{"id":75627,"date":"2024-02-22T15:37:59","date_gmt":"2024-02-22T15:37:59","guid":{"rendered":"https:\/\/touchneurology.com\/?p=75627"},"modified":"2024-02-23T11:12:41","modified_gmt":"2024-02-23T11:12:41","slug":"acute-management-of-seizure-clusters-and-prolonged-seizures-a-review-of-rescue-therapies","status":"publish","type":"post","link":"https:\/\/touchneurology.com\/epilepsy\/journal-articles\/acute-management-of-seizure-clusters-and-prolonged-seizures-a-review-of-rescue-therapies\/","title":{"rendered":"Acute Management of Seizure Clusters and Prolonged Seizures: A Review of Rescue Therapies"},"content":{"rendered":"
Rescue medications are an important part of the treatment regimen for patients with intractable epilepsy, specifically those who experience seizure clusters or prolonged seizure episodes. Rescue medications are prescribed to end seizure activity quickly and effectively in order to prevent further seizure-related morbidities and prevent seizure recurrence. An ideal rescue medication is stable at room temperature, easy to administer, works rapidly to cease seizure activity and has consistent, reliable absorption that allows it to take action rapidly. Intravenous benzodiazepines are used by trained and qualified healthcare providers to treat seizure clusters or status epilepticus but are not safe or feasible for home use. Currently, three rescue medications have been approved for use in the USA by the US Food and Drug Administration (FDA): diazepam rectal gel (Diastat\u00ae<\/sup>;<\/span>\u00a0Valeant Pharmaceuticals<\/span>,\u00a0Laval<\/span>, Canada), midazolam intranasal spray (Nayzilam\u00ae<\/sup>; UCB,\u00a0Brussels, Belgium<\/span>), and diazepam nasal spray (Valtoco\u00ae<\/sup>;\u00a0Neurelis, Inc., San Diego, CA, USA<\/span>).1\u20133<\/sup><\/span>\u00a0In Europe, South America and some Asian countries, buccal midazolam (Buccolam\u00ae<\/sup>;\u00a0Neuraxpharm<\/span>,\u00a0Barcelona<\/span>, Spain) is used to manage prolonged seizures in paediatric and adolescent populations.4<\/sup><\/span>\u00a0<\/sup>Buccal midazolam can also be used off label in adult populations. Furthermore, on-going studies are assessing the safety and efficacy of intramuscular and intrapulmonary administration of benzodiazepines to terminate seizures (Pediatric dose optimization for seizures in emergency medical services (PediDOSE)<\/span>; ClinicalTrials.gov identifier:\u00a0NCT05121324<\/span>).5,6<\/sup><\/span>\u00a0In this review article, we assess currently available formulations of rescue medications in the acute\u00a0management<\/span>\u00a0of\u00a0seizure clusters<\/span>\u00a0and\u00a0prolonged seizures<\/span>, while also highlighting new formulations, devices, and novel drug delivery systems that are currently in research and development stages.<\/span><\/p>\n For the purpose of this review, seizure clusters are defined as \u201cacute episodes of increased repetitive seizures, irrespective of type or grouping, that differ from the person\u2019s usual seizure pattern\u201d.7<\/sup><\/span>\u00a0For rescue medication to be administered correctly, the onset of the seizure must be readily recognized by the patient or caregiver.4<\/sup><\/span><\/p>\n Seizure clusters have been variably defined in the literature as two or more seizures in a 6-hour period, three or more seizures over 24 hours, or two to four seizures in less than 48 hours.8<\/sup><\/span>\u00a0They have been investigated mainly via prospective studies involving seizure diaries.9,10<\/sup><\/span>\u00a0Statistical methods have also been used to identify seizure clusters. These algorithms test the hypothesis that seizures are randomly distributed in time and identify deviations from this pattern. Predictive factors for seizure clusters included high seizure frequency and prior seizure clusters, as observed by a prospective study of 247 patients with epilepsy aged \u226514 years.9<\/sup><\/span>\u00a0This study found a prevalence of seizure clusters of 29.1% in this patient population, which included a large proportion of patients who had no seizures over the year of follow-up (n=110). The prevalence of seizure clusters over the following year increased to 62.7% in patients with a history of seizure clusters.9<\/sup><\/span>\u00a0Another prospective study using seizure diaries reported a 29% prevalence of seizure clusters and found an association with extratemporal epilepsy, remote symptomatic seizures and a history of convulsive status epilepticus.10<\/sup><\/span><\/p>\n In patients with refractory focal epilepsy, seizure cluster prevalence of 57% has been reported, underscoring that patients with medically refractory epilepsy are at the highest risk.8<\/sup><\/span>\u00a0Additionally, in a sample of patients with status epilepticus, one study found 44% of patients suffered from seizure clusters compared to 12.5% without clusters.4<\/sup><\/span><\/p>\n The definition of a prolonged seizure is dynamic, as it is based on the typical individual seizure duration seen in a patient. A seizure that lasts two to three times the normal duration of an individual\u2019s seizures could be considered a prolonged seizure. Rescue medications can also be used to treat prolonged seizures. Although they are used as off-label medications for the treatment of these seizures, this strategy is often employed by healthcare providers, with instructions for patients and caregivers to use rescue medication if seizures persist for >5\u00a0<\/span>minutes.<\/p>\n Prolonged seizures have a higher likelihood of developing into status epilepticus and, therefore, represent a key time-point for early intervention by caregivers.11<\/sup><\/span>\u00a0The International League Against Epilepsy defines status epilepticus as \u201ca condition resulting either from the failure of the mechanisms responsible for seizure termination or from the initiation of mechanisms, which lead to abnormally prolonged seizures\u201d.12<\/sup><\/span>\u00a0The time point at which the normal mechanisms for spontaneously stopping seizures have failed is 5 minutes for convulsive seizures, 10 minutes for focal seizures with and without impairment of consciousness, and 10 minutes for generalized absence seizures<\/span>.12 <\/sup><\/span>The treatment of prolonged seizures with rescue medications can prevent progression to status epilepticus, which, in addition to high morbidity and mortality, results in irreversible neuronal injury and the alteration of seizure networks.<\/p>\n Rescue medications can also be employed for prolonged seizures to stop progression to more disabling seizure types. For example, rescue medication during a prolonged aura can stop the progression to bilateral tonic-clonic seizures or prevent the progression of a focal aware seizure to a focal impaired aware seizure.13<\/sup><\/span><\/p>\n The Seizure Cluster Burden of Illness US survey conducted by the Epilepsy Foundation in 2014 assessed 861 clinicians, patients, and caregivers and found that, although 52% of clinicians reported that over half of their patients had a seizure action plan in place, only 30% of the surveyed patients reported having seizure action plans.14,15<\/sup><\/span>\u00a0Since 2014, both midazolam\u00a0intranasal spray<\/span>\u00a0and diazepam intranasal spray have gained FDA approval.2,3<\/sup><\/span>\u00a0The convenience and efficacy of intranasal medications compared with rectal diazepam gel (the only FDA-approved rescue medication in 2014) could contribute to an increase in patient and caregiver compliance with seizure action plans.<\/p>\n There are many formulations of rescue medications that differ in route, dose and active ingredient, providing a variety of options for prescribers and patients. The drug delivery systems discussed in the contemporary literature include intranasal, rectal, intrapulmonary, intramuscular, intravenous, buccal and sublingual administration (Table 1<\/em><\/span>).4,8,13,14,16\u201326<\/sup><\/span>\u00a0In this article,\u00a0we do not explore all of the aforementioned drug delivery systems but instead briefly describe the most commonly used and clinically relevant methods of rescue medication administration.\u00a0<\/span>The pharmacokinetics and pharmacodynamics of the same medication can vary based on the route of entry. Ensuring that a rescue medication is easy to use, efficacious and with minimal side effects can help increase patient compliance, especially when supplemented with physician-directed education and instructions for use.<\/p>\n Table 1:<\/span>A brief overview of rescue medications4,8,13,14,16\u201326<\/sup><\/span><\/p>\n Route<\/b><\/p>\n<\/td>\n Medication<\/b><\/p>\n<\/td>\n Half-l<\/span>ife (hours<\/b>)<\/p>\n<\/td>\n Time to onset<\/b><\/p>\n (minutes<\/b>)<\/p>\n<\/td>\n Advantages<\/b><\/p>\n<\/td>\n Disadvantages<\/b><\/p>\n<\/td>\n Who can administer<\/b><\/p>\n<\/td>\n<\/tr>\n<\/thead>\n\n Intravenous<\/p>\n<\/td>\n Lorazepam<\/p>\n<\/td>\n 12\u20131418,23<\/sup><\/span><\/p>\n<\/td>\n 1\u2013317<\/sup><\/span><\/p>\n<\/td>\n Rapid and reliable onset of action;<\/p>\n bypasses metabolism directly into the bloodstream.<\/p>\n Extremely reliable<\/p>\n<\/td>\n Complex administration, limited to medical environments with advanced medical providers;23<\/sup><\/span><\/p>\n IV site must be placed, which takes time and increases the risk of infection17<\/sup><\/span><\/p>\n<\/td>\n Trained medical professionals17<\/sup><\/span><\/p>\n<\/td>\n<\/tr>\n Intra-pulmonary<\/p>\n<\/td>\n Alprazolam<\/p>\n<\/td>\n 6\u201315 (oral, IV)*17<\/sup><\/span><\/p>\n<\/td>\n 30 seconds\u20132 minutes4,13<\/sup><\/span><\/p>\n<\/td>\n Large surface area of lungs allows for rapid and efficient absorption;19<\/sup><\/span><\/p>\n targeted to termination of ongoing seizures13<\/sup><\/span><\/p>\n<\/td>\n It may be difficult to administer during impaired aware seizures, however, active inhalation is not necessary for efficacy;13<\/sup><\/span><\/p>\n cough, somnolence, dysgeusia13<\/sup><\/span><\/p>\n<\/td>\n Patient, caregivers13<\/sup><\/span><\/p>\n<\/td>\n<\/tr>\n Intranasal<\/p>\n<\/td>\n Diazepam<\/p>\n<\/td>\n 4914,23<\/sup><\/span><\/p>\n<\/td>\n 2\u20131023<\/sup><\/span><\/p>\n<\/td>\n Easy to administer;16<\/sup><\/span><\/p>\n bypass first-pass metabolism;<\/span>23<\/sup><\/span><\/p>\n <\/span>minimal risk of injury19<\/sup><\/span><\/p>\n<\/td>\n Limited amounts of medication can be delivered;20<\/sup><\/span><\/p>\n facial trauma or nasal obstruction can prevent administration;20<\/sup><\/span><\/p>\n nasal discomfort, somnolence8,20<\/sup><\/span><\/p>\n<\/td>\n Patient, caregivers13<\/sup><\/span><\/p>\n<\/td>\n<\/tr>\n Intranasal<\/p>\n<\/td>\n Midazolam<\/p>\n<\/td>\n 2\u2013614,22<\/sup><\/span><\/p>\n<\/td>\n 3\u2013104,17<\/sup><\/span><\/p>\n<\/td>\n Easy to administer;16<\/sup><\/span><\/p>\n low risk of incorrect dosing;<\/p>\n minimal risk of injury<\/p>\n<\/td>\n Limited amounts of medication can be delivered;20<\/sup><\/span><\/p>\n facial trauma or nasal obstruction can prevent administration;20<\/sup><\/span><\/p>\n nasal discomfort, somnolence8,20<\/sup><\/span><\/p>\n<\/td>\n Patient, caregivers16,17<\/sup><\/span><\/p>\n<\/td>\n<\/tr>\n Intramuscular<\/p>\n<\/td>\n Midazolam<\/p>\n<\/td>\n 2\u2013517,23<\/sup><\/span><\/p>\n<\/td>\n 5\u20131521,23<\/sup><\/span><\/p>\n<\/td>\n Bypasses first-pass metabolism;23<\/sup><\/span><\/p>\n stable formulation without refrigeration;25<\/sup><\/span><\/span><\/span><\/p>\n prolonged effects25<\/sup><\/span><\/span><\/span><\/p>\n<\/td>\n Limited amounts of medication can be delivered;\u00a0variable absoprtion;23<\/sup><\/span><\/sup><\/span><\/p>\n haematoma, pain4<\/sup><\/span><\/p>\n<\/td>\n Patient, caregivers (trained with autoinjector)17,23,26<\/sup><\/span><\/p>\n<\/td>\n<\/tr>\n Buccal<\/p>\n<\/td>\n Midazolam<\/p>\n<\/td>\n 2\u2013417,23<\/sup><\/span><\/p>\n<\/td>\n 5\u20131523<\/sup><\/span><\/p>\n<\/td>\n Rapid effect;22<\/sup><\/span><\/p>\n bypasses first-pass metabolism23<\/sup><\/span><\/p>\n<\/td>\n Medication placement and retention can be difficult in active seizures;17<\/sup><\/span><\/p>\n restricted to children and adolescents;19<\/sup><\/span><\/sup><\/span><\/p>\n inconsistent absorption due to ictal hypersalivation and buccal secretion;Defining seizure cluster and prolonged seizure<\/h1>\n
Seizure clusters<\/h2>\n
Prolonged seizures<\/h2>\n
Seizure action plans<\/h2>\n
Drug delivery systems<\/h1>\n
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