HUD – PAP DEVICE Asklipios Model for the concomitant therapy for unsatisfactory controlled seizures refractory to all antiepileptic drugs and surgery 

 

Epilepsy is not a rare disease per se; however patients that are totally refractory to any treatment including antiepileptic drugs and surgery are the target population.

Epilepsy is a neurological condition, which affects the nervous system. Epilepsy is also known as a seizure disorder. It is usually diagnosed after a person has had at least two seizures that were not caused by some known medical condition like alcohol withdrawal or extremely low blood sugar. The seizures in epilepsy may be related to a brain injury or a family tendency, but most of the time the cause is unknown. A seizure is a sudden surge of electrical activity in the brain that usually affects how a person feels or acts for a short time. Seizures are not a disease in themselves. Instead, they are a symptom of many different disorders that can affect the brain. Some seizures can hardly be noticed, while others are totally disabling. Seizures are classified into two basic groups, partial and generalized.

Partial seizures involve only a portion of the brain at the onset. They can be further divided into two types:

Both types of partial seizures can spread, resulting in secondarily generalized tonic-clonic seizures.

Generalized seizures are those in which the first clinical changes indicate that both hemispheres are initially involved. Consciousness usually is impaired during generalized seizures, although some seizures, such as the myoclonic type, may be so brief that impairment of consciousness cannot be assessed.

Depressive disorders are much more frequent among people with poorly controlled seizures than among people whose seizures have been controlled with medication.

Many people with epilepsy have a poor quality of life due to drug therapies that do not provide adequate seizure relief, undesirable side effects of medications, feelings of nervousness, depression, and lack of control, and still having too many seizures

Other effects of poorly controlled epilepsy may include cognitive and memory impairment, depression, reduced lifetime income, increased use of healthcare services such as Emergency Room visits, increased risk of death in people with severe epilepsy that does not respond to therapy, and accidental injuries, some resulting in death.

The prevalence of active epilepsy (history of the disorder plus a seizure or use of antiepileptic medicine within the past 5 years) is estimated as approximately 2.7 million in the United States.

 

There are 150,000-200,000 new cases of epilepsy diagnosed each year. Of those 45,000 are children under the age of 15.

 

Drug-resistant epilepsy can be a major and disabling neurological disorder. Studies have found that about 10-30% of children's seizures fail to respond to anticonvulsant drugs. Drug resistant seizures can vastly diminish a child's chances in life. They may limit access to educational experiences and decrease the chances of eventually living independently or finding employment. Some children with refractory seizures look forward to a lifetime of rejection and dependency. Three types of childhood epilepsies which are particularly likely to be drug resistant are complex partial epilepsy, West's syndrome and Lennox-Gastaut syndrome.

 

Of the 150,000-200,000 people who develop epilepsy each year, 10 to 20 percent (15,000-20,000) prove to have "medically intractable epilepsy." Medical intractability is defined currently by many investigators as seizures that are not controlled after an adequate trial with 2 first-line AEDs. However, upon failure of Dilantin, Tegretol, and Depakote to control these patients' seizures, their cases should be considered medically refractory. If these 3 drugs fail to control the patient's seizures, additional medications have little chance of producing significant benefit. Of those intractable new patients, 2,000 to 5,000 might be suitable for operations each year in the future, compared with the present annual rate of about 500.  The success rate of epilepsy surgery varies depending of the location of the epileptogenic foci and surgery related incidents. From the literature we may estimate that about 50% percent of patients benefit from surgery (either seizure free or diminishing in seizure frequency and severity), leaving us with potentially about 800-2000 patients refractory to AED’s and surgery per year. 

 

Scientific Rationale for its use as proposed

The scientific rationale used behind the antiepileptic drugs applies directly to the use of PEMF/ionic magnetic induction for the treatment of seizures. Understanding the mechanism of action and pharmacokinetics of AEDs is important in clinical practice so that they can be used effectively, especially in multi-drug regimens.  Many structures and processes are involved in the development of a seizure, including neurons, ion channels, receptors, glia, and inhibitory and excitatory synapses. The AEDs are designed to modify these processes to favor inhibition over excitation in order to stop or prevent seizure activity. We propose also that PEMF may function in the same way.

The AEDs can be grouped according to their main mechanism of action, although many of them have several actions and others have unknown mechanisms of action. The main groups include sodium channel blockers, calcium current inhibitors, gamma-aminobutyric acid (GABA) enhancers, glutamate blockers, carbonic anhydrase inhibitors, hormones, and drugs with unknown mechanisms of action.

The mechanisms of action are related to the different ways to evoke potentials in neurotransmission. Sodium channel blockade is the most common and the well-characterized mechanism of currently available AEDs. AEDs that target these sodium channels prevent the return of the channels to the active state by stabilizing the inactive form. In doing so, repetitive firing of the axons is prevented. The presynaptic and postsynaptic blockade of sodium channels of the axons causes stabilization of the neuronal membranes, blocks and prevents post-tetanic potentiation, limits the development of maximal seizure activity, and reduces the spread of seizures.

Proposed mechanism of action

 

Every molecule has several internal degrees of freedom characterized by its structural and atomic composition and energetic status. Bioenergy is the activation of those internal degrees of freedom of a molecule. PEMF promotes the activation of the internal degrees of freedom seemingly without altering the molecular excitational state and therefore without measurable heat generation. The main difference between bioenergy and heat energy is that bioenergy appears to promote biosynthesis and homeostasis of the cellular environment. On the other hand, the diathermic effect seems to promote decomposition and destruction of complex bio-molecules.

 

All the cells in the body have a weak natural electric current flowing through them. Those currents are caused by electrically charged particles called ions. The ion concentration, distribution and flux will affect the homeostasis of the cell and therefore of the entire body. The application of a magnetic field (PEMF) around the affected tissue should prompt the cell to respond with the generation of weak micro-electrical currents that would influence the concentration, distribution and flux of ions. Promoting a potentially more efficient ion flux prompts the cells to exchange nutrients and “heal” more rapidly. On the other hand PEMF therapy was associated with bone repair, neurotransmission intensification and DNA synthesis (Liboff et al, 1984). All the molecules and atoms in the body are in transitional ionic state where the ionic charge may flow. It has also been suggested that the weak electromagnetic fields initiate mRNA transcription by accelerating electrons moving through DNA. Furthermore Nobel Laureate Albert Szent-Gyorgy established that structured proteins behave like solid state semiconductors or rectifiers. Cell membranes can rectify an induced voltage and this rectifying properties exerted by membrane proteins can cause changes in the intra and extracellular ion concentration stimulating the activity of the Na+/K+ pump. The activation of such a bimolecular process may restore intra and extracellular homeostasis.

 

The application of PEMF to damaged cells has been shown to help accelerate the reestablishing of normal cell potentials. (Kumar et al 2005)

 

There is also evidence in animal models that PEMF seems to have an effect on soft tissue swelling and stabilizes membrane function (Kumar VS et al. 2005) Also there is evidence that PEMF acts on refractory neuropathic pain producing an analgesic effect in more than 50% of the patients treated (Weintraub MI, et al. 2004). This technology was also implicated in the therapy of diabetic polyneuropathy where the conductive function of peripheral nerves was improved as well as the reflex excitability of diverse motoneurons of the spinal cord (Musaev A.V. et al 2003).

 

The possible mechanism of action of PEMF/ion magnetic induction is targeting sodium channels preventing the return of these channels to the active state by stabilizing the inactive form of these channels. In doing so, repetitive firing of the axons is prevented. Also, since GABA binds to a GABA-A receptor, the passage of chloride, a negatively charged ion, into the cell is facilitated via chloride channels. This influx of chloride increases the negativity of the cell (ie, a more negative resting membrane potential). This causes the cell to have greater difficulty reaching the action potential. Therefore PEMF may also act increasing the intra-cellular chloride rendering the neurons into a resting state.

 

Glutamate receptors bind glutamate, an excitatory amino acid neurotransmitter. Upon binding glutamate, the receptors facilitate the flow of both sodium and calcium ions into the cell, while potassium ions flow out of the cell, resulting in excitation. PEMF may act inhibiting or normalizing the flow of sodium and calcium resulting in a normal excitatory state pre-empting misfiring due to over excitation.

 

On September 26, 2005 PulseDynamics applied for the Humanitarian Device Designation in this indication. Please check in the page News and Future developments for more information.

We are expecting a response form the FDA to this application.

Update January 15, 2006

 

On December 12, 2005, the FDA Office of Orphan Products Development has decided that the HUD designation cannot be granted to the device on the base that “…PAP Device Asklipios Model could be a safer alternative to surgery in medically refractory epilepsy patients, we feel that the number of patients who would be eligible for treatment with the device is more than 4000…”

 

Although this decision is a setback for having the device available to refractory epilepsy patients, it is very encouraging that the FDA believes that the PAP Device Asklipios Model could be a safer alternative to surgery in medically refractory epilepsy patients.

 

We are analyzing the alternatives we have to apply for an IDE in this indication and will make the application available as soon as possible.

 

Scientific Information 

Low-frequency repetitive transcranial magnetic stimulation improves intractable epilepsy F. Tergau, U. Naumann, W. Paulus, B. Steinhoff” Lancet. 1999 Jun 26; 353(9171):2209.

Summary: Repetitive transcranial magnetic stimulation (rTMS) induces lasting effects on cortical excitability. In particular, long trains of low-frequency rTMS are described to reduce cortical excitability. Epilepsy is associated with TMS-assessed cortical hyperexcitability. We sought to find out whether patients with epilepsy benefit from low-frequency rTMS treatment on the following grounds: animal experiments have shown that low-frequency repetitive electrical stimulation blocked the development of seizures in rats; and 0·3 Hz rTMS in complex-partial epilepsy of mesiobasal limbic onset has led to a decrease in epileptic spike frequency.

  

Transcranial Magnetic Stimulation in Neurology, Kobayashi M, Pascual-Leone A, Lancet 2003; vol.2(145-156

 

Summary: Transcranial magnetic stimulation (TMS) is a non-invasive tool for the electrical stimulation of neural tissue, including cerebral cortex, spinal roots, and cranial and peripheral nerves. TMS can be applied as single pulses of stimulation, pairs of stimuli separated by variable intervals to the same or different brain areas, or as trains of repetitive stimuli at various frequencies. Single stimuli can depolarise neurons and evoke measurable effects. Trains of stimuli (repetitive TMS) can modify excitability of the cerebral cortex at the stimulated site and also at remote areas along functional anatomical connections. TMS might provide novel insights into the pathophysiology of the neural circuitry underlying neurological and psychiatric disorders, be developed into clinically useful diagnostic and prognostic tests, and have therapeutic uses in various diseases. This potential is supported by the available studies, but more work is needed to establish the role of TMS in clinical neurology.

 

 

Updated March 5, 2006