Abstract
Krumholz A, Wiebe S, Gronseth GS, Gloss DS, Sanchez AM, Kabir AA,
Liferidge AT, Martello JP, Kanner AM, Shinnar S, Hopp JL, French JA
Neurology 2015;84:1705–1713. To provide evidence-based recommendations for treatment of adults
with an unprovoked first seizure. We defined relevant questions and systematically reviewed published
studies according to the American Academy of Neurology's
classification of evidence criteria; we based recommendations on
evidence level. Adults with an unprovoked first seizure should be informed that their
seizure recurrence risk is greatest early within the first 2 years
(21%–45%; Level A), and clinical variables associated with
increased risk may include a prior brain insult (Level A), an EEG
with epileptiform abnormalities (Level A), a significant
brain-imaging abnormality (Level B), and a nocturnal seizure (Level
B). Immediate antiepileptic drug (AED) therapy, as compared with
delay of treatment pending a second seizure, is likely to reduce
recurrence risk within the first 2 years (Level B) but may not
improve quality of life (Level C). Over a longer term (>3
years), immediate AED treatment is unlikely to improve prognosis as
measured by sustained seizure remission (Level B). Patients should
be advised that risk of AED adverse events (AEs) may range from 7%
to 31% (Level B) and that these AEs are likely predominantly mild
and reversible. Clinicians’ recommendations whether to
initiate immediate AED treatment after a first seizure should be
based on individualized assessments that weigh the risk of
recurrence against the AEs of AED therapy, consider educated patient
preferences, and advise that immediate treatment will not improve
the long-term prognosis for seizure remission but will reduce
seizure risk over the subsequent 2 years.Objective
Methods
Results and Recommendations
Commentary
The American Academy of Neurology (AAN) and American Epilepsy Society (AES) posted an evidence-based guideline for management of an unprovoked first seizure in adults. The guideline addresses 1) risks of seizure recurrence after a first seizure, 2) effect of immediate treatment with an AED on short-term risks for seizure recurrence and long-term prognosis, and 3) the risks for adverse events for patients prescribed AEDs immediately after their first seizure. Conclusions include that the risk of recurrent seizure is highest within the first 2 years after a first seizure (21–45%) and that significant risk factors for a recurrent seizure include a prior brain insult such as a stroke or trauma, epileptiform discharges on an EEG, a significant abnormality on brain imaging, or a nocturnal seizure. Immediate treatment with an AED, when compared with delaying treatment until a second seizure, is likely to reduce the recurrence of seizures in the 2 years after the first seizure but has no definitive impact on quality of life. Over the longer term (>3 years) immediate AED treatment is unlikely to improve the prognosis for long-term seizure freedom. Overall, the risks of adverse events from AED treatment ranges from 7 to 31 percent, with most adverse events being predominantly mild and reversible.
With the recent guidelines in mind, this Quantitative Practical Use-Driven Learning Survey in Epilepsy (Q-PULSE) questioned medical directors of leading U.S. epilepsy centers about the management of two different case histories with unprovoked new-onset seizures. To review the QPULSE survey and data referred to in this commentary, please visit https://www.aesnet.org/clinical_resources/Q-PULSE/guideline. Of the 77 subjects who took the survey, 82% (62/77) completed the survey. The structure of the survey, which presented questions based on previous answers, resulted in fewer responses to some questions.
Case #1 involved a 25-year-old man with a relatively definitive history of a new-onset nocturnal generalized tonic–clonic seizure, including bilateral shaking movements with vocalizations and bloody salivation, followed by 15 minutes of stupor and subsequent confusion. Head CT in the ER was negative. For the question of treatment with an “AED in the ER,” responses were 6% “Yes,” 47% “No,” and 47% “It Depends.” Important responses to subsequent questions about this case include the importance of EEG findings (83%) in deciding whether to recommend an AED. Responses also revealed the subsequent increased likelihood of recommending an AED if testing showed left temporal slowing on EEG (30%). In three questions that included patient preference in the decision to start an AED, 71 to 78 percent of respondents rated this as an important factor.
Case #2 involved a single event in a 17-year-old girl who made babbling sounds, with turning to the right and rigid posturing for 30 seconds, with mild confusion following. She presented for evaluation 2 weeks after the seizure, with a normal EEG and MRI. This history is suggestive of a focal seizure with impaired awareness. For the question of starting an AED, responses were 12% “Yes,” 55% “No,” and 33% “It Depends.” Subsequent queries showed that 59% of respondents would pursue additional routine or long-term video EEG studies to inform their decision. In three questions for the second case, 71 to 100 percent of respondents reported that patient preference was important in decision-making for starting an AED.
Comparing the results of Q-PULSE with the recent guidelines for new-onset unprovoked epileptic seizures identifies the complexities of medical decision-making. For example, in case 1, the suggestive (but not definitive) finding for a confirmed diagnosis of epilepsy of focal temporal slowing on EEG showed a trend for more respondents to start an AED. This factor does not fit the stated definition in the guideline as a significant predisposing factor of an epileptiform discharge for subsequent seizures. However, past studies have shown that subjects with focal slowing on an EEG and a negative head CT frequently have associated seizures (1). Additionally, focal slowing as temporal intermittent rhythmic delta activity is strongly suggestive of temporal lobe epilepsy in subjects with chronic epilepsy (2). Therefore, based on the known pathophysiology of epileptic seizures in general, respondents who decided to treat with AEDs because of focal slowing on the EEG were reasonably justified, even though past studies do not necessarily confirm this finding as significant in patients presenting with first seizures. The current guideline states that EEG abnormalities with epileptiform discharges are the most consistently noted EEG-related factor associated with increased risk of seizure recurrence following an unprovoked seizure, and past studies document they are a greater predictor as compared to patients without epileptiform abnormalities (3). However, these findings do not exclude focal slowing as a less specific but still significant factor.
Even more complex is the increased risk of multiple predisposing factors. For example, what is the additional risk of seizure recurrence in case #1, given the focal temporal slowing on EEG and the clinical history of a nocturnal seizure? The guideline authors point to the lack of studies adequately assessing additive effects or covariance of the risk factors for seizure recurrence after a first seizure. Intuitively, a treating physician would reasonably assume that more than one pre-disposing factor (i.e., focal temporal slowing and a nocturnal seizure) would increase risk of seizure recurrence. However, there is little objective evidence to support this assumption.
Importantly, patient preference figures highly in every associated question in the survey. Immediate AED treatment at the time of an unprovoked seizure remains an individualized decision, best addressed by informed discussions between the patient and physician. The perspective of the patient will therefore factor heavily on the decision whether start an AED after a first seizure, which appropriately will affect outcome despite known risks, as stated in the recent guideline.
An important factor in applying the QPULSE findings in clinical practice includes the histories of the seizure. Both cases presented in the current QPULSE are suggestive of a seizure, with relatively typical semiology for a generalized tonic clonic seizure (case 1), and a focal seizure with impaired awareness (case 2). In clinical practice, histories are often less specific. Any probability for recurrence will depend on the differential diagnosis of the initial event, so the current guidelines provide meaningful outcome measures only in proportion to the likelihood that the presenting event is a seizure. Sometimes, withholding treatment with an AED is appropriate due to uncertainty of the etiology of the clinical episode.
The recent guideline for management of an unprovoked first seizure in adults offers welcome, updated information about the objectively documented risk factors for recurrent seizures—as well as AED treatment—in this population. The QPULSE survey highlights the complexity of the clinical situation, where sufficient evidence may or may not exist to guide decisions, highlighting the importance of patient preference in the decision to start an AED after an unprovoked first seizure. As clinicians, we strive for certainty in decision-making, which is aided by the recent guidelines. However, many decisions we make involve details of individual situations, which include the subjective decisions of our patients and complex factors for which evidence-based data does not exist. The recent guidelines and QPULSE survey help us to understand the evidence for decision-making, as well as importance of clinical judgment, reasoning, and problem-solving on an individual level to provide the best care for our patients.