilepsy have also been shown to reduce seizures and thus these programs are definitely needed, especially for epileptic children and their families to improve their quality of life. Rural areas have a higher prevalence rate of epilepsy, but lack of knowledge about the disorder results in misdiagnosis or wrong diagnosis, which leads to aggravation of their disorder, development of anxiety, and fears due to misconception. In a rural area in Ethiopia, almost 17% of the community were found to perceive epilepsy to be a contagious illness or the deeds of an evil spirit, which caused families to fear and become anxious around those suffering from epilepsy. A similar case was seen in rural areas in Nigeria. Therefore, rural health programs and services should also be prioritized and become easily available in order to educate these communities as well as ease their suffering by reducing their anxiety about their health concerns.
Based on case studies, CBT is a proven, effective method of dealing with anxiety among epilepsy patients, especially for adolescents, as CBT not only educates patients about their disorder but also exposes them to situations they would normally fear and provides them with effective anxiety coping skills., For example, a case study done in India on a 27-year-old unmarried man with social phobia showed that CBT managed to significantly improve his condition. He underwent 17 sessions of CBT, in which the nature of his condition was explained in detail as well as the role of psychotherapy in the treatment process, and he was trained to practice a relaxation technique known as Jacobson&'s progressive muscular relaxation whenever he felt stressed or anxious. Repeated exposure to anxiety-triggering situations can help epilepsy patients to overcome their fear of these situations in everyday life. In addition, support from friends and family as well as certain lifestyle changes such as taking up meditation, yoga, healthy food, and socializing can also help epilepsy patients reduce their anxiety and lead a normal life.
Medications to treat anxiety in epilepsy patients include two major routes—taking AEDs that have known anxiolytic properties or, focusing just on treating the anxiety disorder, taking anxiolytic drugs or antidepressants. Common AEDs such as barbiturates, benzodiazepines, and valproate have sedating effects and may potentially be anxiolytic. These drugs potentiate GABA, an inhibitory neurotransmitter that, when it binds to GABAA receptor, causes a sedative effect wherein the neuronal activity slows down, which may also reduce anxiety., Benzodiazepine causes sedation by binding and causing an allosteric positive modulation at the GABAA receptor with α1 subunit, while the anxiolytic effect originates from the allosteric positive modulation of the GABAA receptor with α2 subunit [Figure 3]. Sedation causes relaxation and helps keep seizure attacks at bay as neuronal activity in the brain is also reduced. However, severe sedation can also lead to amnesia. Clonazepam is an example of a benzodiazepine that has both antiepileptic and anxiolytic effects but has a secondary amnestic effect as well; the latter shows the adverse effect of AEDs on cognitive functioning. On the other hand, there are a few AEDs that are effective in treating epilepsy but also possess an anxiogenic effect instead of an anxiolytic effect as a secondary action. Felbamate, an inhibitory drug for glutamate neurotransmission, has been reported to cause anxiety as an adverse effect.,, This is because activating AEDs has the potential to activate other neuronal sites/receptors that may cause anxiety. Therefore, epilepsy patients should be prescribed with sedative AEDs for their own benefit, rather than activating AEDs, especially if they are diagnosed with anxiety. Besides AEDs, epilepsy patients may also be treated with anxiolytic drugs such as selective serotonin reuptake inhibitors (SSRIs) to manage their anxiety. SSRIs such as fluoxetine have been effective in treating anxiety in patients without epilepsy, but those with epilepsy are advised to be cautious for side effects when AED medications are combined with SSRIs as the latter may inhibit the metabolism of AEDs due to SSRI inhibitory action on the CYP450 hepatic enzyme.,
|Figure 3: The sedation and anxiolytic action of benzodiazepines on GABAAreceptor|
Click here to view
The ideal treatment for anxiety among epileptics should be a combination of pharmacological and nonpharmacological approaches. Combined therapy (psychotherapy and medication) or psychotherapy alone can be used as a first-line treatment for anxiety among epilepsy patients. Patients should first educate themselves about their epilepsy and then consult their doctor for the most effective medication available. Patients should not rely on medications alone as a means to treat their anxiety, as medications often have side effects, and dependence on medication can have its own detrimental effects. In terms of medicine, the ideal drug would be one that specifically targets the GABA receptor by enhancing its action, is easily absorbed into the bloodstream, crosses the blood-brain barrier, and has a reduced clearance rate for a longer-lasting effect, but does not alter the GABA receptor permanently in order to avoid dependency. An example of this could be benzodiazepines. However, as the sedative effects of benzodiazepines such as clonazepam may lead to cognitive impairment after chronic use in epilepsy patients, finding the optimum dose and duration of benzodiazepines may place it closest to an ideal drug type for epilepsy patients with anxiety. Nevertheless, no matter how ideal a drug may be, it should not be the only approach epilepsy patients use in managing their anxiety.
| Drug Discovery Model|| |
On the road to the discovery of an ideal drug, diverse types of animal models are used to study the relationship between epilepsy and anxiety. Rats and mice are very commonly used in screening as they tend to resemble the clinical conditions seen in humans more closely and have a fairly similar pathophysiological outline. Acute epileptic animal models such as the maximal electroshock seizure (MES) and pentylenetetrazole (PTZ) tests are more commonly used in epilepsy investigation as they are more feasible and easy to perform. However, acute models tend to generate a vague understanding of the underlying mechanism and relationship between epilepsy and behavioral disorders such as anxiety. MES and PTZ seizure tests are simple screening acute models that have been used in the discovery of AEDs but are limited to identifying only drugs that have similar characteristics as existing drugs and of known mechanisms of action. Therefore, these models are unable to go beyond the existing knowledge and are unable to provide new insights in epilepsy research. Chronic models are more suitable for epilepsy research as they mimic human conditions more accurately. There are two models that are widely used in research for depicting chronic epilepsy, known as status epilepticus (SE) models. These are the pilocarpine and kainic acid models that are mainly used to investigate TLE, which has the highest prevalence rate in the population. Pilocarpine and kainic acid models have shown correlation between behavioral and cognitive comorbidities along with the level of brain damage caused by chronic epilepsy in animals, which can be extended to humans where lesions in the brain cause epilepsy and anxiety. Brain damage cannot be analyzed using acute models, as the introduction of an acute seizure would not be sufficient to cause any brain damage. Nevertheless, chronic models also have their own limitations. These limitations are usually caused by variability in the animal strain used, different laboratory conditions, and altered induction protocols., It is often a challenge for researchers to share their results and make conclusive remarks due to these discrepancies between models and laboratories.
Therefore, it can be construed that relying just on one type of model, either acute or chronic, does not provide reliable or conclusive results. A battery of screening models involving a simple protocol and a clear methodology should be used in epilepsy research. The best approach would be to start with/ first performing a chronic model test wherein status epilepticus is instigated in animals of the same strain before subjecting them to more than one type of behavioral testing, such as the elevated plus maze and the open field test. Once a correlation has been found and brain analysis verifies the mechanism involved, drug screening can be conducted using both acute epileptic models and chronic models.
| Conclusion|| |
Anxiety disorders among epilepsy patients are growing in number every day, not even counting the unreported cases. In spite of the high prevalence of anxiety among epilepsy patients, studies on the relationship between anxiety and epilepsy are still ongoing and not fully understood. There are numerous theories on the risk and the pathophysiology involved in the manifestation of epilepsy-induced anxiety, but none that are concrete and clear. Nevertheless, there are many nonpharmacological interventions and medications available for those diagnosed to manage their anxiety. However, most of the prescribed medications are often accompanied by unfavorable side effects that could possibly increase the burden of the patient. Therefore, the need for an ideal treatment regime is of dire importance in order to provide epilepsy patients with a better life. An ideal drug would be one that is highly effective in terms of pharmacokinetics and pharmacodynamics in treating both the anxiety and epilepsy, with minimal negative effects. The quality of life of epilepsy patients with anxiety can thus be improved with complete understanding of the disorder and appropriate treatment.
The authors acknowledge Ms. Rufi Tambe (ICT, Mumbai, Maharashtra, India) for helping with the language editing of the manuscript.
Financial support and sponsorship
This work is supported by the eScience Fund of Ministry of Science, Technology and Innovation (MOSTI), Malaysia (Grant No. 06-02-10-SF0250).
Conflicts of interest
There are no conflicts of interest.
| References|| |
Maschio M. Brain tumor-related epilepsy. Curr Neuropharmacol 2012;10:124-33.
Kazemi NJ, O&'Brien TJ, Cascino GD. Localization-related epilepsies due to specific lesions. In: Epilepsy: A Comprehensive Textbook. 2nd
ed. Philadelphia, USA: Engel and Pedley; 2008. p. 2511-23.
Hesdorffer DC, Logroscino G, Benn EK, Katri N, Cascino G, Hauser WA. Estimating risk for developing epilepsy: A population-based study in Rochester, Minnesota. Neurology 2011;76:23-7.
López-Gómez M, Espinola M, Ramirez-Bermudez J, Martinez-Juarez IE, Sosa AL. Clinical presentation of anxiety among patients with epilepsy. Neuropsychiatr Dis Treat 2008;4:1235-9.
Vazquez B, Devinsky O. Epilepsy and anxiety. Epilepsy Behav 2003;4(Suppl 4):20-5.
Gaitatzis A, Trimble MR, Sander JW. The psychiatric comorbidity of epilepsy. Acta Neurol Scand 2004;110:207-20.
Edeh J, Toone B. Relationship between interictal psychopathology and the type of epilepsy. Results of a survey in general practice. Br J Psychiatry 1987;151:95-101.
Jacoby A, Baker GA, Steen N, Potts P, Chadwick DW. The clinical course of epilepsy and its psychosocial correlates: Findings from a U.K. Community study. Epilepsia 1996;37:148-61.
Gureje O. Interictal psychopathology in epilepsy. Prevalence and pattern in a Nigerian clinic. Br J Psychiatry 1991;158:700-5.
Perini GI, Tosin C, Carraro C, Bernasconi G, Canevini MP, Canger R, et al
. Interictal mood and personality disorders in temporal lobe epilepsy and juvenile myoclonic epilepsy. J Neurol Neurosurg Psychiatry 1996;61:601-5.
Tellez-Zenteno JF, Patten SB, Jetté N, Williams J, Wiebe S. Psychiatric comorbidity in epilepsy: A population-based analysis. Epilepsia 2007;48:2336-44.
Meador K. Postictal psychiatric symptoms in epilepsy. Epilepsy Curr 2004;4:227-8.
Wittchen HU, Kessler RC, Beesdo K, Krause P, Höfler M, Hoyer J. Generalized anxiety and depression in primary care: Prevalence, recognition, and management. J Clin Psychiatry 2002;63(Suppl 8):24-34.
Bragatti JA, Torres CM, Londero RG, Assmann JB, Fontana V, Martin KC, et al
. Prevalence of psychiatric comorbidities in temporal lobe epilepsy: The value of structured psychiatric interviews. Epileptic Disord 2010;12:283-91.
Nenadović M, Jašović-Gašić M, Vićentić S, Nenadović N, Simonović P. Anxiety in epileptic patients. Psychiatr Danub 2011;23:264-9.
Tang WK, Lu J, Ungvari GS, Wong KS, Kwan P. Anxiety symptoms in patients with frontal lobe epilepsy versus generalized epilepsy. Seizure 2012;21:457-60.
de Oliveira GN, Kummer A, Salgado JV, Portela EJ, Sousa-Pereira SR, David AS, et al
. Psychiatric disorders in temporal lobe epilepsy: An overview from a tertiary service in Brazil. Seizure 2010;19:479-84.
Brandt C, Schoendienst M, Trentowska M, May TW, Pohlmann-Eden B, Tuschen-Caffier B, et al
. Prevalence of anxiety disorders in patients with refractory focal epilepsy - a prospective clinic based survey. Epilepsy Behav 2010;17:259-63.
de Souza EA, Salgado PC. A psychosocial view of anxiety and depression in epilepsy. Epilepsy Behav 2006;8:232-8.
Hamid H, Ettinger AB, Mula M. Anxiety symptoms in epilepsy: Salient issues for future research. Epilepsy Behav 2011;22:63-8.
Goldstein MA, Harden CL. Epilepsy and anxiety. Epilepsy Behav 2000;1:228-34.
Newsom-Davis I, Goldstein LH, Fitzpatrick D. Fear of seizures: An investigation and treatment. Seizure 1998;7:101-6.
Beyenburg S, Mitchell AJ, Schmidt D, Elger CE, Reuber M. Anxiety in patients with epilepsy: Systematic review and suggestions for clinical management. Epilepsy Behav 2005;7:161-71.
Crawford P. Best practice guidelines for the management of women with epilepsy. Epilepsia 2005;46(Suppl 9):117-24.
Blume WT. Low fertility in men with epilepsy: Unhappy, uninterested, unable. Epilepsy Curr 2009;9:69-70.
Falcone T, Timmons-Mitchell J. Pediatric Epilepsy and Anxiety. Neurological Institute: The Cleveland Clinic Foundation; 2013. p. 1-3.
Hills MD. The psychological and social impact of epilepsy. Neurol Asia 2007;12:10-2.
Chapieski L, Brewer V, Evankovich K, Culhane-Shelburne K, Zelman K, Alexander A. Adaptive functioning in children with seizures: Impact of maternal anxiety about epilepsy. Epilepsy Behav 2005;7:246-52.
Williams J, Steel C, Sharp GB, DelosReyes E, Phillips T, Bates S, et al
. Parental anxiety and quality of life in children with epilepsy. Epilepsy Behav 2003;4:483-6.
Tsuchie SY, Guerreiro MM, Chuang E, Baccin CE, Montenegro MA. What about us? Siblings of children with epilepsy. Seizure 2006;15:610-4.
Vibha P, Saddichha S, Akhtar S. Quality of life (QOL) and marital adjustment in epilepsy and comparisons with psychiatric illnesses. Int J Psychosoc Rehabil 2010;14:105-12.
Harden CL, Kossoy A, Vera S, Nikolov B. Reaction to epilepsy in the workplace. Epilepsia 2004;45:1134-40.
Goldstein MA, Harden CL. Continuing exploration of the neuropsychiatry of seizures: A review of anxiety and epilepsy. Epilepsy Behav 2000;1:228-34.
Kimiskidis VK, Triantafyllou NI, Kararizou E, Gatzonis SS, Fountoulakis KN, Siatouni A, et al
. Depression and anxiety in epilepsy: The association with demographic and seizure-related variables Ann Gen Psychiatry 2007;6:28.
Chapouthier G, Venault P. A pharmacological link between epilepsy and anxiety? Trends Pharmacol Sci 2001;22:491-3.
Charney DS. Neuroanatomical circuits modulating fear and anxiety behaviors. Acta Psychiatr Scand Suppl 2003;38-50.
Kalynchuk LE. Long-term amygdala kindling in rats as a model for the study of interictal emotionality in temporal lobe epilepsy. Neurosci Biobehav Rev 2000;24:691-704.
Satishchandra P, Krishnamoorthy ES, van Elst LT, Lemieux L, Koepp M, Brown RJ, et al
. Mesial temporal structures and comorbid anxiety in refractory partial epilepsy. J Neuropsychiatry Clin Neurosci 2003;15:450-2.
Trimble MR, Van Elst LT. The amygdala and psychopathology studies in epilepsy. Ann N
Y Acad Sci 2003;985:461-8.
Sah P, Faber ES, Lopez De Armentia M, Power J. The amygdaloid complex: Anatomy and physiology. Physiol Rev 2003;83:803-34.
Malmgren K, Sullivan M, Ekstedt G, Kullberg G, Kumlien E. Health-related quality of life after epilepsy surgery: A Swedish multicenter study. Epilepsia 1997;38:830-8.
Malmgren K, Starmark JE, Ekstedt G, Rosén H, Sjöberg-Larsson C. Nonorganic and organic psychiatric disorders in patients after epilepsy surgery. Epilepsy Behav 2002;3:67-75.
Cendes F, Andermann F, Gloor P, Gambardella A, Lopes-Cendes I, Watson C, et al
. Relationship between atrophy of the amygdala and ictal fear in temporal lobe epilepsy. Brain 1994;117:739-46.
Drevets WC. Neuroimaging studies of mood disorders. Biol Psychiatry 2000;48:813-29.
Seidenberg M, Hermann B, Noe A, Wyler AR. Depression in temporal lobe epilepsy: Interaction between laterality of lesion and Wisconsin Card Sorting Performance. Neuropsychiatry Neuropsychol Behav Neurol 1995;8:81-7.
Ring HA, Moriarty J, Trimble MR. A prospective study of the early postsurgical psychiatric associations of epilepsy surgery. J Neurol Neurosurg Psychiatry 1998;64:601-4.
Altshuler LL, Devinsky O, Post RM, Theodore W. Depression, anxiety, and temporal lobe epilepsy. Laterality of focus and symptoms. Arch Neurol 1990;47:284-8.
Robinson RG, Szetela B. Mood change following left hemispheric brain injury. Ann Neurol 1981;9:447-53.
Malizia AL, Cunningham VJ, Bell CJ, Liddle PF, Jones T, Nutt DJ. Decreased brain GABA (A)-benzodiazepine receptor binding in panic disorder: Preliminary results from a quantitative PET study. Arch Gen Psychiatry 1998;55:715-20.
Lydiard RB. The role of GABA in anxiety disorders. J Clin Psychiatry 2003;64(Suppl 3):21-7.
Toczek MT, Carson RE, Lang L, Ma Y, Spanaki MV, Der MG, Fazilat S, et al
. PET imaging of 5-HT1A receptor binding in patients with temporal lobe epilepsy. Neurology 2003;60:749-56.
Savic I, Lindström P, Gulyás B, Halldin C, Andrée B, Farde L. Limbic reductions of 5-HT1A receptor binding in human temporal lobe epilepsy. Neurology 2004;62:1343-51.
Merlet I, Ostrowsky K, Costes N, Ryvlin P, Isnard J, Faillenot I, et al
. 5-HT1A receptor binding and intracerebral activity in temporal lobe epilepsy: An [18F] MPPF-PET study. Brain 2004;127:900-13.
Neumeister A, Bain E, Nugent AC, Carson RE, Bonne O, Luckenbaugh DA, et al
. Reduced serotonin type 1A receptor binding in panic disorder. J Neurosci 2004;24:589-91.
Mula M, Monaco F. Antiepileptic drugs and psychopathology of epilepsy: An update. Epileptic Disord 2009;11:1-9.
Nadkarni S, Devinsky O. Psychotropic effects of antiepileptic drugs. Epilepsy Curr 2005;5:176-81.
Ketter TA, Malow BA, Flamini R, White SR, Post RM, Theodore WH. Anticonvulsant withdrawal-emergent psychopathology. Neurology 1994;44:55-61.
Strauss E, Wada J, Moll A. Depression in male and female subjects with complex partial seizures. Arch Neurol 1992;49:391-2.
Otoom S, Al-Jishi A, Montgomery A, Ghwanmeh M, Atoum A. Death anxiety in patients with epilepsy. Seizure 2007;16:142-6.
Scicutella A, Ettinger AB. Treatment of anxiety in epilepsy. Epilepsy Behav 2002;3(Suppl):10-2.
May TW, Pfäfflin M. Psychoeducational programs for patients with epilepsy. Dis Manag Health Out 2005;13:185-99.
Ogata A, Amano K. A psychosocial approach to epileptic patients. Epilepsia 2000;41(Suppl 9):36-8.
Pfäfflin M, Petermann F, Rau J, May TW. The psychoeducational program for children with epilepsy and their parents (FAMOSES): Results of a controlled pilot study and a survey of parent satisfaction over a five-year period. Epilepsy Behav 2012;25:11-6.
Wilmshurst JM, Berg AT, Lagae L, Newton CR, Cross JH. The challenges and innovations for therapy in children with epilepsy. Nat Rev Neurol 2014;10:249-60.
Tekle-Haimanot R, Abebe M, Forsgren L, Gebre-Mariam A, Heijbel J, Holmgren G, et al
. Attitudes of rural people in central Ethiopia towards epilepsy. Soc Sci Med 1991;32:203-9.
Akpan MU, Ikpeme EE, Utuk EO. Teachers&' knowledge and attitudes towards seizure disorder: A comparative study of urban and rural school teachers in Akwa Ibom State, Nigeria. Niger J Clin Pract 2013;16:365-70.
Herbert JD, Gaudiano BA, Rheingold AA, Moitra E, Myers VH, Dalrymple KL, et al
. Cognitive behavior therapy for generalized social anxiety disorder in adolescents: A randomized controlled trial. J Anxiety Disord 2009;23:167-77.
Gracey F, Oldham P, Kritzinger R. Finding out if “The &'me&' will shut down”: Successful cognitive-behavioural therapy of seizure-related panic symptoms following subarachnoid haemorrhage: A single case report. Neuropsychol Rehabil 2007;17:106-19.
Priyamvada R, Kumari S, Prakash J, Chaudhury S. Cognitive behavioral therapy in the treatment of social phobia. Ind Psychiatry J 2009;18:60-3.
Atack JR. Anxioselective compounds acting at the GABA (A) receptor benzodiazepine binding site. Curr Drug Targets CNS Neurol Disord 2003;2:213-32.
Chew RH, Hales RE, Yudofsky SC. What your patients need to know about psychiatric medications. In: Hales RE, Yudofsky SC, editors. Anti-Anxiety Medications. Virginia: American Psychiatric Publishing; 2009. p. 11-3.
Ketter TA, Malow BA, Flamini R, Ko D, White SR, Post RM, et al
. Felbamate monotherapy has stimulant-like effects in patients with epilepsy. Epilepsy Res 1996;23:129-37.
Johannessen SI, Landmark CJ. Antiepileptic drug interactions-Principles and clinical implications. Curr Neuropharmacol 2010;8:254-67.
Stewart SA. The effects of benzodiazepines on cognition. J Clin Psychiatry 2005;66 (Suppl 2):9-13.
Löscher W. Critical review of current animal models of seizures and epilepsy used in the discovery and development of new antiepileptic drugs. Seizure 2011;20:359-68.
Lenck-Santini PP. Cognitive and behavioral comorbidities in epilepsy: The treacherous nature of animal models. Epilepsy Curr 2013;13:182-3.
Hort J, Brozek G, Komárek V, Langmeier M, Mares P. Interstrain differences in cognitive functions in rats in relation to status epilepticus. Behav Brain Res 2000;112:77-83.
[Figure 1], [Figure 2], [Figure 3]
|This article has been cited by|
||An aqueous extract of Khaya senegalensis (Desv.) A. Juss. (Meliaceae) prevents seizures and reduces anxiety in kainate-treated rats: modulation of GABA neurotransmission, oxidative stress, and neuronal loss in the hippocampus
| ||Antoine Kavaye Kandeda, Stéphanie Lewale, Etienne Djeuzong, J. Kouamouo, Théophile Dimo |
| ||Heliyon. 2022; 8(5): e09549 |
|[Pubmed] | [DOI]|
||Role of Short Chain Fatty Acids in Epilepsy and Potential Benefits of Probiotics and Prebiotics: Targeting “Health” of Epileptic Patients
| ||Soomin Kim, Siyeon Park, Tae Gyu Choi, Sung Soo Kim |
| ||Nutrients. 2022; 14(14): 2982 |
|[Pubmed] | [DOI]|
||Effect of rutin on anxiety-like behavior and activity of acetylcholinesterase isoforms in specific brain regions of pentylenetetrazol-treated mice
| ||Maria Anesti,Natalia Stavropoulou,Korina Atsopardi,Fotini N. Lamari,Nikolaos T. Panagopoulos,Marigoula Margarity |
| ||Epilepsy & Behavior. 2020; 102: 106632 |
|[Pubmed] | [DOI]|
||The Efficacy of Mindfulness-Based Cognitive Therapy on Self-Efficacy and Anxiety Among Epileptic Patients
| ||Samaneh Mohamadpour,Fakhri Tajikzadeh,Abdolaziz Aflakseir |
| ||Archives of Neuroscience. 2017; In press(In press) |
|[Pubmed] | [DOI]|