ACEP Clinical Policies Committee, Clinical Policies Subcommittee on Seizures
Clinical policy: Critical issues in the evaluation and management of adult patients presenting to the emergency department with seizures.
Ann Emerg Med. 2004 May;43(5):605-25. doi: 10.1016/S019606440400068X.
Abstract/Text
This clinical policy focuses on critical issues in the evaluation and management of adult patients with seizures. The medical literature was reviewed for articles that pertained to the critical questions posed. Subcommittee members and expert peer reviewers also supplied articles with direct bearing on this policy. This clinical policy focuses on 6 critical questions: What laboratory tests are indicated in the otherwise healthy adult patient with a new-onset seizure who has returned to a baseline normal neurologic status?Which new-onset seizure patients who have returned to a normal baseline require a head computed tomography (CT) scan in the emergency department (ED)?Which new-onset seizure patients who have returned to normal baseline need to be admitted to the hospital and/or started on an antiepileptic drug?What are effective phenytoin or fosphenytoin dosing strategies for preventing seizure recurrence in patients who present to the ED after having had a seizure with a subtherapeutic serum phenytoin level?What agent(s) should be administered to a patient in status epilepticus who continues to seize after having received benzodiazepine and phenytoin?When should electroencephalographic (EEG) testing be performed in the ED? Recommendations for patient management are provided for each 1 of these topics on the basis of strength of evidence (Level A, B, or C). Level A recommendations represent patient management principles that reflect a high degree of clinical certainty; Level B recommendations represent patient management principles that reflect moderate clinical certainty; and Level C recommendations represent other patient management strategies based on preliminary, inconclusive, or conflicting evidence, or based on consensus of the members of the Clinical Policies Committee. This clinical policy is intended for physicians working in hospital-based EDs.
P Jallon, P Loiseau, J Loiseau
Newly diagnosed unprovoked epileptic seizures: presentation at diagnosis in CAROLE study. Coordination Active du Réseau Observatoire Longitudinal de l' Epilepsie.
Epilepsia. 2001 Apr;42(4):464-75.
Abstract/Text
PURPOSE: We describe first unprovoked seizures and newly diagnosed epilepsies at initial presentation, with a special emphasis on epilepsy syndromes, in a large cohort recruited in the mid-1990s in France.
METHODS: The French Foundation for Research on Epilepsy set up a network to conduct a prospective study of patients with newly diagnosed unprovoked seizures. Information was provided by 243 child or adult neurologists. Four neurologists classified each case according to the International League Against Epilepsy (ILAE) criteria. First-seizure patients and patients with previously undiagnosed seizures were compared.
RESULTS: Between May 1, 1995, and June 30, 1996, 1,942 patients aged from 1 month to 95 years were identified: 926 (47.7%) with a single seizure and 1,016 (52.3%) with newly diagnosed epilepsy. All but 17 patients had EEGs. In the first-seizure and newly-diagnosed-epilepsy groups, neuroimaging studies were performed in 78.2 and 68.3% of patients, and medication prescribed in 54.1 and 89.6%, respectively. There were significant differences between the two groups with respect to age at onset and diagnosis, sex, etiology, several specific syndromes, as well as the type and presentation of initial seizure. In patients for whom the first seizure was convulsive, only sex, multiple seizures in a day or status epilepticus, and cryptogenic localization-related syndrome differed between the two groups.
CONCLUSIONS: Approximately half of patients who first came to attention for an unprovoked seizure already met epidemiologic criteria for epilepsy. There were significant differences between the types of patients with a first seizure and those with newly diagnosed epilepsy. One or several seizures at diagnosis did not influence the diagnostic assessment of the patients but had a strong influence on the initiation of treatment.
W A Hauser, J F Annegers, L T Kurland
Incidence of epilepsy and unprovoked seizures in Rochester, Minnesota: 1935-1984.
Epilepsia. 1993 May-Jun;34(3):453-68.
Abstract/Text
The incidence of epilepsy and of all unprovoked seizures was determined for residents of Rochester, Minnesota U.S.A. from 1935 through 1984. Age-adjusted incidence of epilepsy was 44 per 100,000 person-years. Incidence in males was significantly higher than in females and was high in the first year of life but highest in persons aged > or = 75 years. Sixty percent of new cases had epilepsy manifested by partial seizures, and two thirds had no clearly identified antecedent. Cerebrovascular disease was the most commonly identified antecedent, accounting for 11% of cases. Neurologic deficits from birth, mental retardation and/or cerebral palsy, observed in 8% of cases, was the next most frequently identified preexisting condition. The cumulative incidence of epilepsy through age 74 years was 3.1%. The age-adjusted incidence of all unprovoked seizures was 61 per 100,000 person-years. Age- and gender-specific incidence trends were similar to those of epilepsy, but a higher proportion of cases was of unknown etiology and was characterized by generalized onset seizures. The cumulative incidence of all unprovoked seizures was 4.1% through age 74 years. With time, the incidence of epilepsy and of unprovoked seizures decreased in children and increased in the elderly.
S R Benbadis, B R Wolgamuth, H Goren, S Brener, F Fouad-Tarazi
Value of tongue biting in the diagnosis of seizures.
Arch Intern Med. 1995 Nov 27;155(21):2346-9.
Abstract/Text
BACKGROUND: Seizures are rarely witnessed by physicians, and the diagnosis is usually made on the basis of the history. Tongue biting is classically considered to favor a diagnosis of epileptic seizure. The usefulness of tongue biting in the differential diagnosis of seizures was evaluated.
METHODS: A prospective study of the presence of oral lacerations in 106 consecutive patients admitted to our Epilepsy Monitoring Unit and a retrospective study of a population of 45 patients with syncope were performed. The relationship between tongue biting and diagnosis (epileptic vs nonepileptic events) was analyzed.
RESULTS: Of the 106 monitored patients, 63 had episodes characterized by bilateral motor activity, complete loss of consciousness, or both; 34 patients had epileptic seizures, while 29 patients had exclusively nonepileptic episodes. Eight patients suffered an oral laceration; all involved the side of the tongue, and all had documented epileptic seizures. Of the 45 patients with syncope, in only one was the tongue lacerated, and this was at the tip. Tongue biting had a sensitivity of 24% and a specificity of 99% for the diagnosis of generalized tonic-clonic seizures. Lateral tongue biting was 100% specific to grand mal seizures.
CONCLUSION: Tongue biting, particularly if it is lateral, is highly specific to generalized tonic-clonic seizures.
P L Henneman, F DeRoos, R J Lewis
Determining the need for admission in patients with new-onset seizures.
Ann Emerg Med. 1994 Dec;24(6):1108-14.
Abstract/Text
STUDY OBJECTIVES: To determine which adult patients with new-onset seizures require admission and whether those who require admission can be identified in the emergency department.
DESIGN: Retrospective chart review of patients seen during a 5-year period.
SETTING: Urban county teaching hospital in southern California.
PARTICIPANTS: Three hundred thirty-three adult patients with new-onset seizures. Patients were excluded if they had acute head trauma, hypoglycemia from diabetic therapy, or alcohol- or recreational drug-related seizures.
INTERVENTIONS: Standardized medical evaluation including physical examination, CBC, SMA-7 (electrolytes, blood urea nitrogen, creatinine, glucose), calcium, cranial computed tomography (CT), lumbar puncture if indicated, and admission to the hospital.
RESULTS: Forty-six percent of patients (136 of 294) admitted to our hospital required admission as judged by a retrospective evaluation of the ED and hospital course. The numbers of patients who had a clinically significant result with each part of the evaluation were: physical examination, 75 of 333 (23%); CBC, 25 of 319 (8%); SMA-7, 21 of 329 (6%); calcium, 2 of 208 (1%); CT, 134 of 325 (41%); and lumbar puncture, 19 of 227 (8%). Ninety-five percent of patients requiring admission (129 of 136) were detected by the standardized medical evaluation.
CONCLUSION: One half of patients with new-onset seizures require admission. Patients with new-onset seizures who require admission can usually be detected by a standardized medical evaluation in the ED.
Practice parameter: neuroimaging in the emergency patient presenting with seizure (summary statement). American College of Emergency Physicians, American Academy of Neurology, American Association of Neurological Surgeons, American Society of Neuroradiology.
Ann Emerg Med. 1996 Jul;28(1):114-8.
Abstract/Text
Paul Cleary, Simon Shorvon, Raymond Tallis
Late-onset seizures as a predictor of subsequent stroke.
Lancet. 2004 Apr 10;363(9416):1184-6. doi: 10.1016/S0140-6736(04)15946-1.
Abstract/Text
UNLABELLED: BACKGROUND Cerebrovascular disease is thought to be a major cause of epilepsy in late life. We investigated the hypothesis that the onset of seizures after the age of 60 years in people with no history of overt stroke might be associated with an increased risk of subsequent stroke.
METHODS: Data were obtained from the UK General Practice Research Database on 4709 individuals who had seizures beginning at or after the age of 60 years, and on 4709 randomly selected controls with no history of seizures, matched for age, sex, and general practice. Individuals with a history of cerebrovascular disease, other acquired brain injury, brain tumour, drug or alcohol misuse, or dementia were not eligible for inclusion. Computerised patients' records were searched for subsequent diagnoses of stroke.
FINDINGS: Log-rank testing, adjusted for matching, showed a highly significant difference in stroke-free survival between the two groups (p<0.0001). With a Cox's model, we estimated that the relative hazard of stroke at any point for people with seizures compared with the control group was 2.89 (95% CI 2.45-3.41).
INTERPRETATION: Our findings show that the onset of seizures in late life is associated with a striking increase in the risk of stroke. Further research is warranted to assess the benefit of specific interventions to prevent stroke in patients with seizures.
Jennifer M L Hon, Jo J Bhattacharya, Carl E Counsell, Vakis Papanastassiou, Vaughn Ritchie, Richard C Roberts, Robin J Sellar, Charles P Warlow, Rustam Al-Shahi Salman, SIVMS Collaborators
The presentation and clinical course of intracranial developmental venous anomalies in adults: a systematic review and prospective, population-based study.
Stroke. 2009 Jun;40(6):1980-5. doi: 10.1161/STROKEAHA.108.533034. Epub 2009 Apr 23.
Abstract/Text
BACKGROUND AND PURPOSE: Reported risks of hemorrhage from intracranial developmental venous anomalies (DVAs) vary, so we investigated this in a systematic review and population-based study.
METHODS: We systematically reviewed the literature (Ovid Medline and Embase to November 7, 2007) and selected studies of >or=20 participants with >or=1 DVA(s) that described their clinical presentation and/or their clinical course over a specified follow-up period. We also identified every adult first diagnosed with a DVA in Scotland from 1999 to 2003 and followed them in a prospective, population-based study.
RESULTS: Of 2068 articles detected by the literature search, 15 met our inclusion criteria and described clinical presentation, 8 of which also described the clinical course of DVAs. In the 15 studies of 714 people first presenting with a DVA, 61% were incidental findings, the mode of presentation was unclear in 23%, 6% presented with nonhemorrhagic focal neurological deficit, 6% had caused symptomatic hemorrhage, 4% were associated with epileptic seizure, and <1% were associated with infarction. In studies of the clinical course of 422 people with a DVA, the hemorrhage rate after first presentation ranged from 0% to 1.28% per year. In the population-based study of 93 adults with DVAs, 98% were incidental, 1% presented with symptomatic hemorrhage, and 1% presented with an infarct, but there were no symptomatic hemorrhages or infarcts in 492 person-years of follow-up (0% per person-year; 95% CI, 0% to 0.7%).
CONCLUSIONS: Intracranial DVAs have a benign presentation and clinical course.
Steven A Sandstrom, David J Anschel
Use of serum prolactin in diagnosing epileptic seizures: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology.
Neurology. 2006 Aug 8;67(3):544-5; author reply 544-5. doi: 10.1212/01.wnl.0000234968.40364.31.
Abstract/Text
Yuichi Kubota, Hidetoshi Nakamoto, Takakazu Kawamata
[Electroencephalographic features of nonconvulsive status epilepticus].
Brain Nerve. 2015 May;67(5):575-83. doi: 10.11477/mf.1416200183.
Abstract/Text
Continuous EEG monitoring (cEEG) has been recently applied in a neurocritical care setting in the US. The purpose of cEEG is primarily to detect nonconvulsive status epilepticus (NCSE) and secondarily, to evaluate the treatment of NCSE. It is difficult to diagnose NCSE in cEEG because of its variability. In the American Clinical Neurophysiology Society's Standardized Critical Care EEG Terminology 2012, EEG localization is placed under major term 1 and is classified as Lateralized (L), Generalized (G), Bilateral Independent (BI), and Multifocal (Mf). Morphology is placed under major term 2 and is classified as periodic, rhythmic, and spike-and-wave. Although there are no unequivocal criteria for the diagnosis of NCSE, the appearance of spatial and temporal changes in the EEG is essential for diagnosis.
Maurizio A Leone, Alessandra Solari, Ettore Beghi, FIRST Group
Treatment of the first tonic-clonic seizure does not affect long-term remission of epilepsy.
Neurology. 2006 Dec 26;67(12):2227-9. doi: 10.1212/01.wnl.0000249309.80510.63.
Abstract/Text
We followed 419 patients with a first, unprovoked, primarily or secondarily generalized tonic-clonic seizure, randomized to immediate antiepileptic treatment or to treatment only in the event of seizure recurrence. The probability of achieving a 2-year remission was 72 vs 57% at 3 months, 84 to 79% at 3 years, and 85 to 86% at 10 years (p = NS). The probability of entering 5-year remission was 47 to 40, 58 to 58, and 64 to 64% (p = NS). Early treatment does not affect the long-term prognosis of epilepsy.
L J Bonnett, C Tudur-Smith, P R Williamson, A G Marson
Risk of recurrence after a first seizure and implications for driving: further analysis of the Multicentre study of early Epilepsy and Single Seizures.
BMJ. 2010 Dec 7;341:c6477. Epub 2010 Dec 7.
Abstract/Text
OBJECTIVE: To determine for how long after a first unprovoked seizure a driver must be seizure-free before the risk of recurrence in the next 12 months falls below 20%, enabling them to regain their driving licence.
DESIGN: Randomised controlled trial: Multicentre study of early Epilepsy and Single Seizures (MESS).
SETTING: UK hospital outpatient clinics from 1 January 1993 to 31 December 2000.
PARTICIPANTS: People entered MESS if they had had one or more unprovoked seizures and both the participant and the clinician were uncertain about the need to start antiepileptic drug treatment. The subset of people used for this analysis comprised participants aged at least 16 years with a single unprovoked seizure.
MAIN OUTCOME MEASURE: Risk of seizure recurrence in the 12 months after a seizure-free period of 6, 12, 18, or 24 months from the date of the first (index) seizure. Regression modelling was used to investigate how antiepileptic treatment and several clinical factors influence the risk of seizure recurrence.
RESULTS: At six months after the index seizure the risk of recurrence in the next 12 months for those who start antiepileptic drugs was significantly below 20% (unadjusted risk 14%, 95% confidence interval 10% to 18%). For patients who did not start treatment the risk estimate was less than 20% but the upper limit of the confidence interval was greater than 20% (18%, 13% to 23%). Multivariable analyses identified subgroups with a significantly greater than 20% risk of seizure recurrence in the 12 months after a six month seizure-free period, such as those with a remote symptomatic seizure with abnormal electroencephalogram results.
CONCLUSION: After a single unprovoked seizure this reanalysis of MESS provides estimates of seizure recurrence risks that will inform policy and guidance about regaining an ordinary driving licence. Further guidance is needed as to how such data should be utilised; in particular, whether a population approach should be taken with a focus on the unadjusted results or whether attempts should be made to individualise risk. Guidance is also required as to whether the focus should be on risk estimates only or on the confidence interval as well. If the focus is on the estimate only our unadjusted estimates suggest that treated and untreated patients are eligible to drive after being seizure-free for six months. If the focus is also on confidence intervals, direction is needed as to whether a conservative or liberal approach should be taken.
TRIAL REGISTRATION: Current Controlled Trials ISRCTN98767960.
A Marson, A Jacoby, A Johnson, L Kim, C Gamble, D Chadwick, Medical Research Council MESS Study Group
Immediate versus deferred antiepileptic drug treatment for early epilepsy and single seizures: a randomised controlled trial.
Lancet. 2005 Jun 11-17;365(9476):2007-13. doi: 10.1016/S0140-6736(05)66694-9.
Abstract/Text
BACKGROUND: The relative risks and benefits of starting or withholding antiepileptic drug treatment in patients with few or infrequent seizures are unclear. We sought to compare policies of immediate versus deferred treatment in such patients and to assess the effects of these policies on short-term recurrence and long-term outcomes.
METHODS: We undertook an unmasked, multicentre, randomised study of immediate and deferred antiepileptic drug treatment in 1847 patients with single seizures and early epilepsy. Outcomes comprised time to first, second, and fifth seizures; time to 2-year remission; no seizures between years 1 and 3 and between years 3 and 5 after randomisation; and quality of life. Analysis was by intention to treat.
FINDINGS: 404 patients invited to join the trial did not consent to randomisation; 722 were subsequently assigned immediate treatment with antiepileptic drugs and 721 were assigned deferred treatment. Immediate treatment increased time to first seizure (hazard ratio 1.4 [95% CI 1.2 to 1.7]), second seizure (1.3 [1.1 to 1.6]), and first tonic-clonic seizure (1.5 [1.2 to 1.8]). It also reduced the time to achieve 2-year remission of seizures (p=0.023). At 5-years follow-up, 76% of patients in the immediate treatment group and 77% of those in the deferred treatment group were seizure free between 3 and 5 years after randomisation (difference -0.2% [95% CI -5.8% to 5.5%]). The two policies did not differ with respect to quality of life outcomes or serious complications.
INTERPRETATION: Immediate antiepileptic drug treatment reduces the occurrence of seizures in the next 1-2 years, but does not affect long-term remission in individuals with single or infrequent seizures.
N R Temkin
Antiepileptogenesis and seizure prevention trials with antiepileptic drugs: meta-analysis of controlled trials.
Epilepsia. 2001 Apr;42(4):515-24.
Abstract/Text
PURPOSE: To synthesize evidence concerning the effect of antiepileptic drugs (AEDs) for seizure prevention and to contrast their effectiveness for provoked versus unprovoked seizures.
METHODS: Medline, Embase, and The Cochrane Clinical Trials Register were the primary sources of trials, but all trials found were included. Minimal requirements: seizure-prevention outcome given as fraction of cases; AED or control assigned by random or quasi-random mechanism. Single abstracter. Aggregate relative risk and heterogeneity evaluated using Mantel-Haenszel analyses; random effects model used if heterogeneity was significant.
RESULTS: Forty-seven trials evaluated seven drugs or combinations for preventing seizures associated with fever, alcohol, malaria, perinatal asphyxia, contrast media, tumors, craniotomy, and traumatic brain injury. Effective: Phenobarbital for recurrence of febrile seizures [relative risk (RR), 0.51; 95% confidence interval (CI), 0.32-0.82) and cerebral malaria (RR, 0.36; CI, 0.23-0.56). Diazepam for contrast media-associated seizures (RR, 0.10; CI, 0.01-0.79). Phenytoin for provoked seizures after craniotomy or traumatic brain injury (craniotomy: RR, 0.42; CI, 0.25-0.71; TBI: RR, 0.33; CI, 0.19-0.59). Carbamazepine for provoked seizures after traumatic brain injury (RR, 0.39; CI, 0.17-0.92). Lorazepam for alcohol-related seizures (RR, 0.12; CI, 0.04-0.40). More than 25% reduction ruled out valproate for unprovoked seizures after traumatic brain injury (RR, 1.28; CI, 0.76-2.16), and carbamazepine for unprovoked seizures after craniotomy (RR, 1.30; CI, 0.75-2.25).
CONCLUSIONS: Effective or promising results predominate for provoked (acute, symptomatic) seizures. For unprovoked (epileptic) seizures, no drug has been shown to be effective, and some have had a clinically important effect ruled out.
Allan Krumholz, Samuel Wiebe, Gary S Gronseth, David S Gloss, Ana M Sanchez, Arif A Kabir, Aisha T Liferidge, Justin P Martello, Andres M Kanner, Shlomo Shinnar, Jennifer L Hopp, Jacqueline A French
Evidence-based guideline: Management of an unprovoked first seizure in adults: Report of the Guideline Development Subcommittee of the American Academy of Neurology and the American Epilepsy Society.
Neurology. 2015 Apr 21;84(16):1705-13. doi: 10.1212/WNL.0000000000001487.
Abstract/Text
OBJECTIVE: To provide evidence-based recommendations for treatment of adults with an unprovoked first seizure.
METHODS: 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.
RESULTS AND RECOMMENDATIONS: 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.
© 2015 American Academy of Neurology.
G Schierhout, I Roberts
Prophylactic antiepileptic agents after head injury: a systematic review.
J Neurol Neurosurg Psychiatry. 1998 Jan;64(1):108-12.
Abstract/Text
OBJECTIVE: To determine the effectiveness and safety of prophylactic antiepileptic agents in the management of acute traumatic head injury.
METHODS: Systematic review of randomised controlled trials identified using MEDLINE, EMBASE, CINAHL, Dewent Biotechnology abstracts, and specialised databases of randomised controlled trials, by searching reference lists and contacting investigators.
RESULTS: Ten eligible randomised controlled trials were identified, including 2036 patients. The pooled relative risk (RR) for early seizure prevention was 0.34 (95% confidence interval (95%CI) 0.21-0.54); based on this estimate, for every 100 patients treated, 10 would be kept seizure free in the first week. Seizure control in the acute phase was not accompanied by a reduction in mortality (RR=1.15; 95% CI 0.89-1.51), a reduction in death and neurological disability (RR=1.49; 95% CI 1.06-2.08 for carbamazepine and RR=0.96; 95% CI 0.72-1.26 for phenytoin) or a reduction in late seizures (pooled RR=1.28; 95% CI 0.90-1.81). The pooled relative risk for skin rashes was 1.57 (95% CI 0.90-2.75).
CONCLUSIONS: Prophylactic antiepileptic drugs are effective in reducing early seizures, but there is no evidence that treatment with such drugs reduces the occurrence of late seizures, or has any effect on death and neurological disability. Insufficient evidence is available to establish the net benefit of prophylactic treatment at any time after injury.
N R Temkin, S S Dikmen, A J Wilensky, J Keihm, S Chabal, H R Winn
A randomized, double-blind study of phenytoin for the prevention of post-traumatic seizures.
N Engl J Med. 1990 Aug 23;323(8):497-502. doi: 10.1056/NEJM199008233230801.
Abstract/Text
BACKGROUND: Antiepileptic drugs are commonly used to prevent seizures that may follow head trauma. However, previous controlled studies of this practice have been inconclusive.
METHODS: To study further the effectiveness of phenytoin (Dilantin) in preventing post-traumatic seizures, we randomly assigned 404 eligible patients with serious head trauma to treatment with phenytoin (n = 208) or placebo (n = 196) for one year in a double-blind fashion. An intravenous loading dose was given within 24 hours of injury. Serum levels of phenytoin were maintained in the high therapeutic range (3 to 6 mumol of free phenytoin per liter). Follow-up was continued for two years. The primary data analysis was performed according to the intention to treat.
RESULTS: Between drug loading and day 7, 3.6 percent of the patients assigned to phenytoin had seizures, as compared with 14.2 percent of patients assigned to placebo (P less than 0.001; risk ratio, 0.27; 95 percent confidence interval, 0.12 to 0.62). Between day 8 and the end of year 1, 21.5 percent of the phenytoin group and 15.7 percent of the placebo group had seizures; at the end of year 2, the rates were 27.5 percent and 21.1 percent, respectively (P greater than 0.2 for each comparison; risk ratio, 1.20; 95 percent confidence interval, 0.71 to 2.02). This lack of a late effect could not be attributed to differential mortality, low phenytoin levels, or treatment of some early seizures in patients assigned to the placebo group.
CONCLUSIONS: Phenytoin exerts a beneficial effect by reducing seizures only during the first week after severe head injury.
Bernard S Chang, Daniel H Lowenstein, Quality Standards Subcommittee of the American Academy of Neurology
Practice parameter: antiepileptic drug prophylaxis in severe traumatic brain injury: report of the Quality Standards Subcommittee of the American Academy of Neurology.
Neurology. 2003 Jan 14;60(1):10-6.
Abstract/Text
OBJECTIVE: To review the evidence regarding antiepileptic drug (AED) prophylaxis in patients with severe traumatic brain injury (TBI) in order to make practice recommendations.
METHODS: The authors identified relevant studies by searching multiple databases and reviewing reference lists of other sources. They included studies that prospectively compared post-traumatic seizure rates in patients given AED prophylaxis vs controls. Each study was graded (class I to IV) according to a standard classification-of-evidence scheme and results were analyzed and pooled.
RESULTS: Pooled class I studies demonstrated a significantly lower risk of early post-traumatic seizures (those occurring within 7 days after injury) in patients given phenytoin prophylaxis compared to controls (relative risk 0.37, 95% CI 0.18 to 0.74). Pooled class I and class II studies demonstrated no significant difference in the risk of late post-traumatic seizures (those occurring beyond 7 days after injury) in patients given AED prophylaxis compared to controls (relative risk 1.05, 95% CI 0.82 to 1.35). Serum AED levels were suboptimal in these studies and adverse effects were mild but frequent.
CONCLUSIONS: For adult patients with severe TBI, prophylaxis with phenytoin is effective in decreasing the risk of early post-traumatic seizures. AED prophylaxis is probably not effective in decreasing the risk of late post-traumatic seizures. Further studies addressing milder forms of TBI, the use of newer AEDs, the utility of EEG, and the applicability of these findings to children are recommended.
Nickalus R Khan, Matthew A VanLandingham, Tamara M Fierst, Caroline Hymel, Kathryn Hoes, Linton T Evans, Rory Mayer, Fred Barker, Paul Klimo
Should Levetiracetam or Phenytoin Be Used for Posttraumatic Seizure Prophylaxis? A Systematic Review of the Literature and Meta-analysis.
Neurosurgery. 2016 Dec;79(6):775-782. doi: 10.1227/NEU.0000000000001445.
Abstract/Text
BACKGROUND: Posttraumatic seizure (PTS) is a significant complication of traumatic brain injury (TBI).
OBJECTIVE: To perform a systematic review and meta-analysis to compare levetiracetam with phenytoin for seizure prophylaxis in patients diagnosed with severe TBI.
METHODS: An inclusive search of several electronic databases and bibliographies was conducted to identify scientific studies that compared the effect of levetiracetam and phenytoin on PTS. Independent reviewers obtained data and classified the quality of each article that met inclusion criteria. A random effects meta-analysis was then completed.
RESULTS: During June and July 2015, a systematic literature search was performed that identified 6097 articles. Of these, 7 met inclusion criteria. A random-effects meta-analysis was performed. A total of 1186 patients were included. The rate of seizure was 35 of 654 (5.4%) in the levetiracetam cohort and 18 of 532 (3.4%) in the phenytoin cohort. Our meta-analysis revealed no change in the rate of early PTS with levetiracetam compared with phenytoin (relative risk, 1.02; 95% confidence interval, 0.53-1.95; P = .96).
CONCLUSION: The lack of evidence on which antiepileptic drug to use in PTS is surprising given the number of patients prescribed an antiepileptic drug therapy for TBI. On the basis of currently available Level III evidence, patients treated with either levetiracetam or phenytoin have similar incidences of early seizures after TBI.
ABBREVIATIONS: ADE, adverse drug eventAED, antiepileptic drugCI, confidence intervalOR, odds ratioPTS, posttraumatic seizureTBI, traumatic brain injury.
Anthony Marson, Girvan Burnside, Richard Appleton, Dave Smith, John Paul Leach, Graeme Sills, Catrin Tudur-Smith, Catrin Plumpton, Dyfrig A Hughes, Paula Williamson, Gus A Baker, Silviya Balabanova, Claire Taylor, Richard Brown, Dan Hindley, Stephen Howell, Melissa Maguire, Rajiv Mohanraj, Philip E Smith, SANAD II collaborators
The SANAD II study of the effectiveness and cost-effectiveness of valproate versus levetiracetam for newly diagnosed generalised and unclassifiable epilepsy: an open-label, non-inferiority, multicentre, phase 4, randomised controlled trial.
Lancet. 2021 Apr 10;397(10282):1375-1386. doi: 10.1016/S0140-6736(21)00246-4.
Abstract/Text
BACKGROUND: Valproate is a first-line treatment for patients with newly diagnosed idiopathic generalised or difficult to classify epilepsy, but not for women of child-bearing potential because of teratogenicity. Levetiracetam is increasingly prescribed for these patient populations despite scarcity of evidence of clinical effectiveness or cost-effectiveness. We aimed to compare the long-term clinical effectiveness and cost-effectiveness of levetiracetam compared with valproate in participants with newly diagnosed generalised or unclassifiable epilepsy.
METHODS: We did an open-label, randomised controlled trial to compare levetiracetam with valproate as first-line treatment for patients with generalised or unclassified epilepsy. Adult and paediatric neurology services (69 centres overall) across the UK recruited participants aged 5 years or older (with no upper age limit) with two or more unprovoked generalised or unclassifiable seizures. Participants were randomly allocated (1:1) to receive either levetiracetam or valproate, using a minimisation programme with a random element utilising factors. Participants and investigators were aware of treatment allocation. For participants aged 12 years or older, the initial advised maintenance doses were 500 mg twice per day for levetiracetam and valproate, and for children aged 5-12 years, the initial daily maintenance doses advised were 25 mg/kg for valproate and 40 mg/kg for levetiracetam. All drugs were administered orally. SANAD II was designed to assess the non-inferiority of levetiracetam compared with valproate for the primary outcome time to 12-month remission. The non-inferiority limit was a hazard ratio (HR) of 1·314, which equates to an absolute difference of 10%. A HR greater than 1 indicated that an event was more likely on valproate. All participants were included in the intention-to-treat (ITT) analysis. Per-protocol (PP) analyses excluded participants with major protocol deviations and those who were subsequently diagnosed as not having epilepsy. Safety analyses included all participants who received one dose of any study drug. This trial is registered with the ISRCTN registry, 30294119 (EudraCt number: 2012-001884-64).
FINDINGS: 520 participants were recruited between April 30, 2013, and Aug 2, 2016, and followed up for a further 2 years. 260 participants were randomly allocated to receive levetiracetam and 260 participants to receive valproate. The ITT analysis included all participants and the PP analysis included 255 participants randomly allocated to valproate and 254 randomly allocated to levetiracetam. Median age of participants was 13·9 years (range 5·0-94·4), 65% were male and 35% were female, 397 participants had generalised epilepsy, and 123 unclassified epilepsy. Levetiracetam did not meet the criteria for non-inferiority in the ITT analysis of time to 12-month remission (HR 1·19 [95% CI 0·96-1·47]); non-inferiority margin 1·314. The PP analysis showed that the 12-month remission was superior with valproate than with levetiracetam. There were two deaths, one in each group, that were unrelated to trial treatments. Adverse reactions were reported by 96 (37%) participants randomly assigned to valproate and 107 (42%) participants randomly assigned to levetiracetam. Levetiracetam was dominated by valproate in the cost-utility analysis, with a negative incremental net health benefit of -0·040 (95% central range -0·175 to 0·037) and a probability of 0·17 of being cost-effectiveness at a threshold of £20 000 per quality-adjusted life-year. Cost-effectiveness was based on differences between treatment groups in costs and quality-adjusted life-years.
INTERPRETATION: Compared with valproate, levetiracetam was found to be neither clinically effective nor cost-effective. For girls and women of child-bearing potential, these results inform discussions about benefit and harm of avoiding valproate.
FUNDING: National Institute for Health Research Health Technology Assessment Programme.
Copyright © 2021 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.
Anthony Marson, Girvan Burnside, Richard Appleton, Dave Smith, John Paul Leach, Graeme Sills, Catrin Tudur-Smith, Catrin Plumpton, Dyfrig A Hughes, Paula Williamson, Gus A Baker, Silviya Balabanova, Claire Taylor, Richard Brown, Dan Hindley, Stephen Howell, Melissa Maguire, Rajiv Mohanraj, Philip E Smith, SANAD II collaborators
The SANAD II study of the effectiveness and cost-effectiveness of levetiracetam, zonisamide, or lamotrigine for newly diagnosed focal epilepsy: an open-label, non-inferiority, multicentre, phase 4, randomised controlled trial.
Lancet. 2021 Apr 10;397(10282):1363-1374. doi: 10.1016/S0140-6736(21)00247-6.
Abstract/Text
BACKGROUND: Levetiracetam and zonisamide are licensed as monotherapy for patients with focal epilepsy, but there is uncertainty as to whether they should be recommended as first-line treatments because of insufficient evidence of clinical effectiveness and cost-effectiveness. We aimed to assess the long-term clinical effectiveness and cost-effectiveness of levetiracetam and zonisamide compared with lamotrigine in people with newly diagnosed focal epilepsy.
METHODS: This randomised, open-label, controlled trial compared levetiracetam and zonisamide with lamotrigine as first-line treatment for patients with newly diagnosed focal epilepsy. Adult and paediatric neurology services across the UK recruited participants aged 5 years or older (with no upper age limit) with two or more unprovoked focal seizures. Participants were randomly allocated (1:1:1) using a minimisation programme with a random element utilising factor to receive lamotrigine, levetiracetam, or zonisamide. Participants and investigators were not masked and were aware of treatment allocation. SANAD II was designed to assess non-inferiority of both levetiracetam and zonisamide to lamotrigine for the primary outcome of time to 12-month remission. Anti-seizure medications were taken orally and for participants aged 12 years or older the initial advised maintenance doses were lamotrigine 50 mg (morning) and 100 mg (evening), levetiracetam 500 mg twice per day, and zonisamide 100 mg twice per day. For children aged between 5 and 12 years the initial daily maintenance doses advised were lamotrigine 1·5 mg/kg twice per day, levetiracetam 20 mg/kg twice per day, and zonisamide 2·5 mg/kg twice per day. All participants were included in the intention-to-treat (ITT) analysis. The per-protocol (PP) analysis excluded participants with major protocol deviations and those who were subsequently diagnosed as not having epilepsy. Safety analysis included all participants who received one dose of any study drug. The non-inferiority limit was a hazard ratio (HR) of 1·329, which equates to an absolute difference of 10%. A HR greater than 1 indicated that an event was more likely on lamotrigine. The trial is registered with the ISRCTN registry, 30294119 (EudraCt number: 2012-001884-64).
FINDINGS: 990 participants were recruited between May 2, 2013, and June 20, 2017, and followed up for a further 2 years. Patients were randomly assigned to receive lamotrigine (n=330), levetiracetam (n=332), or zonisamide (n=328). The ITT analysis included all participants and the PP analysis included 324 participants randomly assigned to lamotrigine, 320 participants randomly assigned to levetiracetam, and 315 participants randomly assigned to zonisamide. Levetiracetam did not meet the criteria for non-inferiority in the ITT analysis of time to 12-month remission versus lamotrigine (HR 1·18; 97·5% CI 0·95-1·47) but zonisamide did meet the criteria for non-inferiority in the ITT analysis versus lamotrigine (1·03; 0·83-1·28). The PP analysis showed that 12-month remission was superior with lamotrigine than both levetiracetam (HR 1·32 [97·5% CI 1·05 to 1·66]) and zonisamide (HR 1·37 [1·08-1·73]). There were 37 deaths during the trial. Adverse reactions were reported by 108 (33%) participants who started lamotrigine, 144 (44%) participants who started levetiracetam, and 146 (45%) participants who started zonisamide. Lamotrigine was superior in the cost-utility analysis, with a higher net health benefit of 1·403 QALYs (97·5% central range 1·319-1·458) compared with 1·222 (1·110-1·283) for levetiracetam and 1·232 (1·112, 1·307) for zonisamide at a cost-effectiveness threshold of £20 000 per QALY. Cost-effectiveness was based on differences between treatment groups in costs and QALYs.
INTERPRETATION: These findings do not support the use of levetiracetam or zonisamide as first-line treatments for patients with focal epilepsy. Lamotrigine should remain a first-line treatment for patients with focal epilepsy and should be the standard treatment in future trials.
FUNDING: National Institute for Health Research Health Technology Assessment programme.
Copyright © 2021 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.
Phil E M Smith
Initial Management of Seizure in Adults.
N Engl J Med. 2021 Jul 15;385(3):251-263. doi: 10.1056/NEJMcp2024526.
Abstract/Text
A Polycarpou, P Papanikolaou, J P A Ioannidis, D G Contopoulos-Ioannidis
Anticonvulsants for alcohol withdrawal.
Cochrane Database Syst Rev. 2005 Jul 20;(3):CD005064. doi: 10.1002/14651858.CD005064.pub2. Epub 2005 Jul 20.
Abstract/Text
BACKGROUND: Alcohol withdrawal syndrome is a cluster of symptoms that occurs in alcohol-dependent people after cessation or reduction in alcohol use. This systematic review focuses on the evidence of anticonvulsants' use in the treatment of alcohol withdrawal symptoms.
OBJECTIVES: To evaluate the effectiveness and safety of anticonvulsants in the treatment of alcohol withdrawal.
SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (The Cochrane Library Issue 3, 2004); MEDLINE (1966 to October 2004); EMBASE (1988 to October 2004) and EU-PSI PSI-Tri database with no language and publication restrictions and references of articles.
SELECTION CRITERIA: All randomized controlled trials examining the effectiveness, safety and overall risk-benefit of an anticonvulsant in comparison with a placebo or other pharmacological treatment or another anticonvulsant were considered.
DATA COLLECTION AND ANALYSIS: The authors independently assessed trial quality extracted data.
MAIN RESULTS: Forty-eight studies, involving 3610 people were included. Despite the considerable number of randomized controlled trials, there was a variety of outcomes and of different rating scales that led to a limited quantitative synthesis of data. For the anticonvulsant versus placebo comparison, therapeutic success tended to be more common among the anticonvulsant-treated patients (relative risk (RR) 1.32; 95% confidence interval (CI) 0.92 to 1.91), and anticonvulsant tended to show a protective benefit against seizures (RR 0.57; 95% CI 0.27 to 1.19), but no effect reached formal statistical significance. For the anticonvulsant versus other drug comparison, CIWA-Ar score showed non-significant differences for the anticonvulsants compared to the other drugs at the end of treatment (weighted mean difference (WMD) -0.73; 95% CI -1.76 to 0.31). For the subgroup analysis of carbamazepine versus benzodiazepine, a statistically significant protective effect was found for the anticonvulsant (WMD -1.04; 95% CI -1.89 to -0.20), p = 0.02), but this was based on only 260 randomized participants. There was a non-significant decreased incidence of seizures (RR 0.50; 95% CI 0.18 to 1.34) favouring the patients that were treated with anticonvulsants than other drugs, and side-effects tended to be less common in the anticonvulsant-group (RR 0.56; 95% CI 0.31 to 1.02).
AUTHORS' CONCLUSIONS: It is not possible to draw definite conclusions about the effectiveness and safety of anticonvulsants in alcohol withdrawal, because of the heterogeneity of the trials both in interventions and the assessment of outcomes. The extremely small mortality rate in all these studies is reassuring, but data on other safety outcomes are sparse and fragmented.
Laura Amato, Silvia Minozzi, Simona Vecchi, Marina Davoli
Benzodiazepines for alcohol withdrawal.
Cochrane Database Syst Rev. 2010 Mar 17;(3):CD005063. doi: 10.1002/14651858.CD005063.pub3. Epub 2010 Mar 17.
Abstract/Text
BACKGROUND: Alcohol abuse and dependence represents a serious health problem worldwide with social, interpersonal and legal interpolations. Benzodiazepines have been widely used for the treatment of alcohol withdrawal symptoms. Moreover it is unknown whether different benzodiazepines and different regimens of administration may have the same merits.
OBJECTIVES: To evaluate the effectiveness and safety of benzodiazepines in the treatment of alcohol withdrawal.
SEARCH STRATEGY: Cochrane Drugs and Alcohol Group' Register of Trials (December 2009), PubMed, EMBASE, CINAHL (January 1966 to December 2009), EconLIT (1969 to December 2009). Parallel searches on web sites of health technology assessment and related agencies, and their databases.
SELECTION CRITERIA: Randomized controlled trials examining effectiveness, safety and risk-benefit of benzodiazepines in comparison with placebo or other pharmacological treatment and between themselves. All patients were included regardless of age, gender, nationality, and outpatient or inpatient therapy.
DATA COLLECTION AND ANALYSIS: Two authors independently screened and extracted data from studies.
MAIN RESULTS: Sixty four studies, 4309 participants, met the inclusion criteria.- Comparing benzodiazepines versus placebo, benzodiazepines performed better for seizures, 3 studies, 324 participants, RR 0.16 (0.04 to 0.69), no statistically significant difference for the other outcomes considered.- Comparing benzodiazepines versus other drugs, there is a trend in favour of benzodiazepines for seizure and delirium control, severe life threatening side effect, dropouts, dropouts due to side effects and patient's global assessment score. A trend in favour of control group was observed for CIWA-Ar scores at 48 hours and at the end of treatment. The results reach statistical significance only in one study, with 61 participants, results on Hamilton anxiety rating scale favour control MD -1.60 (-2.59 to -0.61)- Comparing different benzodiazepines among themselves,results never reached statistical significance but chlordiazepoxide performed better- Comparing benzodiazepine plus other drug versus other drug, results never reached statistical significance.- In the comparison of fixed-schedule versus symptom-triggered regimens, results from a single study, with 159 participants, favour symptom-triggered regimens MD -1.10 [-3.27, 1.07] for CIWA-Ar scores at the end of treatment. Differences in isolated trials should be interpreted very cautiously.
AUTHORS' CONCLUSIONS: Benzodiazepines showed a protective benefit against alcohol withdrawal symptoms, in particular seizures, when compared to placebo and a potentially protective benefit for many outcomes when compared with other drugs. Nevertheless, no definite conclusions about the effectiveness and safety of benzodiazepines was possible, because of the heterogeneity of the trials both in interventions and the assessment of outcomes.
