Widely Used Drug No More Effective Than FDA Approved Medication in Treating Epileptic Seizures in Children

A National Institutes of Health-sponsored study published in the Journal of the American Medical Association (JAMA) showed that lorazepam - a widely used but not yet Food and Drug Administration (FDA) approved drug for children - is no more effective than an approved benzodiazepine, diazepam, for treating pediatric status epilepticus.

Status epilepticus is a state in which the brain is in a persistent state of seizure. By the age of 15, 4 to 8 percent of children experience a seizure episode, which can be life threatening if they aren’t stopped immediately. Status epilepticus is a continuous, unremitting seizure lasting longer than five minutes or recurrent seizures without regaining consciousness between seizures for more than five minutes.

Before this current study, published April 23, there was no evidence indicating which of the two treatments might prove more effective. Although it is not yet approved by the FDA, James M. Chamberlain, MD, Division Chief of Emergency Medicine at Children’s National Health System, the study’s principal investigator, estimates that lorazepam is used as first-line therapy in most emergency departments.

“The study results provide reassurance to emergency medicine personnel who must act within minutes,” said Chamberlain. The study was conducted at 11 hospitals in the United States using the infrastructure of the Pediatric Emergency Care Applied Research Network (PECARN), under a contract from the National Institutes of Health’s (NIH) Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD).

Both lorazepam and diazepam are used to treat status epilepticus. Diazepam, also known as Valium, is the only one of the two drugs to have been approved by the FDA for use in adults and children.

Lorazepam, marketed under the trade name Ativan, has been approved by the FDA only for use in adults. Once the FDA has approved a drug for use in adults, physicians may then prescribe it for other uses and in pediatric patients if, in their best judgment, they believe their patients will benefit.

“Sometimes physicians are forced to rely on their best judgment alone,” said George Giacoia, MD, of the NICHD’s Obstetric and Pediatric Pharmacology and Therapeutics Branch. “However, it’s always better to make treatment decisions on the evidence that comes only from conducting large comparison studies. We now know that lorezapam offers no advantage over diazepam in treating pediatric seizure disorder, and that diazepam is more suited to use by emergency teams.”

In 2007, the National Institutes of Health’s Pediatric Seizure study sought to determine which of two drugs—diazepam or lorazepam—was more effective in treating the life-threatening condition, status epilepticus. This condition can occur without warning. For reasons not fully understood, a child may be gripped by continuous seizures, which, if not stopped within minutes, may lead to brain damage or even death.

Because of the random nature of seizures and their significantly life altering affects, lorezapam is commonly prescribed to treat status epilepticus in children, even though it hasn’t been specifically approved for that use. The results of the Pediatric Seizure study do not support the use of lorezapam instead of diazepam for treating status epilepticus, Dr. Chamberlain said.  Also, because lorezapam needs to be refrigerated and diazepam does not, diazepam is more suited for use by ambulance crews.

A few previous studies indicated that lorazepam might be more effective at ending a seizure and might be less likely than diazepam to depress breathing—a side effect of benzodiazapines, the category of medications that includes both drugs.

In their study, Chamberlain and colleague wrote, “There is no conclusive evidence to support lorazepam as a superior treatment and there is little consensus as to which is the preferred agent.”

The current study was the largest, most comprehensive comparison study of the two treatments for pediatric seizure disorder. Dr. Chamberlain and his colleagues enrolled 310 children at the 11 institutions, between 2008 and 2012. The researchers found that both medications successfully halted seizures in 70 percent of cases, and each had rates of severe respiratory depression of less than 20 percent.

It’s important that “we get the most important scientific information about such medications so there are government approvals for pediatric use,” Chamberlain said. “Pediatric patients are not just small adults.”

(Image: Alamy)

Animal study shows promising path to prevent epilepsy

Duke Medicine researchers have identified a receptor in the nervous system that may be key to preventing epilepsy following a prolonged period of seizures.

Their findings from studies in mice, published online in the journal Neuron on June 20, 2013, provide a molecular target for developing drugs to prevent the onset of epilepsy, not just manage the disease’s symptoms.

"Unfortunately, there are no preventive therapies for any common disorder of the human nervous system – Alzheimer’s, Parkinson’s, schizophrenia, epilepsy – with the exception of blood pressure-lowering drugs to reduce the likelihood of stroke," said study author James O. McNamara, M.D., professor of neurobiology at Duke Medicine.

Epilepsy is a serious neurological disorder marked by recurring seizures. Temporal lobe epilepsy – where seizures occur in the region of the brain where memories are stored and language, emotions and senses are processed – is the most common form, and can be devastating. Because afflicted individuals have seizures that impair their awareness and may have associated behavioral problems, they may have difficulty with everyday activities, including holding a job or obtaining a driver’s license.

Conventional therapies to treat epilepsy address the disease’s symptoms by trying to reduce the likelihood of having a seizure. However, many people with temporal lobe epilepsy still have seizures despite taking these drugs.

"This study opens a promising new avenue of research into treatments that may prevent the development of epilepsy," said Vicky Whittemore, PhD, a program director at the National Institute of Neurological Disorders and Stroke, who oversees the grants that funded this study.

Retrospective studies of people with severe temporal lobe epilepsy reveal that many of them initially have an episode of prolonged seizures, known as status epilepticus. Status epilepticus is often followed by a period of seizure-free recovery before people start to experience recurring temporal lobe seizures.

In animal studies, inducing status epilepticus in an otherwise healthy animal can cause them to become epileptic. The prolonged seizures in status epilepticus are therefore thought to cause or importantly contribute to the development of epilepsy in humans.

"An important goal of this field has been to identify the molecular mechanism by which status epilepticus transforms a brain from normal to epileptic," said McNamara. "Understanding that mechanism in molecular terms would provide a target with which one could intervene pharmacologically, perhaps to prevent an individual from becoming epileptic."

Earlier research in epilepsy flagged a receptor in the nervous system called TrkB as a key player in transforming the brain from normal to epileptic. In the current study, McNamara and his colleagues sought to confirm if TrkB was important for status epilepticus-induced epilepsy.

Using an approach combining chemistry and genetic analyses, the researchers studied normal and genetically altered mice. The genetically altered mice were unique in that a drug, 1NMPP1, inhibited TrkB in their brains. If the drug stopped the genetically altered mice from becoming epileptic, this genetic approach would prove that inhibiting TrkB prevents the onset of epilepsy.

When the researchers caused status epilepticus in the animals, both the normal and genetically modified mice developed epilepsy. However, treatment with 1NMPP1 after the prolonged period of seizures prevented epilepsy in the genetically altered but not the normal mice.

"This demonstrated that it is possible to intervene following status epilepticus and prevent the animal from becoming epileptic," McNamara said.

Importantly, the researchers only administered treatment with 1NMPP1 for two weeks, which was sufficient to prevent epilepsy from developing in the mice when tested many weeks later. The results suggest that a preventive therapy may only need to be given for a limited period of time following the initial bout of prolonged seizures, not an individual’s entire life, which could prevent unnecessary side effects that come with long-term use of drugs.

In future studies, the researchers hope to determine the exact time window in which TrkB signaling needs to be repressed to prevent the onset of epilepsy. Long term, this research provides a molecular target for developing the first drugs to prevent epilepsy.

"This study provides a strong rationale for the development of selective inhibitors of TrkB signaling," said McNamara.

Promising new finding for therapies to treat persistent seizures in epileptic patients

In a promising finding for epileptic patients suffering from persistent seizures known as status epilepticus, researchers reported today that new medication could help halt these devastating seizures. To do so, it would have to work directly to antagonize NMDA receptors, the predominant molecular device for controlling synaptic activity and memory function in the brain.

"Despite the development of new medications to prevent seizures, status epilepticus remains a life-threatening condition that can cause extensive brain damage in the patients that survive these persistent seizures," said David E. Naylor, MD, PhD, a lead researcher at the Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center (LA BioMed) and corresponding author of the new study. "Our research holds promise for the development of new therapies to treat this devastating condition because we have found a potential new target for medical intervention that should bolster the current standard therapies to treat the acute seizures. It may also prevent the long-term adverse effects of persistent seizure activity on the brain."

The research, reported online in the Neurology of Disease journal, used animal models to assess cellular activity in the brain during persistent seizures. It found that the seizure activity seemed to force the NMDA receptors from the interior to the surface of nerve cells causing their activity to increase by approximately 38%.

"The increased presence of the NMDA receptors on the cell surface during these seizures may explain the successful use of NMDA antagonists – medication that inhibits the activity of the NMDA receptors in the brain – in the latter stages of a seizure, long after other medications have stopped working," said Dr. Naylor. "We concluded that medications that suppress the activity of the NMDA receptors, in conjunction with other medications, may be successful in stopping persistent seizures. Further research is, of course, needed."