1. Field of the Invention
The invention pertains to a method of treating a medical disorder using heat transfer, electrical stimulation, and/or delivery of medication so as to stop or prevent abnormal cell activity, thus treating the disorder to improve function of an affected body tissue. The method improves effectiveness of stimulation for treating disorders of function of brain or elsewhere in central nervous system, or in peripheral nerve. The method may be used to treat epilepsy, for treatment of brain disorders other than epilepsy, for spinal disorders, and for disorders of other body organs and tissues.
2. Description of Related Art
Epilepsy is a significant medical problem, as nearly 1% of the United States population is affected by this disease at any given time, constituting about 2.6 million people. In 1991 dollars, the direct costs for the treatment of epilepsy in the United States were 1.8 billion dollars and the indirect costs amounted to 8.5 billion dollars. Thus, the disorder is a significant health problem and a need exists for improved treatments to control the disease and alleviate its burden on society as a whole.
Epileptic seizures occur because of an abnormal intensity and synchronized firing of brain cells. The fundamental neuronal disturbance during a seizure consists of large amplitude, sustained depolarization (depolarizing shift), on top of which rides a protracted volley of action potentials. The depolarizing shift (DS) is a complex phenomenon whose triggering mechanism is not fully understood. One hypothesis is that DS is a postsynaptic potential, amplified by slow calcium currents. Electrical activity is normally terminated toward the end of depolarization at which time potassium conductance is increased, making cells refractory to further stimulus (hyperpolarization). Generalized seizures can begin over essentially the entire brain at one time, while others, known as focal or partial seizures, begin in a localized area of the brain and then spread. Thus, both widespread and localized mechanisms appear to be involved in the occurrence of seizures. As an example, seizures manifest themselves as seizure discharges affecting the cerebral cortex, the outer most layer of the brain, though paradoxically, stimulation of the thalamus and other subcortical regions, located deeper within the brain, have been shown to not only initiate but also control or even prevent seizures. Evidence suggests that the thalamus and the substantia nigra are involved in the development of certain kinds of seizures. Even more widespread mechanisms might be involved, as evidenced by the successful use of vagal nerve stimulation for treatment of some seizures. The vagus nerve is located in the neck and extends to the brain stem from which it has widespread connections throughout the brain, including branches to the thalamus. Studies have shown that chronic vagal nerve stimulation can reduce seizures by 50% or more in a third of treated patients. The vagal nerve simulator has recently been released as a commercial product. Information thus far indicates that it is moderately effective, but only rarely controls seizures completely.
Direct electrical stimulation has been applied to the cortex of humans for mapping purposes since the 1930s, but a complication of cortical stimulation can be the unwanted occurrence of afterdischarges. Recently, investigators have shown, however, that brief pulses of stimulation (BPS) can terminate afterdischarges (ADs), if appropriately applied. Preliminary data also suggests that stimulus is often more effective when exerted at peak negativity of AD waveform, and that phase of waveform at which stimulation is most effective varies. If one accepts ADs as one model for epilepsy in humans, this raises the possibility that appropriately applied stimulation could abort spontaneous seizure activity in human brain. This may be explained again using the analogy of cardioverter defibrillator where a single pulse stimulus is applied to chest. Stimulus, if synchronized to R wave, depolarizes the whole heart muscle at the same time and lets a single pulse source (SA node) take over. However, if not synchronized to the repolarization wave, stimulus will induce cardiac fibrillation, since some parts of tissue are in process of recovery from previous depolarization and therefore will be susceptible to another depolarizing stimulus. This asynchrony may cause the chaos called “cardiac fibrillation”. It results from excitation of some parts of tissue while the rest is electrically silent for a few milliseconds before it “fires up”. Therefore, successful cortical stimulation needs to be applied soon before (presumed) single generator spreads, and stimulation will be more likely to be successful if synchronized to portion of wave that is most sensitive to stimulation. With cardiac defibrillator, electrical shock, given to heart in synchrony with R wave of QRS complex, depolarizes whole tissue, and lets normal pacemaker resume its rhythm. Electrical stimuli pace, cardiovert, or defibrillate heart by changing transmembrane potential. Electrically induced neuronal synchrony also could play a role in effects of brief pulse stimulation on ADs in brain, perhaps by changing neuronal membrane potentials of a group of cells in stimulated region.
Electrical stimulation has been in use to terminate acute and chronic medical conditions such as cardiac arrhythmias (cardioverter defibrillator, pacemaker), tremor (thalamic stimulation), and seizures (vagus nerve stimulation, thalamic stimulation). Electrical stimulation provides a non-surgical means for impairing generation of localized seizures. Thus, acute cortical stimulation applied directly to site of epileptiform discharge at onset of event could become a treatment for seizures, just as in experimental animal models, medication application to a seizure focus can suppress or eliminate seizure activity.
Repetitive electrical stimulation, given in an appropriate manner and in an appropriate location in either archicortex or neocortex, is well known to produce long-term depression of cortical responsiveness as well as inhibition of kindling. A single pulse can desynchronize, and thus diminish amplitude of, population spikes in rat CA1 hippocampus. Low-frequency stimulation of amygdala for 15 minutes suppresses occurrence of generalized kindled seizures in rats. Stimulation of perforant pathway (but not hippocampus) of patients with implanted depth electrodes results in greater paired pulse suppression on epileptogenic side. Appropriately delivered transcortical magnetic stimulation can reduce cortical excitability in volunteers. A trial is underway to determine whether periodic transcortical magnetic stimulation might reduce seizure frequency. Electroconvulsive therapy (ECT) can transiently abort non-convulsive status epilepticus. In patients with spike-and wave-discharges, motor evoked potential amplitude can decrease during slow wave, and may either decrease or remain unchanged during spike. The mechanisms proposed to account for these phenomena include inhibitory mechanisms, possibly located in specific cortical layers or cerebral pathways, and possibly mediated by outward potassium currents, by properties of calcium channels, or by GABA receptors.
In some patients, seizures are sufficiently localized such that removal of a particular area of brain may result in complete seizure control. Electrical stimulation provides a non-surgical means for impairing generation of localized seizures. In experimental animal models, drug application to a seizure focus can suppress or eliminate seizure activity.
Hypothermia is known to have a protective effect on brain both in experimental animal preparations and in humans. This protective effect on brain is one reason for employing hypothermia in medical procedures, such as cardiac surgery. Hypothermia alters electrical activity of cortex in models of brain ischemia, and decreases production of excitatory neurotransmitters glutamate and dopamine. Hypothermia also appears to reduce occurrence, frequency, and amplitude of cortical potentials and suppresses seizure activity. Cooling is thought to prevent or abort seizures by reducing cortical excitability. Cooling brain tissue can be safely accomplished when properly undertaken. For example, irrigation of temporal horn of lateral ventricle with ice-cold liquid to cool hippocampus has been successful in acutely altering memory functions in humans with no apparent adverse effects.
It is well known that temperature affects nerve conduction and responsiveness. For example, peripheral nerve conduction velocity decreases, and wave duration increases, during hypothermia. This may be because cooling increases sodium permeability less than it subsequently inactivates sodium permeability and increases potassium permeability during recovery process; slowing of recovery process increases amplitude. Decreased conduction velocity and increased wave duration “disperses” potentials that arrive more centrally, and this in turn result in a decrease in responsivity of spinal and cerebral neurons. One study found, in man, that conduction decrease occurred at a rate of 1.84 meters/sec/degree between 36° C. and 23° C. Another found the decrease to be 1.98 meters/sec/degree between 35.5° C. and 23.5° C. Similar findings have been reported by others. Stevenson et al. showed augmentation of spinal cord evoked response with hypothermia, but depression of responses in thalamic relay, midbrain reticular neurons. Others have reported an increase in duration but not amplitude of action potentials recorded intracellularly from individual afferent fibers and interneurons in dorsal columns and dorsal roots.
In multiple sclerosis, the “hot bath test” has long been used as a clinical test: a warm bath can bring out symptoms of multiple sclerosis. Conduction block of multiple sclerosis is increased by higher temperatures. Conversely, conduction block can be overcome by reducing temperature.
In muscle diseases such as amyotrophic lateral sclerosis and myasthenia gravis, cooling can increase surface area of M wave. Cooling can improve weakness of myasthenia gravis and myasthenic syndrome. In myasthenia gravis, for example, drooping of eyes due to eye muscle weakness can be improved by placing an ice pack over them. During electromyography, jitter that occurs with myasthenia gravis decreases in response to cooling. On the other hand, weakness of paramyotonia congenita increases with lower temperatures.
Patients who have an aura prior to seizures, and who have an implanted vagus nerve stimulator can manually activate the stimulator, which successfully aborts seizures in some cases. However, to be of maximum benefit, stimulation (of whatever type) must occur as early as possible during seizures. Recordings with implanted electrodes often demonstrate seizure patterns exist before a patient is aware of an impending seizure. Early reaction to, or prevention of, seizure onset necessitates detection of abnormal discharges as soon as possible. Numerous of approaches toward detection of seizures have been explored. A number of methods have been tried in an attempt to predict seizure onset. These methods have included assessing amplitude, frequency, and other characteristics of raw EEG waves, as well as more advanced signal processing techniques, including some based on time-frequency localization, image processing, and identification of time-varying stochastic systems. In one attempt, using these methods, accuracy was 100%, compared to the current standard of visual recognition. Detection was sufficiently rapid to allow prediction of clinical onset in 92% of seizures by a mean of 15.5 sec. Methods based on non-linear analysis and chaos theory have been used as well. Previously, an EEG seizure detector based on an artificial neural network was developed, with input quantifying amplitude, slope, curvature, rhythmicity, and frequency components of EEG in a 2 sec epoch. An advantage of this approach is that computer detection may be modified to fit seizure pattern, or patterns, of an individual patient. Alternatively, several rule based or template matching methods for seizure detection may be employed, as well as methods using neural networks modeling seizures as chaotic attractors. All of the approaches just mentioned can sample the EEG continuously, thus providing possibility for delivering treatment if a change in EEG is detected.
Therefore, although a number of detection methods have been tried, no one method has been entirely successful. Moreover, many methods are computationally intensive, so that calculation using an implantable microchip is not feasible. Finally, the methods described in essence consider activity occurring at single sites, with sites analyzed one by one. However, pathologic activities such as epileptic seizures involve the brain over more extended regions, so that an optimal predictive technique would assess the brain both spatially and temporally.
U.S. Pat. No. 5,713,923 to Ward et al. (Ward '923) discloses techniques for treating epilepsy using a combination of electrical stimulation of brain and drug infusion to neural tissue. Stimulation may be directed to increase output of inhibitory structures, such as cerebellum, thalamus, or brain stem, or may inactivate epileptogenic areas. These methods tend to be based on chronic stimulation of brain inhibitory systems, with the goal of decreasing the background propensity to epileptogenesis. Historically, stimulation of inhibitory structures alone has not been particularly successful in seizure management. Ward '923 uses an implantable electrode to sense seizure onset, which permits regulatable stimulation of brain during initial seizure activity. The combination of drug infusion with brain stimulation as disclosed in Ward '923, however, would fail to be effective in many types of seizures. Many drugs are not particularly stable at body temperature, rendering them unsuitable for long term storage in an implanted infusion device. Certain risks exist for patients receiving combined therapy of Ward '923, including an increased risk for seizure propagation due brain stimulation as well as drug related side effects. Thus, while suitable for controlling some seizures, a substantial population of patients have seizures which cannot be treated using the methodology of Ward '923.
The Medtronic ITREL stimulator (Medtronic Inc., Minneapolis, Minn., USA) uses asymmetric pulse phases so that, for example, the positive phase could be of higher amplitude and shorter duration, and the negative phase of lower amplitude and lower duration. It does not utilize the dynamic feedback as a means of insuring charge balance.
U.S. Pat. Nos. 5,716,377 to Rise, 5,735,814 to Elsberry, 5,782,798 to Rise, and 5,792,186 to Rise disclose methods of treating other brain disorders using methodologies similar to Ward '923. These methodologies have the same combinations of advantages and disadvantages as does Ward '923, with disadvantages overcome by the present invention. U.S. Pat. No. 5,938,689 to Fischell discloses methods of electrode placement and configuration but does not disclose means of activity sensing or detection, or methods of brain stimulation. U.S. Pat. No. 6,016,449 to Fischell (Fischell '449) discloses a multiple electrode closed loop, responsive system for treatment of brain diseases. Fischell '449 envisions detection using electrodes near or within brain and then, after event detection, responding by stimulating brain or other parts of body, or by releasing medication. However, predictions of seizure occurrence and the optimal timing and locality of treatment are not suitably provided for by Fischell '449.
Therefore, a need exists to improve therapeutic options available to persons with medical disorders associated with detectable abnormal cell activity, such as epilepsy.
USPTO Backgrounds
USPTO Backgrounds