[Pharmacotherapy and intensive care aspects of status epilepticus: update 2020/2021]. / Pharmakotherapie und intensivmedizinische Aspekte des Status epilepticus: Update 2020/2021.

Focused treatment of epileptic emergencies, and in particular status epilepticus (SE), require a reliable differentiation of epileptic syndromes. In these cases, and especially in cases with predominant non-motor symptoms, clinical and electroencephalographic expertise is necessary. In 2020 the German guidelines for the management of SE were updated, which adhere to a strict stage-based treatment algorithm. The staged approach includes the administration of benzodiazepines, antiepileptic drugs and anesthetic agents. So far, efforts failed to determine the most effective and safest antiepileptic drug without interaction potential. Therefore, for the differentiated treatment of SE, individual pre-existing medical conditions and concomitant circumstances must be considered, added by the experience of the medical team. Therapeutic interventions especially for refractory forms of SE have been shown to be complex with relevant implications concerning intensive care aspects. Consequently, the modern treatment strategy of SE is characterized by an interdisciplinary approach. Future research is needed to define the optimal treatment of non-convulsive SE, in particular regarding the time point and degree of treatment escalation with associated ethical considerations.

The unmet need for rapid epileptic seizure termination (REST).

Approximately 40% of epilepsy patients will continue to experience breakthrough seizures despite stable antiepileptic drug regimens. Rescue treatments have demonstrated efficacy and safety for select seizure emergencies. Outpatient administered intranasal and rectally delivered medications are regulatory approved for acute repetitive seizures (ARS), and injectable benzodiazepines are indicated for parenteral treatment of established status epilepticus. Despite these advances, no studies have been shown to abort an ongoing seizure following patient or caregiver home administration of therapy at the first clinical sign of seizure onset. Such treatment would require rapid systemic absorption without intravenous access, and evidence of seizure cessation within minutes of administration that is superior to placebo (eg, seizure self-regulation). Rapid epileptic seizure termination (REST) treatment may apply to multiple seizure emergencies beyond ARS, including focal or generalized seizures preceded by an aura, flurries of absence or myoclonic seizures, or prolonged focal and generalized seizures at high risk of progression to status epilepticus. Novel investigational drug delivery systems have demonstrated feasibility of intraictal delivery and seizure cessation by two minutes. Ongoing randomized trials of REST treatment for diverse seizure emergencies hold the potential to decrease bouts of mental and physical incapacitation in patients with drug-resistant epilepsy.

A systematic review of seizure clusters: Prevalence, risk factors, burden of disease and treatment patterns.

Seizure clusters (SCs) are episodes of consecutive seizures that occur within a short period. The treatment patterns of rescue medications (RMs), as well as the burden of SCs, have not been assessed. A systematic literature search on Embase.com (in PubMed and Embase), supplemented with keyword-based and bibliographic searches, identified 44 articles for disease burden, three treatment guidelines, and three articles for treatment patterns. Common SC definitions were ≥3 seizures/24 h, ≥2/24 h and ≥2/6 h. The rate of SCs in prospective studies ranged from 21.7 %-42.5 %. The frequency of status epilepticus (SE) was higher in SC patients. SCs were associated with higher seizure frequency, higher risk of treatment resistance, and lower likelihood of seizure remission. Quality of life (QoL) was lower in children with SCs than in those with isolated seizures. Seizure-related hospitalization was more common in SC than non-SC patients. SCs adversely affected the productivity of patients and their caregivers. In outpatients with SCs, RMs were prescribed to 24.6 %-89.6 % and utilized by 15.6 %-44.5 %, with rates being higher in children. Key reasons for RM under-utilization were lack of seizure action plans, poor physician-patient communication, and concerns with administration route. In conclusion, SCs are associated with a higher risk of SE, treatment resistance, and low rate of seizure remission. They adversely affect patient and caregiver QoL and work productivity. However, RMs are under-prescribed, and there is an urgent need to improve recognition of SCs, improve use of seizure action plans, and remove barriers to RM use.

Conversion of a soluble diazepam prodrug to supersaturated diazepam for rapid intranasal delivery: Kinetics and stability.

The low aqueous solubility of diazepam (DZP) presents a challenge in formulating nasal sprays without the use of organic solvents. One approach to overcome this challenge involves co-administration of a soluble prodrug, avizafone (AVF), with a converting enzyme to produce supersaturated DZP at the site of administration. In addition to overcoming solubility issues, the supersaturated state of DZP provides an increased driving force for enhanced permeation across nasal mucosa. However, supersaturated solutions are metastable, and there is a limit to the degree of supersaturation (S) that can be reached without causing spontaneous phase separation of the solute. The aim of this article was to determine how formulation parameters affect the rate of DZP supersaturation, maximum degree of supersaturation, and phase separation kinetics. A model enzyme, Aspergillus oryzae protease (AOP), was used to convert AVF to DZP, via an open ring intermediate (ORI). A second derivative UV spectroscopic method was developed to simultaneously monitor DZP solution concentration and the time course of DZP phase separation. Fitting a kinetic model, with prior knowledge of the enzyme kinetic parameters, the rate constant for conversion of ORI to DZP was found to be 0.470 ±â€¯0.012 min-1. Kinetics and supersaturated solution stability were studied as a function of formulation parameters, including temperature, pH, buffering agent, AVF concentration, and enzyme concentration. The maximum aqueous solution concentration for DZP at 32 °C was determined to be 1.22 ±â€¯0.03 mM DZP (S = 9.38) and was insensitive to changes in formulation parameters, excepting temperature. Supersaturated solutions of DZP could be maintained at the maximum concentration for >24 h, even in the presence of phase separated DZP. Polarized light microscopy, PXRD, and DSC analysis indicated that the phase separated DZP was amorphous upon formation and remained so for >24 h. Our findings suggest that co-administration of AVF with a suitable human converting enzyme will provide a viable mechanism for IN delivery of DZP and result in very rapid and complete absorption to quickly terminate seizure emergencies.

A review of intranasal formulations for the treatment of seizure emergencies.

Epileptic seizure emergencies are life-threatening conditions, which in their most severe form, status epilepticus, have a high mortality rate if not quickly terminated. Treatment requires rapid delivery of anti-epileptics such as benzodiazepines to the brain. The nasal route is attractive due to its non-invasiveness, potential for direct nose to brain delivery, high vascularity, relatively large absorptive surface area, and avoidance of intestinal/liver metabolism. However, the limited volume of the nasal cavity and poor water solubility of anti-epileptics restrict absorption, leading to insufficient therapeutic brain levels. This review covers various formulation approaches adopted to improve nasal delivery of drugs, especially benzodiazepines, used to treat seizure emergencies. Other general topics such as nasal anatomy, challenges to nasal delivery, and drug/formulation considerations for nose to brain delivery are also discussed.

Intravenous lacosamide in seizure emergencies: Observations from a hospitalized in-patient adult population.

PURPOSE: to evaluate the efficacy and safety of intravenous (IV) lacosamide (LCM) in the treatment of seizure clusters (SC) and status epilepticus (SE) in hospitalized adult patients. METHODS: we prospectively analyzed treatment response, seizure outcome, and adverse effects of IV LCM in 38 patients with seizure emergencies (15 with SC, 23 with SE) during a hospital stay. The loading dose of IV LCM was 200-400mg and the maintenance dose was 200-400mg daily. Response to IV LCM was evaluated within 20min, 4h and 24h of LCM infusion. RESULTS: an acute anti-seizure effect after IV LCM was especially evident when it was first used - (SC) or second line (established SE) treatment. In particular, 87% of SC patients (13/15) and 80% of established SE (8/10) demonstrated response to LCM treatment, while no patients with super-refractory SE (0/8) responded to IV LCM according to our criteria. The loading of IV LCM was well tolerated, with mild adverse effects (2/38 temporary dizziness). In most patients, during and after administration of the loading dose of IV LCM a temporary (30min-1h) sedation was observed. No ECG and laboratory values-changes were documented in any of the patients. CONCLUSIONS: LCM is an effective and well-tolerated treatment when used to treat SC in hospitalized adult patients. As add-on therapy, it may be useful to stop seizure activity in patients with focal SE not responding to first/second-line intravenous AEDs.

A pilot study assessing the bioavailability and pharmacokinetics of diazepam after intranasal and intravenous administration in healthy volunteers.

Diazepam rectal gel (Diastat(®)) is the only FDA-approved product indicated for acute repetitive seizures. Despite its proven efficacy, most older children and adults object to this route of administration. As a result, many patients do not realize the benefit of a therapy that can improve outcomes and decrease healthcare costs. Intranasal administration of benzodiazepines offers a potential alternative. The primary objective of this study was to compare the bioavailability and pharmacokinetics of two novel intranasal (IN) diazepam (DZP) formulations versus intravenous (IV) administration in healthy volunteers. Twenty-four healthy volunteers were randomized into an open-label, three-way crossover study. 10mg doses of two investigational intranasal DZP formulations (solution, suspension) and a 5mg IV dose of commercially available DZP injectable, USP were given. A two-week washout period separated treatments. Plasma samples for DZP analysis were collected pre-dose and at regular intervals up to 240 h post-dose. DZP concentration-time data were analyzed using a non-compartmental pharmacokinetics approach. Exposure following administration of DZP IN solution (absolute bioavailability - 97%) was greater than the IN suspension (absolute bioavailability - 67%). Mean Cmaxvalues for the suspension and solution formulations were 221 ng/mL and 272 ng/mL, respectively. Median time to maximum concentration (Tmax) was 1h and 1.5h for suspension and solution formulation, respectively. Both investigational intranasal formulations were well tolerated. The results of this pilot study indicate that development of an intranasal diazepam formulation with high bioavailability, reasonable variability, and good tolerability is feasible.