Current Literature In Clinical Science
Auras Are Frequent in Patients With Generalized Epilepsy
Auras in Generalized Epilepsy. Dugan S, Carlson C, Bluvstein J, Chong DJ, Friedman D, Kirsch HE; EPGP Investigators. Neurology 2014;83:1444–1449.
OBJECTIVE: We studied the frequency of auras in generalized epilepsy (GE) using a detailed semistructured diagnostic interview. METHODS: In this cross-sectional study, participants with GE were drawn from the Epilepsy Phenome/ Genome Project (EPGP). Responses to the standardized diagnostic interview regarding tonic–clonic (grand mal) seizures were then examined. This questionnaire initially required participants to provide their own description of any subjective phenomena before their “grand mal seizures.” Participants who provided answers to these questions were considered to have an aura. All participants were then systematically queried regarding a list of specific symptoms occurring before grand mal seizures, using structured (closed-ended) questions. RESULTS: Seven hundred ninety-eight participants with GE were identified, of whom 530 reported grand mal seizures. Of these, 112 (21.3%) reported auras in response to the open-ended question. Analysis of responses to the closed-ended questions suggested that 341 participants (64.3%) experienced at least one form of aura. CONCLUSIONS: Auras typically associated with focal epilepsy were reported by a substantial proportion of EPGP subjects with GE. This finding may support existing theories of cortical and subcortical generators of GE with variable spread patterns. Differences between responses to the open-ended question and closed-ended questions may also reflect clinically relevant variation in patient responses to history-taking and surveys. Open-ended questions may underestimate the prevalence of specific types of auras and may be in part responsible for the underrecognition of auras in GE. In addition, structured questions may influence participants, possibly leading to a greater representation of symptoms.
Commentary An aura is usually considered to be the initial component of a seizure that occurs prior to alteration or loss of consciousness. It is distinguished from a premonitory or prodromal sensation largely in the time domain: auras immediately precede a developing seizure, while prodromal experiences occur well in advance of the seizure—more than 30 minutes by some definitions. The term “aura” is often further restricted to the subjective experience of a developing seizure, excluding conscious, objective motor symptoms. Often, the terms “aura” and “simple partial seizure” are considered synonymous; an aura is the recalled subjective experience of the beginning of a focal seizure. The specific experience of the aura is largely determined by the locus of onset of the focal seizure. Despite a general consensus regarding this terminology, it has been long recognized that generalized from onset seizures may present exceptions to the “rule” that generalized seizures are not preceded by auras. Just how commonly these exceptions occur has not been clear. The distinction is more than purely academic, as the presence of an aura is often taken as evidence of a focal epilepsy, with implications for diagnostic
Epilepsy Currents, Vol. 15, No. 2 (March/April) 2015 pp. 75–77 © American Epilepsy Society
testing, treatment choices, and prognosis for a patient with new onset seizures. Interpreting subjective experiences reported by patients and drawing the correct conclusions from them is not an exact science. Nearly 25 years ago, van Donselaar and colleagues examined the usefulness of auras for epilepsy classification (1). They studied 149 patients with new onset generalized seizures, 67 of whom reported a sensation prior to loss of consciousness. The patients’ own descriptions of these sensations were presented to a panel of six neurologists, who were asked to address two questions: First, was the sensation the aura of a focal seizure or a nonspecific symptom? Second, on the basis of this report, was the seizure more likely a secondarily generalized tonic–clonic seizure, a generalized from onset seizure, or indeterminate? The agreement among the neurologists was relatively poor, with kappa statistics in the neighborhood of 0.25. Seizure classifications based on the aura frequently conflicted with the ultimate classification made with the benefit of EEG, imaging, and other data. Patients with feelings that preceded their seizure were more likely to have generalized spike wave abnormalities on EEG, even for those in whom the neurologists judged the feelings to be a specific aura. The authors concluded that interpretation of auras was subject to substantial inter-rater variability, and not a reliable way to distinguish primary and secondarily generalized seizures. Over the years, other work supported this theme. Nakken and colleagues reported on the occurrence and characteris-
75
Auras in Generalized Epilepsy
tics of auras in a large population-based epilepsy cohort (2). They used structured interviews of 1897 twins and their close relatives with epilepsy. The patients were first asked an openended question about whether they experienced an aura or warning before their seizures. Affirmative responses were followed by a series of closed-ended questions to better characterize the nature of the aura. Auras were reported in 58% of patients with localization-related epilepsy but also in 13% of patients with generalized epilepsy. The epilepsy monitoring unit setting may afford better opportunities to characterize symptoms in the context of welldefined epilepsy syndromes. In 2006, Boylan and coworkers studied 154 adult patients admitted to their EMU over the course of 1 year (3). The patients were asked whether they had “symptoms seconds or minutes before their seizures,” followed by free text descriptions from those who reported symptoms. The presence of a reported aura did not distinguish those with focal from those with generalized epilepsy. In all, 70% of those with generalized epilepsy reported aura symptoms. In this relatively small sample, some auras were found to be specific to patients with focal epilepsy (e.g., auditory hallucinations, déjà vu), but others, such as an epigastric rising sensation, were reported in both groups. Some authors—including this report from Boylan—have allowed preceding myoclonus or other objective symptoms as auras. Still, these reports suggest there is a relatively high prevalence of aura-like symptoms in patients with generalized epilepsy who are “supposed” to have alteration of consciousness from seizure onset. How can this be explained? In parallel with these reports of auras in generalized epilepsy has been the growing understanding that “generalized” may be a misnomer. This has been a component of the debate over seizure classification, with the term “generalized” now recognized as not truly generalized but “occurring in and rapidly engaging bilaterally distributed networks” (4). Intensive study of generalized epilepsy frequently yields focal findings. The clinical semiology of generalized from onset seizures commonly includes focal features such as version or asymmetric myoclonus (5). Surface EEG frequently contains shifting focal as well as generalized spike wave discharges (6). Dense array EEG shows a more focal ictal onset in some presumed generalized seizures (7), and fMRI and MEG studies identify specific cortical involvement in spike wave discharges (8, 9). It is possible that select thalamocortical networks may be operative in some generalized seizures, producing focal motor symptoms when there is greater involvement of frontal networks, and visual auras when posterior networks are preferentially involved (10). The recent work by Dugan and coworkers builds and expands on prior studies of auras in generalized epilepsies. The authors leveraged the detailed data obtained from a large number of patients enrolled in the Epilepsy Phenome/ Genome Project. A strict definition of generalized epilepsy was used, and a similarly well-defined focal epilepsy population was identified for comparison. A semi-structured interview began with open-ended questions about symptoms prior to seizures and followed with a series of closed-ended questions in all subjects. Symptoms suggestive of buildup of generalized
76
seizure activity (myoclonus, absence) were excluded, as were nonspecific symptoms, such as dizziness or fatigue. Of those with generalized epilepsy, 21.3% reported auras upon openended questioning. Those reporting auras were older and had experienced more seizures, suggesting that greater experience with seizures might lead to better identification of auras. The most commonly reported auras in patients with generalized epilepsy were cephalic sensations or limb stiffening or shaking, but auras typically associated with focal epilepsy—including déjà vu, visual, and auditory phenomena—were also reported. Upon closed-ended questioning, 64.3% of these patients with generalized epilepsy reported aura symptoms. In comparison, 39.9% of patients with focal epilepsy reported auras upon open-ended questioning, and 68.4% upon closed-ended questioning. Thus, patients with generalized epilepsy frequently report auras, including those typically associated with focal epilepsy, and in this study were as likely as those with focal epilepsy to report auras on closed-ended questions. One could argue that closed-ended questions might prompt suggestible patients, but there are at least two counterarguments to this: First, closed-ended questions might instead assist patients who have difficulty articulating the symptoms they experience prior to seizures. Second, neurologists frequently employ closed-ended questions when interviewing patients, so findings from the structured interview may mirror clinical practice. Auras in patients with generalized epilepsies may actually be underappreciated in clinical practice, as clinicians may be biased in their use of closed-ended questions, exploring pre-seizure symptoms less often in patients in whom the clinician is forming a generalized epilepsy hypothesis. The present study provides additional evidence in a relatively large, well-characterized epilepsy population, that auras in generalized epilepsy are relatively common. The flaws in the “generalized” construct of generalized epilepsies may underlie the seemingly focal aspects of EEG, semiology, functional imaging—and reported auras—in patients with generalized epilepsy. An awareness that auras are frequent in generalized epilepsy will help prevent clinicians from being unduly biased by auras toward diagnosis of focal epilepsy. By David Spencer, MD References 1. van Donselaar CA, Geerts AT, Schimsheimer RJ. Usefulness of an aura for classification of a first generalized seizure. Epilepsia 1990;31:529– 535. 2. Nakken KO, Solaas MH, Kjeldsen MJ, Friis ML, Pellock JM, Corey LA. The occurrence and characteristics of auras in a large epilepsy cohort. Acta Neurol Scand 2009;119:88–93. 3. Boylan LS, Labovitz DL, Jackson SC, Starner K, Devinsky O. Auras are frequent in idiopathic generalized epilepsy. Neurology 2006;67:343– 345. 4. Berg AT, Berkovic SF, Brodie MJ, Buchhalter J, Cross JH, van Emde Boas W, Engel J, French J, Glauser TA, Mathern GW, Moshe SL, Nordli D, Plouin P, Scheffer IE. Revised terminology and concepts for organization of seizures and epilepsies: Report of the ILAE Commission on Classification and Terminology, 2005–2009. Epilepsia 2010;51:676–685.
Auras in Generalized Epilepsy
5. Casaubon L, Pohlmann-Eden B, Khosravani H, Carlen PL, Wennberg R. Video-EEG evidence of lateralized clinical features in primary generalized epilepsy with tonic–clonic seizures. Epileptic Disorder 2003;5:149–156. 6. Lombroso CT. Consistent EEG focalities detected in subjects with primary generalized epilepsies monitored for two decades. Epilepsia 1997;38:797–812. 7. Holmes MD, Brown M, Tucker DM. Are “generalized” seizures truly generalized? Evidence of localized mesial frontal and frontopolar discharges in absence. Epilepsia 2004;45:1568–1579.
8. Aghakhani Y, Bagshaw AP, Benar CG, Hawco C, Andermann F, Dubeau F, Gotman J. fMRI activation during spike and wave discharges in idiopathic generalized epilepsy. Brain 2004;127(Pt 5):1127–1144. 9. Stefan H, Paulini-Ruf A, Hopfengartner R, Rampp S. Network characteristics of idiopathic generalized epilepsies in combined MEG/EEG. Epilepsy Res 2009;85:187–198. 10. Gungor-Tuncer O, Baykan B, Altindag E, Bebek N, Gurses C, Gokyigit A. Prevalence and characteristics of visual aura in idiopathic generalized epilepsy. Epilepsy Behav 2012;25:573–576.
77
Auras Are Frequent in Patients With Generalized Epilepsy
Auras in Generalized Epilepsy. Dugan S, Carlson C, Bluvstein J, Chong DJ, Friedman D, Kirsch HE; EPGP Investigators. Neurology 2014;83:1444–1449.
OBJECTIVE: We studied the frequency of auras in generalized epilepsy (GE) using a detailed semistructured diagnostic interview. METHODS: In this cross-sectional study, participants with GE were drawn from the Epilepsy Phenome/ Genome Project (EPGP). Responses to the standardized diagnostic interview regarding tonic–clonic (grand mal) seizures were then examined. This questionnaire initially required participants to provide their own description of any subjective phenomena before their “grand mal seizures.” Participants who provided answers to these questions were considered to have an aura. All participants were then systematically queried regarding a list of specific symptoms occurring before grand mal seizures, using structured (closed-ended) questions. RESULTS: Seven hundred ninety-eight participants with GE were identified, of whom 530 reported grand mal seizures. Of these, 112 (21.3%) reported auras in response to the open-ended question. Analysis of responses to the closed-ended questions suggested that 341 participants (64.3%) experienced at least one form of aura. CONCLUSIONS: Auras typically associated with focal epilepsy were reported by a substantial proportion of EPGP subjects with GE. This finding may support existing theories of cortical and subcortical generators of GE with variable spread patterns. Differences between responses to the open-ended question and closed-ended questions may also reflect clinically relevant variation in patient responses to history-taking and surveys. Open-ended questions may underestimate the prevalence of specific types of auras and may be in part responsible for the underrecognition of auras in GE. In addition, structured questions may influence participants, possibly leading to a greater representation of symptoms.
Commentary An aura is usually considered to be the initial component of a seizure that occurs prior to alteration or loss of consciousness. It is distinguished from a premonitory or prodromal sensation largely in the time domain: auras immediately precede a developing seizure, while prodromal experiences occur well in advance of the seizure—more than 30 minutes by some definitions. The term “aura” is often further restricted to the subjective experience of a developing seizure, excluding conscious, objective motor symptoms. Often, the terms “aura” and “simple partial seizure” are considered synonymous; an aura is the recalled subjective experience of the beginning of a focal seizure. The specific experience of the aura is largely determined by the locus of onset of the focal seizure. Despite a general consensus regarding this terminology, it has been long recognized that generalized from onset seizures may present exceptions to the “rule” that generalized seizures are not preceded by auras. Just how commonly these exceptions occur has not been clear. The distinction is more than purely academic, as the presence of an aura is often taken as evidence of a focal epilepsy, with implications for diagnostic
Epilepsy Currents, Vol. 15, No. 2 (March/April) 2015 pp. 75–77 © American Epilepsy Society
testing, treatment choices, and prognosis for a patient with new onset seizures. Interpreting subjective experiences reported by patients and drawing the correct conclusions from them is not an exact science. Nearly 25 years ago, van Donselaar and colleagues examined the usefulness of auras for epilepsy classification (1). They studied 149 patients with new onset generalized seizures, 67 of whom reported a sensation prior to loss of consciousness. The patients’ own descriptions of these sensations were presented to a panel of six neurologists, who were asked to address two questions: First, was the sensation the aura of a focal seizure or a nonspecific symptom? Second, on the basis of this report, was the seizure more likely a secondarily generalized tonic–clonic seizure, a generalized from onset seizure, or indeterminate? The agreement among the neurologists was relatively poor, with kappa statistics in the neighborhood of 0.25. Seizure classifications based on the aura frequently conflicted with the ultimate classification made with the benefit of EEG, imaging, and other data. Patients with feelings that preceded their seizure were more likely to have generalized spike wave abnormalities on EEG, even for those in whom the neurologists judged the feelings to be a specific aura. The authors concluded that interpretation of auras was subject to substantial inter-rater variability, and not a reliable way to distinguish primary and secondarily generalized seizures. Over the years, other work supported this theme. Nakken and colleagues reported on the occurrence and characteris-
75
Auras in Generalized Epilepsy
tics of auras in a large population-based epilepsy cohort (2). They used structured interviews of 1897 twins and their close relatives with epilepsy. The patients were first asked an openended question about whether they experienced an aura or warning before their seizures. Affirmative responses were followed by a series of closed-ended questions to better characterize the nature of the aura. Auras were reported in 58% of patients with localization-related epilepsy but also in 13% of patients with generalized epilepsy. The epilepsy monitoring unit setting may afford better opportunities to characterize symptoms in the context of welldefined epilepsy syndromes. In 2006, Boylan and coworkers studied 154 adult patients admitted to their EMU over the course of 1 year (3). The patients were asked whether they had “symptoms seconds or minutes before their seizures,” followed by free text descriptions from those who reported symptoms. The presence of a reported aura did not distinguish those with focal from those with generalized epilepsy. In all, 70% of those with generalized epilepsy reported aura symptoms. In this relatively small sample, some auras were found to be specific to patients with focal epilepsy (e.g., auditory hallucinations, déjà vu), but others, such as an epigastric rising sensation, were reported in both groups. Some authors—including this report from Boylan—have allowed preceding myoclonus or other objective symptoms as auras. Still, these reports suggest there is a relatively high prevalence of aura-like symptoms in patients with generalized epilepsy who are “supposed” to have alteration of consciousness from seizure onset. How can this be explained? In parallel with these reports of auras in generalized epilepsy has been the growing understanding that “generalized” may be a misnomer. This has been a component of the debate over seizure classification, with the term “generalized” now recognized as not truly generalized but “occurring in and rapidly engaging bilaterally distributed networks” (4). Intensive study of generalized epilepsy frequently yields focal findings. The clinical semiology of generalized from onset seizures commonly includes focal features such as version or asymmetric myoclonus (5). Surface EEG frequently contains shifting focal as well as generalized spike wave discharges (6). Dense array EEG shows a more focal ictal onset in some presumed generalized seizures (7), and fMRI and MEG studies identify specific cortical involvement in spike wave discharges (8, 9). It is possible that select thalamocortical networks may be operative in some generalized seizures, producing focal motor symptoms when there is greater involvement of frontal networks, and visual auras when posterior networks are preferentially involved (10). The recent work by Dugan and coworkers builds and expands on prior studies of auras in generalized epilepsies. The authors leveraged the detailed data obtained from a large number of patients enrolled in the Epilepsy Phenome/ Genome Project. A strict definition of generalized epilepsy was used, and a similarly well-defined focal epilepsy population was identified for comparison. A semi-structured interview began with open-ended questions about symptoms prior to seizures and followed with a series of closed-ended questions in all subjects. Symptoms suggestive of buildup of generalized
76
seizure activity (myoclonus, absence) were excluded, as were nonspecific symptoms, such as dizziness or fatigue. Of those with generalized epilepsy, 21.3% reported auras upon openended questioning. Those reporting auras were older and had experienced more seizures, suggesting that greater experience with seizures might lead to better identification of auras. The most commonly reported auras in patients with generalized epilepsy were cephalic sensations or limb stiffening or shaking, but auras typically associated with focal epilepsy—including déjà vu, visual, and auditory phenomena—were also reported. Upon closed-ended questioning, 64.3% of these patients with generalized epilepsy reported aura symptoms. In comparison, 39.9% of patients with focal epilepsy reported auras upon open-ended questioning, and 68.4% upon closed-ended questioning. Thus, patients with generalized epilepsy frequently report auras, including those typically associated with focal epilepsy, and in this study were as likely as those with focal epilepsy to report auras on closed-ended questions. One could argue that closed-ended questions might prompt suggestible patients, but there are at least two counterarguments to this: First, closed-ended questions might instead assist patients who have difficulty articulating the symptoms they experience prior to seizures. Second, neurologists frequently employ closed-ended questions when interviewing patients, so findings from the structured interview may mirror clinical practice. Auras in patients with generalized epilepsies may actually be underappreciated in clinical practice, as clinicians may be biased in their use of closed-ended questions, exploring pre-seizure symptoms less often in patients in whom the clinician is forming a generalized epilepsy hypothesis. The present study provides additional evidence in a relatively large, well-characterized epilepsy population, that auras in generalized epilepsy are relatively common. The flaws in the “generalized” construct of generalized epilepsies may underlie the seemingly focal aspects of EEG, semiology, functional imaging—and reported auras—in patients with generalized epilepsy. An awareness that auras are frequent in generalized epilepsy will help prevent clinicians from being unduly biased by auras toward diagnosis of focal epilepsy. By David Spencer, MD References 1. van Donselaar CA, Geerts AT, Schimsheimer RJ. Usefulness of an aura for classification of a first generalized seizure. Epilepsia 1990;31:529– 535. 2. Nakken KO, Solaas MH, Kjeldsen MJ, Friis ML, Pellock JM, Corey LA. The occurrence and characteristics of auras in a large epilepsy cohort. Acta Neurol Scand 2009;119:88–93. 3. Boylan LS, Labovitz DL, Jackson SC, Starner K, Devinsky O. Auras are frequent in idiopathic generalized epilepsy. Neurology 2006;67:343– 345. 4. Berg AT, Berkovic SF, Brodie MJ, Buchhalter J, Cross JH, van Emde Boas W, Engel J, French J, Glauser TA, Mathern GW, Moshe SL, Nordli D, Plouin P, Scheffer IE. Revised terminology and concepts for organization of seizures and epilepsies: Report of the ILAE Commission on Classification and Terminology, 2005–2009. Epilepsia 2010;51:676–685.
Auras in Generalized Epilepsy
5. Casaubon L, Pohlmann-Eden B, Khosravani H, Carlen PL, Wennberg R. Video-EEG evidence of lateralized clinical features in primary generalized epilepsy with tonic–clonic seizures. Epileptic Disorder 2003;5:149–156. 6. Lombroso CT. Consistent EEG focalities detected in subjects with primary generalized epilepsies monitored for two decades. Epilepsia 1997;38:797–812. 7. Holmes MD, Brown M, Tucker DM. Are “generalized” seizures truly generalized? Evidence of localized mesial frontal and frontopolar discharges in absence. Epilepsia 2004;45:1568–1579.
8. Aghakhani Y, Bagshaw AP, Benar CG, Hawco C, Andermann F, Dubeau F, Gotman J. fMRI activation during spike and wave discharges in idiopathic generalized epilepsy. Brain 2004;127(Pt 5):1127–1144. 9. Stefan H, Paulini-Ruf A, Hopfengartner R, Rampp S. Network characteristics of idiopathic generalized epilepsies in combined MEG/EEG. Epilepsy Res 2009;85:187–198. 10. Gungor-Tuncer O, Baykan B, Altindag E, Bebek N, Gurses C, Gokyigit A. Prevalence and characteristics of visual aura in idiopathic generalized epilepsy. Epilepsy Behav 2012;25:573–576.
77
