Background:
Epilepsy is considered a disease which has a persistence tendency for patients to experience epileptic seizures and also by the neurobiological, psychological, cognitive, and social sequel of this condition. An epileptic seizure is the signs and/or symptoms that occur transiently due to abnormal synchronous or excessive neuronal activity that occurs in the brain. A seizure can be characterized as an event and that epilepsy as the disease that involves recurrent unprovoked seizures.[1] International league against epilepsy(ILAE) named six etiologies for epilepsy which include: structural causes, genetic causes, infectious causes, metabolic causes, immune causes and unknown causes. The ILAE also classified the etiologies of seizures in (2017) into: Generalized onset, Focal onset and unknown onset. The ILAE divided epilepsy into four categories: generalized epilepsy, focal epilepsy, combined generalized/focal epilepsy and an unknown category. [10] Epilepsy diagnosis is mainly clinical and largely depends on a careful history taken from the good eyewitnesses. The EEG may help in epilepsy classification, but normal EEG may be observed in patients with epilepsies and abnormal findings in patients without epilepsy.[2] Magnetic resonance imaging should be the imaging investigation of choice and is particularly important in those who have epilepsy that occurred before two years or in adulthood, who have a focal onset as suggested by history, from the examination, or by electroencephalography (unless it is clear that it is a benign focal epilepsy) and in whom there are still seizures despite using first line medication.[3] The plan of management for patients with epilepsy (PWE) focus on three main goals: to control seizures, to avoid the side effects of the drug, and to maintain the quality of life (QOL) or to restore it.[4] Immediate anti-seizure drug therapy is usually not necessary in individuals after a single seizure and is typically reserved for individuals who are at high risk of recurrent seizures or patients who developed more than one unprovoked seizures.[4]
Psychogenic non-epileptic seizures (PNES) are conditions that clinically resemble epileptic seizures, but don’t have physiological dysfunction of central nervous system but instead can be determined psychogenical.[7] Many Psychosocial stressors may result for those who are vulnerable to have emergence of PNES, include bereavement, unwanted pregnancy and ongoing abuse; physically, verbally, or sexually.[7] Duration that is prolonged, course that is fluctuating, movements that are asynchronous, movements of the head or the body that are from side-to-side, thrusting of the pelvis, crying during the ictal phase, ictal eye closing, memory recall, and postictal confusion absence were the most reliable signs in distinguishing PNES from epileptic seizure. What is important to recall is that there is no exact feature that is either specific or sensitive for PNES.[7] Manifestations of PNES include unresponsive behavior with motor manifestations mimicking a generalized convulsion or a complex partial type is the manifestation that is most common of a PNES.[7] PNES most likely don’t occur during sleep but epileptic seizures can occur during sleep. There are many convulsive-like motor activities that can occur in PNES. Motor activities of the epileptic seizure usually present as a brief tonic posturing or a synchronized convulsion within which motor activity progression is defined; in PNES movements are more often variable, asynchronous and waxing and waning over the ictus course. Movements that can suggest PNES include thrashing, writhing, opisthotonus (arched back), pelvic thrusts and jactitation or side to side rolling. Rapid alerting and reorientation is common after PNES but uncommon with epileptic seizures.[7] The best diagnostic tool available is Video-EEG.[8] Consistent history with PNES and typical event recording of typical semiological PNES features with electroencephalogram (EEG) recording showing absence of epileptiform activity before the attack, during it, or thereafter is the best measure to reach the diagnosis. History, semiology and video EEG suggesting PNES combination gives the “documented” PNES level. However, recognizing PNES even in situations with very low levels of certainty is important, because not everyone in the world has video EEG access and clinicians and patients may need to adjust treatment choices (maybe about tapering inappropriate antiepileptic drugs or starting psychological treatment) when the diagnosis is not completely certain. Such uncertainty levels can be characterized in descending order as “clinically established,” “most likely,” and “possible”.[9] Prevalence estimates of concurrent epilepsy in patients diagnosed with PNES vary from 5 to 56 percent, in part because of differing diagnostic criteria used to determine when both conditions have occurred together.[7]
Stigma is a status which found when components of labeling, categorizing, disconnection, discrimination and loss of status occur together in a situation of power that permits them to unfold. In other words stigma is the bearing the disease burden and also the heaviness of labeling as lower or being infected by those who are not diseased and in better power or situation to label the diseased person and losing them their status in the community.[6] Stigma perceived by the PWE patient can be classified into four major types, Enacted, Felt in patients, and coaching and courtesy in their families. Enacted stigma refers to real discrimination events towards PWE because of their disease, i.e. it happens when others –because of many reasons- label, naming, or act in discriminative ways towards PWE. Mainly it is because of misconceptions and/or lack of knowledge of the disease. Many fear from PWE as they are thought to be in sin or with demonic possession, others believe epilepsy is infectious. Felt stigma is explained as the shame from having an epilepsy and the repressive fear of contracting Enacted stigma. Coaching stigma occurs in ashamed parents who tend to teach their sons that epilepsy is an unsought uniqueness or moral weight they have to bear. Courtesy stigma on the other hand is when stigma is extended from labeled individuals to their relatives. [6]
Problem statement:
Co-existence of epilepsy and psychogenic non-epileptic seizure places an even greater challenge for both psychiatrists and neurologists in following up their patients, as PNES also may lead to being misdiagnosed as a true seizure by some neurologists. Almost all patients’ relatives consider PNES as a true seizure before consulting their neurologist, which may create some sort of stress and loss of hope in relatives (as the patients may be already on drugs and well controlled) and create or increase epilepsy stigma in patients and their families. Misunderstanding PNES as true seizure by either the patients and/or their family may lead them (especially in Sudan) to lose hope in medical therapy and seek help from a traditional healer (ex. herbal remedy and Sheikh). PNES is not uncommon where the estimates are 2-50/100,000 in the general population [11], but it is much larger in patients having epilepsy where 20–40% of those in inpatients in monitoring units of epilepsy and between 5% to 10% of those in outpatients in epileptic clinics have PNES.[12] The lack of appropriate diagnosis of PNES among epileptic patients can results in the increase of an anti-epileptic drugs dose in a potentially harmful way as well as the diagnosis of refractory epilepsy.[3] Patients who are admitted to monitoring units of video-EEG because of a diagnosis of drug-resistant epilepsy one among every five of them are found later to be suffering from PNES; the PNES coin is pseudo-refractory epilepsy.[13] Psychogenic epilepsy is among the top 10 critical neuropsychiatric conditions according to the International League Against Epilepsy (ILAE).[13] According to the reports PNES presence is usually due to financial, interpersonal and psychiatric problems.[14] Depressive, anxiety disorders and relationship problems are more prevalent among PNES patients in comparing them to the general population and even to those with epilepsy which has a strong impact on the QOL.[11] Stigma is another problem encountered in both types, but the perceived stigma risk experience is 42% higher in PNES patients than in patients with epilepsy.[15] Despite of all this most researchers have studied PNES alone while few studies have conducted on the subgroups of patients having both PNES and epilepsy and on the relation between PNES and its associated co-morbidities.
Justification:
As far as we know there is not enough data regarding the PNES prevalence, factors increasing its risk and the associated co-morbidities; so our study aim is to measure the PNES prevalence among adult epileptic patients and to formulate a relationship between PNES and multiple different factors. Globally this area of co-existence between epilepsy and PNES is not that clear and not researched thoroughly. Also in Sudan there is no available literature. By the end of this research I expect to find an estimated prevalence of PNES among Sudanese adult patients who have epilepsy, and a relation between other independent variables and the PNES prevalence among adult epileptic patients. There must be a clear base of literature regarding the relation between PNES and epilepsy, so to avoid mixing between the two conditions by patients or their relatives, and to further prevent misdiagnosing by the neurologists.
Objectives:
General objective:
To assess the PNES prevalence among adult Sudanese epileptic patients who are attending Daoud charity clinic, 2021.
Specific objectives:
1- To find out the PNES prevalence among Sudanese adult patients with epilepsy.
2- To study the relation between psychogenic non-epileptic seizures and the type of epilepsy.
3- To demonstrate the relation between psychogenic non-epileptic seizures and epilepsy duration.
4- To identify the relation between psychogenic non-epileptic seizures and the type of anti-epileptic drugs.
5- To illustrate the relation between psychogenic non-epileptic seizures and the number of anti-epileptic drugs.
6- To measure the relation between psychogenic non-epileptic seizures and treatment duration.
7- To estimate the relation between psychogenic non-epileptic seizures and the stigma of epilepsy.
Literature review:
Definitions:
In 2005 epilepsy conceptually was defined as a brain disorder that can be characterized by a persistence tendency to experience epileptic seizures, the application practically of this is routinely defined as having more than one unprovoked seizures >24h apart. Then in 2014 the task force of ILAE considers epilepsy to be a brain disease characterized if any of these conditions has been found: two unprovoked seizures at least occurring >24h apart, one seizure that is unprovoked and at least there is a 60% probability of having another seizure as the general risk following two unprovoked seizures, happening during the next ten years, epilepsy syndrome diagnosis. [16,17,18]
Classification of epilepsy informs many risks of comorbidities like intellectual disability, learning difficulties, and some psychiatric features “like autism spectrum disorder”, and risk of mortality such as unexpected sudden death in epilepsy. Classification has three levels starting with type of seizure (seizures first must be differentiated from convulsive syncope, parasomnias, movement disorders, and the other non-epileptic events), then epilepsy types which are generalized epilepsy, focal epilepsy, combined generalized and focal epilepsy, and unknown epilepsy group, and the last level is epilepsy syndrome (it’s a collection of features often has age-dependent, seizure triggers, diurnal variation, and sometimes prognosis), also epilepsy may has comorbidities such as psychiatric dysfunction and intellectual dysfunction.[17]
According to the anatomical origin of epileptic focus epilepsy has been classified into four categories:
Is the type that is most common of localized epileptic seizures to occur. Patients with this type of seizures can hallucinate visions, sounds, tastes and smells for the period of the seizure, as well as feel an inability to explain their sensations afterwards.[19]
This site is the commonest after temporal lobe of localized epilepsy, seizures within the frontal lobe can cause uncontrollable muscle twitching. Patients with this type of seizures may have asymmetrical kicking movements or legs’ movements such as riding a bicycle, because of certain muscle control centers over-stimulation in the brain.[19]
- Occipital Lobe epilepsy :
Epilepsy affecting this site account for about five and ten percent of total cases of epilepsy, patients with this type typically will have visual hallucinations in form of flashing or repeated images, involuntary movements of the eye, or partial blindness.[19]
Most patients with this type of localized epilepsy have aura which is somatosensory that can present as painful dysesthesias, aphasia and though vertigo, disturbances of body image also occur. If supplementary motor area propagation occurs, hyper motor manifestations will be noted. Complex hallucinations auditory or visual in addition to automatisms may appear when temporo-limbic propagation occurs. [20]
General principles of anti-epileptic drugs (AEDs) treatment (NICE, 2012):
1-It is recommended that children, young people and adults should be treated with a single AED (mono-therapy) whenever that is possible.
2-If the initial mono-therapy is not successful, then mono-therapy using another drug or a treatment with a second drug can be added. Caution is needed during the change-over period. Failure of an AED either due to continued seizures or adverse effects, another drug should be commenced (which is either another first-line or instead second-line drug) and increasing to an appropriate or maximum dose that can be tolerated and then slow tapering of the first drug may be done.
3-If the latter AED is not helpful; one of the two drugs may be tapered, depending on their relative efficacies, side effect profiles and drugs tolerability before starting another drug. Some patients will need more than 2 AEDs.[5]
4- The recommendations are that two drugs combinations either as an adjunctive or ‘add-on’ therapy must be considered only when mono-therapy trials with the tolerated dose of AED have not aborted the seizures. If attempts at combination do not give the desired effects, treatment should be reverted to the regimen (mono-therapy or combination) that showed to be the most acceptable to the patient, that is to provide the best balance between effectiveness in decreasing seizure occurrence and tolerability of adverse effects.
5- When choosing combination therapy, considerations about interactions of AEDs and comorbidities should be sought.
6- If there is no improvement after two adequate trials of AEDs, the patient should be referred for epilepsy surgery evaluation.[5]
PNES:
Psychogenic non-epileptic seizures are a functional neurological disorder/ subtype of conversion disorder, which are neurobehavioral disorders at the neurology and psychiatry interface. [21]
The definitions adopted in the literature to describe psychogenic non-epileptic seizures (PNES), include the following:
- An observed sudden, usually time‐limited paroxysmal change in behavior or consciousness looks like phenomenologically (semiologically) an epileptic seizure.
- There are no characteristic changes seen in electrophysiology that occur with an epileptic seizure (i.e., the absence of ictal or postictal electroencephalography [EEG] changes).
- No evidence of other causes for the episodes.
- Evidence or strong suspicion of psychogenic processes as causative factors. [22]
Clinical features of PNES:
Differentiating Epileptic seizures (ES) from PNES could be clinically challenging. A review detailing signs retrospectively that can distinguish PNES suggested that favoring a PNES diagnosis for events that show a course that is fluctuating, movements that are asynchronous or side-to-side, a long duration, crying at the or eye closure at the onset of the ictal phase, ictal crying and post-ictal recall of information when presented ictally. In addition, urinary incontinence and tongue biting do not reliably distinguish between ES and PNES. A study done prospectively of 120 seizure attacks in 35 consecutive subjects showed that preserved consciousness documented by the video, eye twitching, and the attenuation of the intensity of the event by eyewitnesses reliably predicted PNES; sudden onset, ictal eye-opening and confusion/sleep post-ictally reliably suggests ES. It is also important to know that apart from all of the above, additional diagnoses should also be checked and ruled out including panic attacks, paroxysmal movement disorders and physiologic non-epileptic events that includes cardiac arrhythmias and other disorders.[21] Although there is no definitive single clinical feature that can distinguish PNES from ES, PNES diagnostic suggestive features including duration that is longer, pre-seizure anxiety, negative emotion (i.e., fear) that occurs throughout the events, ictal dissociation, and post-seizure weeping. Fewer reports of ictal self-injury and post-seizure aches and amnesia may also favors the possibility of PNES.[23]
Risk factors:
PNES and physical brain injury may be associated; the latter could have a role in their development: pathogenesis of PNES may be contributed by head injury. There are documented cases of resective surgeries of epilepsy or other intracranial neurosurgery followed by psychogenic seizure. Recent studies found associations between psychogenic seizure disorders and right hemisphere pathologies, non-specific interictal electroencephalography abnormalities, neuropsychological deficits and MRI changes. [24] The most common psychiatric mechanism is thought to be a conversion disorder. And there are some evidences from neuroimaging studies that suggest PNES may actually reflect sensorimotor alterations, cognitive control, emotional regulation/processing and integration of neural circuits. [21]
In a study that was conducted in 2017 in Puerto Rico, on clinical records of PNES patients, a secondary analysis was done for 34 records of PNES patients. 76% (n=26) of those patients were females, in agreement with the hypothesis of PNES being more prevalent among females. Trauma history related to sexual, physical, or emotional abuse (reported by 47%), and stressful life events (reported by 94%), in addition to symptoms of depression (reported by 50%) were among the reported risk factors. [25] A similar study was conducted in India in 2020 to understand the dissociative experiences and stressors related to patients of PNES. A total of 89 patients were screened. Assessment for history of abuse revealed physical abuse in childhood in 7 (10%) patients, 9 (12.6%) patients gave history of being physically eaten, and 6 (8.5%) had been abused sexually as adults. Using the dissociative scale of experiences (DES), the total mean score was noted to be 38.14 ± 14.1 (scores above 30 = high dissociation), indicating a high level of dissociation .The mean score regarding stressful life events was noted to be 98.28 ± 87.1, indicating that the majority of patients complained of stressful life events, especially marital and family conflicts. In addition, the analysis of various types of stressors revealed that 40% of patients experienced a stress prior to the PNES.[26]
Diagnosis and treatment:
Although PNES is a common differential for epilepsy, misdiagnosis or delay in diagnosis is common with up to 75% of patients being first diagnosed with epilepsy, and an average delay of seven to ten years making a significant burden on the patient 's family and health system. [29,30]
Diagnosis of PNES may be challenging due to difficulty in availability of comprehensive neurological and psychiatric assessment plus EEG monitoring at the same setting. Sometimes seizure of interest may be not detected in initial video EEG requiring long term monitoring.[31] Due to these factors non-epileptic seizure task force of ILAE design staged approach for diagnosis based on history witnessed event and EEG with different level of certainty.[32]
The mainstay effective treatment of PNES is psychotherapy with cognitive behavioral therapy (CPT) being the most efficient. If there is no benefit of an antiepileptic drug it should be tapered. Pharmacologic intervention is used for treatment of comorbid illness.[31] An exploratory study in Brazil in 2018, of patients whose age was more than 16 years had been admitted to prolonged monitoring by video-electroencephalogram were evaluated for the features related to demographic, epileptogenic and psychiatric. Detailed psychiatric assessment was performed by M.I.N.I.-plus 5.0, Beck Depression Inventory, Beck Anxiety Inventory, and the Childhood Trauma Questionnaire (CTQ) was conducted. Data collection was done before reaching the final diagnosis and patients were compared.[33] 86 total patients were included from which 25 (29%) were with PNES. Twelve (14%) were with only PNES, 13 (15%) with ES and PNES and the rest of the 61 (71%) were with ES-only, Out of 122 patients that had been admitted to the epilepsy monitoring unit. Two or more seizure types (p˂0.001), past psychiatric disorder history and nonspecific hyperintensities of the white matter on MRI (p < .001) were associated with ES and PNES coexistence. Also, significantly higher emotional neglect and abuse had been found among these patients (p < .002 and 0.001, respectively). Somatization, which includes conversion disorder, constituted the most commonly diagnosed disorder in PNES- only patients (83%) and patients with co-both PNES and ES (69.2%), distinguishing both of them from patients with ES-only (p < .001). This high prevalence of the co-existence PNES/ES in this study reinforced the need to investigate properly PNES in depth.[33] Another similar study conducted in Italy in 2020 with the aim to explore psychopathological features in a sample of referred youth with PNES either alone or with ES, compared with ES control group. Thirty-four patients were between 12 years to 21 years, 15 males and 19 females, were found in the study, 7 of them had both PNES and ES, 15 of them had PNES and 12 patients had ES. Then comparison of the three groups was conducted according to psychiatric diagnoses, life stressors, psychopathological dimensions and personality traits that include interpersonal reactivity, alexithymia and resilience, the assessment was done with structured measures. Patients with PNES with ES or PNES alone were found to have a greater mood disorder incidence, had increased frequency of lifetime traumatic experiences, were impaired more severely, and lower level resilience. All of the above groups presented alexithymic traits and emotional dysregulation.[34] A review done systematically of all published observational studies (from inception to Dec. 2016) was done in order to determine the correlates, frequency and outcomes of dual diagnosis. All of the studies that were reporting a diagnosis of any age of both PNES and epilepsy were included. Observational study designs had been included with the exception of all case reports as well as case series with less than 10 participants.
The mean epilepsy frequency in PNES patients across those studies was noted to be 22% (95% confidence intervals range between 20% to 25%,: 0% to 90%) also the mean PNES frequency in those epileptic patients was noted to be 12% (95% CI range from 10% to 14%, range: 1% to 62%). That means caution should be taken when viewing this high heterogeneity of such pooled estimates. A number of correlates of dual diagnosis also had been reported. Some studies described the differences in seizures semiology in patients with both diagnoses vs. patients with either PNES alone or epilepsy alone. However, the majority of these correlates were found to be inconclusive. Outcomes had been examined in a few of these studies in dual diagnosed patients. In clinical practice dual diagnosis is common, especially in those patients who had been referred to specialized services, and needs careful diagnosis and management.[35] In a study conducted in Sudanese adult patients with epilepsy by Khabab Abbasher and his colleagues 40 out of 720 patients had PNES with the most commonly affected age group being those between ages 18 to 25 . It was observed that PNES is more common among patients with idiopathic epilepsy, and is more common in women (75%) than in men which was said to be due to the more cultural stressors among Sudanese epileptic women. It’s important to note that all PNES patients (40) had normal EEG.[36] Markus Reubera and Christian E. Elger (Psychogenic non-epileptic seizures: review and update 2003) concluded if PNES are managed to be recognized early patients will do better if, outcome was found also to be better among children and younger adults . More intelligent patients and people in higher socioeconomic classes do better. There is a relationship found between PNES semiology and outcome had been found with less dramatic seizures had been linked to better prognosis (no tonic clonic like seizures; no tongue biting history, ictal incontinence, or PNES status). Finally, there were an associations found between maladaptive personality dissociative tendencies or wider somatization and poor prognosis.[37] A systematic review done by Gislaine Baroni et.al (2016) mentioned that epilepsy may act as a ‘risk factor’ for PNES, for high prevalence of psychiatric disorders and due to psychosocial factors. Although psychiatric symptoms usually occur with temporal lobe epilepsy, they point out that they are also found in other epileptic conditions and that abnormalities in brain structure may increase risk not only for ES, but also for other cognitive and psychiatric disorders. When both of them co-exist, PNES onset almost always preceded by ES as in raising important issues for an underlying psychiatric comorbidities of epilepsy that are related to physiopathological mechanisms.[38] In a German study conducted by Reuber and his colleges (2003), out of 329 patients in whom PNES diagnosis had been established 68 women and 22 men had additional epilepsy. 26.8 years was the mean age of PNES onset. In all cases PES started after epileptic seizures. The PNES semiology in 61.1% was convulsive, in 23.3% was tonic, in 10.0% was flaccid and in 5 % was sensory. In 64.4% of patients there was clear loss of consciousness. In 40.0% the semiology and the epileptic seizures of these patients were similar. They conclude that in epileptic patients, female gender, visual memory deficits, global NPS impairment and lower IQ these all are associated with higher PNES risk. Other factors that are organic or biological, especially the epileptogenic lesion lateralization and epilepsy onset age are not found to be associated with a greater PNES risk.[39] According to study conducted by Robert Hopner at Germany (2014) ESs are a common comorbidity in patients with PNESs, being present in one-third of the patients with PNES. There is a significant difference at onset; PNES only patients are significantly older than those with PNESs with epilepsy. A very theoretical explanation for this difference in onset might be because patients with ESs are already familiarized with a paroxysmal attacks of the organic disorder and, thus, tend to gain psychogenic paroxysmal disorder more easily.[40] According to American study done by Jagan A. Pillai and Sheryl R. Haut (Patients with epilepsy and psychogenic non-epileptic seizures 2011) non-epileptic seizures have been noted to follow epileptic seizures immediately, suggesting that seizure experience in susceptible individuals can provoke PNES. A possibility has subsequently been raised that disorders like epilepsy that can impair self-monitoring or emotional functions may contribute to conversion disorder and thereby PNES. The study suggests that the more commonly noted seizure type in epileptic patients with PNES in comparing to those with just epilepsy during EEG video recording are frontal seizures.[41]
Stigma:
Few studies addressed the issue of stigma attached to PNES. A 2017 exploratory study, conducted in the United Kingdom, compared the perceived stigma nature in PNES patients (n=47) against individuals with epilepsy (n=78). Greater stigma level was reported in patients who had PNES than epileptic patients (p=0.04). The study indicated that in PNES patients the perceived stigma risk development was 42% greater than in epileptic patients. These findings can suggest that most of the patients who had PNES (87.2%) reported a degree of perceived stigma. [27] The same exploratory analysis done previously about the perceived stigma nature in PNES patients compared to epileptic patients. Recruitment for 78 epileptic and 47 PNES patients was done from a hospital of the United Kingdom or membership organizations for persons living with seizures. All of them were asked to have a questionnaire series about health-related components for quality-of-life (NEWQOL-6D), anxiety (GAD-7), depression (NDDI-E), seizure frequency and severity (LSSS-3), and illness perception (B-IPQ). There was just one question that had been taken from the NEWQOL-6D was measuring perceived stigma. A higher perceived stigma level was reported in PNES patients than epileptic patients (p = 0.04). The results showed that the perceived stigma risk in PNES patients was 42% greater than the risk of having it in epilepsy. Seizure frequency, anxiety and depression and perceived stigma were highly associated in epilepsy but not in PNES. In the two conditions, self-control and stigma were associated (rho ≥ 0.34, p ≤ 0.01). Findings indicated that most(87.2%) of persons having PNES reported some degree of perceived stigma, which indicates greater risk than that in epilepsy.[27]
Another study on stigma among PNES patients was conducted in 2020 in the USA. 43 individuals with PNES and 165 individuals with epilepsy were recruited. Compared with epileptic patients, there is a shorter duration of the disease, higher seizure frequency, poorer psychosocial health, normal diagnostic data and fewer anti-seizure medications among individuals with PNES. There was a higher stigma level in PNES patients compared to epileptic patients. In addition to that, 28 PNES caregivers and 99 epileptic caregivers were recruited. Caregiver stigma was also higher among caregivers of PNES patients, and this was associated negatively with QOL of patients and positively with the anxiety of the patient and caregiver. [28]