Further studies to see if effect is due to transneural transport may be needed In a study by Hussain, et al in the Biological and Synthetic Membranes, 1989, IN administration in humans of lipophilic propranolol resulted in blood levels similar to those observed following IV administration (60 ng/ml)
Objective: To compare the safety and efficacy of midazolam given intranasally with diazepam given intravenously in the treatment of children with prolonged febrile seizures. Design: Prospective randomized study. Setting: Pediatric emergency department in a general hospital. Subjects: 47 children aged six months to five years with prolonged febrile seizure (at least 10 minutes) during a 12 month period. Interventions: Intranasal midazolam (0.2 mg/kg) and intravenous diazepam (0.3 mg/kg). Main outcome measures: Time from arrival at hospital to starting treatment and cessation of seizures. Results: Intranasal midazolam and intravenous diazepam were equally effective. Overall, 23 of 26 seizures were controlled with midazolam and 24 out of 26 with diazepam. The mean time from arrival at hospital to starting treatment was significantly shorter in the midazolam group (3.5 (SD 1.8) minutes, 95% confidence interval 3.3 to 3.7) than the diazepam group (5.5 (2.0), 5.3 to 5.7). The mean time to control of seizures was significantly sooner (6.1 (3.6), 6.3 to 6.7) in the midazolam group than the diazepam group (8.0 (0.5), 7.9 to 8.3). No significant side effects were observed in either group. Conclusion: Seizures were controlled more quickly with intravenous diazepam than with intranasal midazolam, although midazolam was as safe and effective as diazepam. The overall time to cessation of seizures after arrival at hospital was faster with intranasal midazolam than with intravenous diazepam. The intranasal route can possibly be used not only in medical centers but in general practice and, with appropriate instructions, by families of children with recurrent febrile seizures at home.
Greg: These 3 slides are from the ANTs patients. The first 2 show that focal discharges on the EEG can be seen focally on biopolar recordings from the ANTs electrodes (they are shown at a different gain in referential and bipolar montages. The last slide shows a delay from the right frontal to left frontal regions (across the callosum) to the ANTs: I.e. frontal regions to thalamus in this patient with a right frontal focus with rapid spread. The ANTs stimulator stopped her falls. This slide supports a proposed functional disruption of conduction from the frontal to more central regions, which might be responsible for the therapeutic effect (the stim. Was off the entire time these recordings were obtained).
New Therapies and News from Clinical Trials Jacqueline A French MD NYU Epilepsy Center
Definition of Drug Resistant Epilepsy (International League Against Epilepsy)
“ Drug resistant epilepsy may be defined as failure of adequate trials of two tolerated and appropriately chosen and used antiepileptic drug schedules (whether as monotherapies or in combination) to achieve sustained seizure freedom.”
No seizure frequency requirement
How Common is Drug Resistant Epilepsy? Long-Term Follow-Up of Mixed Population (N=525) * *Epilepsy Unit, Glasgow, Scotland 1984-1997 Kwan P, Brodie MJ. N Engl J Med 342:314, 2000 Seizure-free 63% (n=333) Uncontrolled 37% (n=192)
Resistance vs Syndrome Semah F et al. Neurology 51:1256, 1998 45% 35% 82% 27% % of Seizure-Free Patients n 33 337 445 294 Global disturbance Genetic Known Cause Unknown cause Generalized Focal 0 20 40 60 80 100 Difficult to control Easy to control
Seizure Control vs Lesion Location / Etiology Post-stroke Vascular Tumor Normal Head Cortical Isolated Dual malformation MRI trauma dysgenesis hippocampal pathology* sclerosis *HS + another lesion Semah F et al. Neurology 51:1256, 1998 0 20 40 60 80 100 0 20 40 60 80 100 % of Seizure-Free Patients 54% 50% 46% 42% 30% 24% 11% 3% n 26 57 50 268 50 81 224 38 Difficult to control Easy to control
Rapid and extensive absorption through the nasal mucosa
Convenient and easy administration
Comparative Efficacy of IN MDZ vs IV DZP Lahat E, et al. BMJ . 2000;321:83-86. Dose = 0.3 mg/kg Dose = 0.2 mg/kg N=47 children with febrile seizures (>10 min) 3.5 min 5 min 6.1 min 8 min Main outcome measures: Time from arrival at hospital to drug administration & time to seizure cessation Observation period = 60 minutes
Who can be in a clinical trial of a new therapy?
People on 2-3 stable antiepileptic drugs, still experiencing more than one seizure/month (often requires 3-4)
Able to keep seizure counts
Usually over 18, unless trial is specifically for children
Designed to detect abnormal electrical activity in the brain and to deliver small amounts of electrical stimulation to suppress seizures before there are any seizure symptoms.
Electrodes are placed within the brain or rest on the brain surface in the area of the seizure focus (where seizures start).
Designed to continuously monitor brain electrical activity from the electrodes and, after identifying the "signature" of a seizure's onset, deliver brief and mild electrical stimulation with the intention of suppressing the seizure.