Epilepsy Research Benchmarks Progress Update 2007-2009: Area III

A. Identify and characterize the full range and age specificity of comorbidities in people with epilepsy.

Background: 
Compared to those without epilepsy, people with epilepsy are more likely to develop or report certain neuropsychiatric conditions, including depression, anxiety, sleep disturbances, cognitive impairment, and psychosis, as well as poor physical health outcomes, such as pain and arthritis, heart disease, and even sudden unexpected death.  Research suggests that the presence and severity of these conditions varies across individuals and different types of epilepsy.  Better characterization of the comorbid conditions of epilepsy will advance our understanding of their causes and risk factors.  

Summary of Advances:
Several recent studies have provided new information on the range and frequency of conditions beyond seizures affecting both adult and pediatric populations of people with epilepsy. This research is also providing insights into factors that affect individuals’ susceptibility for developing certain comorbidities.

• Community-based and broad population studies have found that adults diagnosed with epilepsy are more likely than people without epilepsy to report anxiety, depression, or suicidal behaviors [147, 148]. A population-based survey in 19 U.S. states found that adults with active epilepsy or a history of epilepsy were more likely to report worse health-related quality of life [149], and a retrospective study found that a prior history of psychosis was more common in cases of new-onset epilepsy than in people without epilepsy [150].
   
• A longitudinal study of children with newly diagnosed epilepsy found that approximately one in four showed below normal cognitive function. Factors associated with poorer cognitive function in this and other research included young age at epilepsy onset, symptomatic cause (due to an insult or an underlying cause like abnormal brain development), and continued treatment [151, 152]. Additional studies reported deficits in attention, cognition, and neuropsychological function in children at the onset of seizures [153, 154] and associated the presence of comorbid cognitive and behavioral deficits at epilepsy onset with worse prospective cognitive development [155].

B. Identify predictors and underlying mechanisms that contribute to co-morbidities.

Background: 
In the past, cognitive and behavioral comorbidities of epilepsy have been viewed largely as consequences of seizures that would disappear with adequate seizure control.  However, this view has been challenged by more recent findings that these conditions may be present at or before the onset of epilepsy and that they do not always or fully improve with seizure control. 

Summary of Advances:
Research in people and animal models is advancing our understanding of the factors that contribute to comorbidities, which could include shared mechanisms that cause both seizures and other conditions, neurobiological effects of recurrent seizures, side effects of anticonvulsant medications, and psychological responses to living with epilepsy.  Some recent findings are highlighted below; for additional references, see [156-163].

• Advancing technologies for imaging and recording brain structure and function are providing new clues into the neurobiological basis of cognitive and behavioral impairments that can accompany epilepsy [164-176].  For example, one brain imaging study found that compared to age-matched controls, children with new onset epilepsy showed a delayed developmental increase in white matter volume, which contains neuronal fibers connecting brain regions [177]. Another study using a technique called transcranial magnetic stimulation (TMS) showed evidence for altered brain excitability up to 24 hours before and after a generalized tonic-clonic seizure, suggesting a potential basis for cognitive impairment that can accompany poorly controlled epilepsy [178].  Several studies using positron emission tomography (PET) imaging have shown evidence for altered signaling by the neurotransmitter serotonin, suggesting  a mechanism in common with primary major depressive disorders [165, 179]. The continued application of these new technologies, particularly in research that combines multiple measures of brain structure and function, is a promising area of research toward understanding the comorbidities of epilepsy. 
   
• Repeated seizures in childhood have been associated with later cognitive and behavioral deficits, but the roles of the seizures themselves or other underlying mechanisms are unclear.  In children with prior epilepsy but otherwise normal neurological exams and average or above average intelligence, even after the resolution of seizures, information processing speed remained significantly lower than in siblings without a history of epilepsy [180]. Rats subjected to experimental seizures early in life showed spatial memory deficits and abnormal activity in neurons important for mapping and retrieving spatial information [181, 182]. In addition, learning and memory deficits in rats with prior febrile seizures correlated with changes in the hippocampus visible on MRI brain scans, suggesting potential biomarkers for lasting deficits following prolonged seizures early in life.
   
• Temporal lobe epilepsy (TLE) is the most common form of non-acquired, focal epilepsy in adults and is often associated with cognitive deficits. In a rat model of TLE, pharmacologically inducing an initial prolonged seizure (status epilepticus) leads to a period of epileptogenesis, and then to chronic, spontaneous seizures. Longitudinal assessments on memory tasks during epileptogenesis in this model showed impaired spatial memory and soon after status epilepticus, occurring before the onset of spontaneous seizures and persisting into the chronic seizure stage without further change [183]. A longitudinal study of people with TLE showed evidence for hindered cognitive development but not for ongoing progressive decline following TLE onset [184], and a study in children suggested that early TLE may impair the development of processes important for modulation of memory by emotional information [185].  
   
• Research in populations with other conditions that often overlap with epilepsy, such as autism and Fragile X Syndrome, can also shed light on the basis of cognitive and behavioral comorbdities.  Genotype-phenotype analysis showed an over-representation of seizures among symptoms previously reported in association with genetic loci linked to autism [186], and  a large population-based study found that CNS hemorrhage, edema, and seizures in pre-term infants were associated with the later development of autism [187].

C. Determine the optimal treatments for the neuropsychiatric and cognitive co-morbidities in people with epilepsy.

Background:
Efforts to develop treatments for the epilepsies must extend beyond controlling or preventing seizures to include ameliorating the cognitive, behavioral, and emotional difficulties that are increasingly recognized as part of the spectrum of challenges affecting quality of life for people with epilepsy.

Summary of Advances:
Some recent reports have drawn on existing research to suggest guidelines for the diagnosis and treatment of comorbidities in epilepsy. In addition, by identifying the underlying mechanisms of the cognitive and behavioral comorbidities of epilepsy, research in people with epilepsy and in animal models is also suggesting new strategies to treat or prevent these deficits. 

• An expert panel of members of the Epilepsy Foundation’s Mood Disorders Initiative published a consensus statement on the evaluation and treatment of people with epilepsy and affective disorders, with a particular focus on depression [187, 188].  The goals of the statement were to begin to address needs for improving treatment of depression in people with epilepsy by providing information to clinicians about the condition and current barriers to treatment, and by making recommendations on treatment options. In the area of attention deficit hyperactivity disorder (ADHD), recent studies suggest that methylphenidate is similarly effective for treating ADHD in children with and without epilepsy [189, 190].
• In a rat model of TLE, an important component of inflammatory signaling pathways called interleukin 1beta (IL-1β) has been implicated in both the development of seizures and as a mediator of depression. Blocking the actions of IL-1β improved measures of depression in this model, suggesting a therapeutic role for inhibitors in this pathway [191]. In another study, treatment with the anticonvulsant drug ethosuximide improved measures of depression in a rodent model of absence epilepsy [71] (see also mention of this model in Area I). In mouse models of TSC, both learning and memory impairments and epilepsy improved after treatment with rapamycin, a drug that inhibits the mTOR signaling pathway implicated in this disorder [26, 192].
• Research in people who undergo surgery to treat intractable epilepsy is also leading to a better understanding of the brain networks that underlie language and memory impairments in this population. Understanding these networks – through behavioral testing, new imaging technologies, microelectrode recordings, functional connectivity studies, and cortical surface mapping – could improve predictions for who is at risk for postoperative or natural decline. It could also alter treatment approaches to avoid such decline, by for example, offering surgery earlier for some patients, altering surgical approach to avoid functional networks, or improving methods of presurgical functional mapping [193-206].

D. Prevent or limit other adverse consequences occurring in people with epilepsy.

Background:
Some people with epilepsy are also at risk for other types of conditions beyond behavioral and cognitive comorbidities, including sudden unexpected death in epilepsy (SUDEP), sleep disturbances, and systemic problems affecting bone health and hormonal and reproductive function.

Summary of advances:
SUDEP is defined as the “sudden, unexpected, witnessed or unwitnessed, nontraumatic and non-drowning death in a patient with epilepsy where the postmortem examination does not reveal a toxicologic or anatomic cause of death, with or without evidence of a seizure and excluding documented status epilepticus” [207].  Recent research advances toward understanding the causes of SUDEP and efforts to raise awareness and work toward prevention include:

• Two recent clinical studies characterized adverse effects on respiration by seizures and found that both partial and generalized seizures could lead to reduced blood oxygen levels [208, 209]. In many cases, reduced oxygen saturation was associated with central apnea, or temporary loss of signaling between the brain and the muscles that control breathing.  These findings are relevant to case reports suggesting central apnea as one mechanism in SUDEP, and to the known high risk of SUDEP in uncontrolled generalized convulsions.  Other clinical studies have reported changes in cardiac function in people with epilepsy that may be associated with SUDEP [210-215].
   
• Epilepsy has been observed in a mouse model with mutations in a gene that causes sudden cardiac death in humans [216]. This animal model provides evidence that genes and mutations underlying potentially fatal cardiac defects may also be present in human epilepsy, suggesting a potential risk factor for SUDEP in some people with epilepsy.  Also in SUDEP animal model research, some studies have focused on changes in autonomic nervous system function [217], and another pointed to a role for overactivation of adenosine receptors after seizures and to caffeine as a potential preventive intervention [218].  As a possible primate model, sudden unexpected and unexplained death was observed in a research colony of baboons studied as models of primary generalized epilepsy [219]. Postmortem analyses revealed lung defects with similarities to some human SUDEP cases.
   
• The American Epilepsy Society and the Epilepsy Foundation have established a Joint Task Force on SUDEP, the first organized effort of major epilepsy organizations to raise awareness of and solve the problem of SUDEP.  The Task Force was convened to assess current knowledge about SUDEP, and to recommend ways to work towards its elimination [220]. One outcome was a 2008 NINDS-sponsored workshop on SUDEP, attended by national and international clinicians, researchers, patient advocates, and ethics and legal experts.  In addition, Citizens United for Research in Epilepsy (CURE) recently established a new grant program targeting SUDEP research.

Prior research has suggested that epilepsy is associated with sleeping disturbances such as interrupted, insufficient, or poor quality sleep, obstructive sleep apnea, and excessive daytime somnolence; and that sleep disturbances among people with epilepsy may be a risk factor for poor seizure control.  Recent noteworthy studies to better determine the prevalence of such sleep disturbances and their relationship to the clinical course of epilepsy include:

• In terms of prevalence, compared to children without epilepsy, one study found that children with epilepsy had, on average, a significantly higher frequency of sleep problems (falling asleep before being put to bed, prolonged time to fall asleep after being put to bed, nocturnal awakenings, daytime sleeping, and others) [221].  In another study of adult epilepsy outpatients, insomnia was found in 25%, obstructive sleep apnea in 28%, and excessive daytime somnolence in 17%, with the latter in particular associated with lower quality of life [222]. A study in older adult patients with epilepsy found undiagnosed REM sleep behavior disorders (RBD) in 12.5% subjects studied.  RBD episodes may be misinterpreted as seizures, and these results suggest screening for RBD may be important in older patients with epilepsy reporting nocturnal seizures [223].
   
• Other studies are beginning to shed light on how sleep disorders may affect the occurrence of seizures in people with epilepsy. For example, compared to patients whose seizures were in remission or had recently improved, those with relatively recent seizure onset or exacerbation were substantially more likely to have obstructive sleep apnea. The results of this small case-control study suggest that obstructive sleep apnea may be a causal factor in worsening seizures in older adults with epilepsy [224]. A small pilot trial in adult patients with both refractory epilepsy and obstructive sleep demonstrated the feasibility of a larger, definitive clinical trial to test the hypothesis that continuous positive airway pressure (CPAP) treatment may reduce seizures [225].

The examples below highlight recent and ongoing research activities focused on the developmental outcomes of offspring born to mothers with epilepsy, as well as efforts to develop practice guidelines and recommendations for improving the treatment of epilepsy during pregnancy.

• With support from the Epilepsy Therapy Project and the Milken Foundation, the Healthy Outcomes for Pregnancies in Epilepsy (HOPE) project was an international expert panel convened to discuss current knowledge and needs related to strategies to improve pregnancy outcomes in women with epilepsy [226-231].  In addition, the American Academy of Neurology and the American Epilepsy Society jointly conducted three evidence-based systematic reviews of pregnancy-related studies among women with epilepsy resulting in recommendations for pregnancy counseling and care in women with epilepsy, and for additional research needs [232-234].
   
• The NEAD (Neurodevelopmental Effects of Antiepileptic Drugs) study enrolled pregnant women with epilepsy who were taking a single antiepileptic agent in a prospective multi-center study in the U.S. and the U.K.  An interim analysis of cognitive outcomes in 309 children at 3 years of age found that those exposed to valproate during pregnancy had significantly lower IQ scores than those exposed to other antiepileptic drugs [235].  In other research, a study in a rat model of TLE suggested that maternal epilepsy itself may not be detrimental to the developing fetus [236].
   
• The North American Pregnancy Registry was established to obtain and publish information on the frequency of major malformations, such as heart defects, spina bifida and cleft lip, among infants whose mothers had taken one or more antiepileptic drugs to prevent seizures or to treat any other medical condition. As of May 2010, enrollment in the registry included 7537 pregnancies in the U.S. and Canada.

Although bone health problems have been reported in people with epilepsy, it remains unclear whether they are due to antiepileptic drug (AED) use, which could adversely affect bone metabolism, or whether they are related to other factors such as poor general health, co-occurring medical conditions or neuromuscular impairments, or lifestyle behaviors. Recent research advances from studies focused on this issue include:

• A prospective population-based study followed bone mineral density changes in older men treated with different types of AEDs known as enzyme-inducing or non-enzyme inducing depending on their mechanism of action.  In the study, men treated for epilepsy or other conditions with non-enzyme inducing AEDs (most commonly gabapentin) had more significant more bone loss when compared to controls [237].  In another study, decreased bone mineral density in adults treated with valproate, a non-enzyme inducing AED, did not correlate with length of treatment, suggesting valproate may not have long term effects on bone [238]. The study adds to contradictory findings about valproate’s effects on bone, pointing to a need for well-designed prospective studies to address the question.
   
• Other research has begun to provide evidence into possible mechanisms for an effect of AEDs on bone metabolism.  One study that looked at people and rats found that decreased bone mineral density and increased bone turnover after longterm phenytoin treatment was independent of vitamin D levels, suggesting alternative mechanisms to some previously proposed for the effects of AEDs on bone [239, 240].

E. Develop effective methods for diagnosis, treatment and prevention of non-epileptic seizures (NES).

Background:
Non-epileptic seizures (NES) are episodes that outwardly resemble epileptic seizures but that are not accompanied by aberrant neuronal activity characteristic of epilepsy. NES may have physiological or psychological origins, can occur in people with as well as without epilepsy, and may account for as many as 20% of referrals to epilepsy centers.  Improved understanding and recognition of NES could inform better treatments and ways to reduce the burden and costs associated with diagnostic evaluation and ineffective and potentially harmful use of anticonvulsant drugs.

Summary of advances:
The differential and timely diagnosis of NES and epilepsy remains an important challenge to limiting the burden and cost of delaying appropriate treatment. Although research continues to confirm the value and importance of short and long-term monitoring with combined video and electroencephalography (VEEG) recordings of brain activity for NES diagnosis, recent studies have also highlighted the need for a multifaceted approach.  Other efforts have focused on the underlying causes and risk factors for NES and on developing effective treatments.

• One study found only moderate inter-rater reliability of VEEG for NES diagnosis, underscoring the difficulty and subjective nature of NES diagnosis and the importance of integrating clinical history and physical exam findings with the results of VEEG [241]. A number of studies have begun to look at other factors that may differentiate between epileptic and non-epileptic seizures, such as linguistic analysis of patients’ accounts of their seizures [242-244] or patterns of breathing and types of body movements [245].  Researchers have also developed and prospectively validated a 53-item self-administered questionnaire to screen for NES patients that inquires about sociodemographics, clinical and seizure-related information, and psychosocial variables [246].
   
• Much of the research literature concerning common susceptibility factors for and causes of NES focuses on demographics and the description of co-morbid psychiatric disorders in NES patients, with findings showing high rates of depression, anxiety, post-traumatic stress disorder (PTSD), dissociation, and other somatoform symptoms in which physical symptoms mimic disease or injury in the absence of an identifiable physical cause. Recent articles have underscored the heterogeneity of potential causes of NES and their comorbidities [247-252].
   
• A number of recent studies have added to the evidence that approaches based on cognitive behavioral therapy (CBT) and psychodynamic therapy may be effective treatments for NES. In trials and case reports, such approaches decreased the frequency of NES and also improved measures of depression, anxiety, somatic symptoms, quality of life, and overall psychosocial functioning [253-256]. Efforts are also underway to test pharmacological treatments for NES [257].
   
• Determining what is currently considered “treatment as usual” is an important step toward improving care for NES. Responses to the first known survey of national practices [258] showed that most American Epilepsy Society clinicians reported discussing the diagnosis of NES with patients, with 69% of neurologists continuing to follow patients after diagnosis. Antiepileptic drugs were tapered by 83% of the respondents, and 47% prescribed psychotropic medications if co-morbid psychiatric conditions were diagnosed.