DAVID A. STEENBLOCK, M.S., D.O.

Invited Presentation for the World Future Conference, May 1996

Washington, D.C.

In this the sixth year of the decade of the brain--much progress has been made toward the ultimate goal of total and complete functional repair of brain injuries secondary to a variety of diverse causes such as stroke, trauma, and asphyxiation. Tantalizing clues are being discovered which clearly indicate that complete central nervous system neuronal repair will be a distinct possibility in the not too distant future.

A multitude of pharmaceutical companies are racing to find, patent and market remedies for the treatment and "cure" of acute stroke. These methods include intracerebral catheterization and infusion of tissue plasminogen activator or other fibrinolytic (thrombolytic) agents, retrograde transvenous neuroperfusion and the use of a variety of neuroprotective agents to protect ischemic neurons from excessive excitotoxic neurotransmitter release, apoptosis (programmed cell death) and cell death.

Approximately 400,000 persons suffer a stroke per year in the United States. Of these 70% (280,000) will suffer the type of stroke (thrombotic or embolic) that is treatable by the use of catheters and thrombolytic agents. Of these, only a small percent will be able to get to a hospital with a cath lab that has the highly trained personnel that would be able to catheterize the person’s intracerebral arteries or veins and to infuse oxygenated blood or the clot busting enzymes safely. Thus most acute stroke and brain injured will still require remedial therapy over extended periods of time and they will continue to suffer great disabilities or death. In the United States there are over 2 million people who suffer from the disabilities caused by stroke and brain injuries. Even if suddenly all new stroke patients were to be cured by some miraculous new therapy, the majority of these two million chronically disabled people will continue to live and suffer for at least the next 10 to 20 years. The brain damage that occurs during a stroke, traumatic brain injury, birth injury (cerebral palsy), near-drowning, or asphyxia is caused by a lack of oxygen to the brain. The rapid replacement of oxygen to these oxygen starved brains would produce such a miraculous cure. In the future various techniques will be available to insert oxygen into the parts of the brain that is lacking oxygen. At this time two of these techniques are experimental and undergoing FDA clinical trials while the third has been in use for 30 years but is little appreciated by the medical field.

The first experimental technique is the use of an intracerebral arterial catheter to deliver clot-busting enzymes to the blood clot in the brain which dissolves the clot and allows the blood to flow once more. The use of these enzymes for use i.v. has already been approved by the FDA and patients so treated were 30% more likely to have minimal or no disability after three months.(NINDS) Unfortunately, this enzyme has to be given within three hours after a stroke and had symptomatic intracerebral hemorrhages occur within 36 hours in 6.4% of the patients.

The second type of experimental therapy attacks the problem of lack of oxygen in a different manner. In this technique known as retrograde transvenous perfusion being pioneered by Dr. John Frazee of the Department of Neurosurgery at UCLA, a catheter is inserted into a femoral artery and this oxygenated arterial blood is passed through a mechanical pump into two more catheters which are placed into the jugular veins and threaded under fluoroscopy up into the brain. At that time, small balloons on the ends of these venous catheters are expanded to partially occlude the veins. The pump is turned on and oxygenated blood from the femoral artery passes up into the brain and flows through the area of the brain that was dying from lack of oxygen. The oxygen levels rise and the patient recovers while the blood clot dissolves on its own or the clot-busting enzymes are given. So far only two patients have been treated with this technique but both had spectacular cures of their strokes with no residual paralysis.

The third technique has been used clinically for the last 30 years and thousands of patients have benefited from it’s use in the treatment of both acute and chronic stroke conditions. This technique gets oxygen into the damaged parts of the brain by putting the patient into a sealed, pressurized chamber and having them breath oxygen that is also pressurized. Oxygen is forced to dissolve in the blood plasma which otherwise is not capable of oxygen transportation to the tissues. Under pressure, the plasma can accept enough oxygen to be able to nourish tissues without the help of the RBC (red blood cells). Thus in a stroke where there is swelling and ionic changes of the inner lining of the blood vessels due to lack of oxygen, the RBC clump up (aggregate to form small clumps of cells) and are unable to pass through the small capillaries that normally supply the oxygen starved area with blood. That part of the brain that is dying from lack of oxygen is receiving plasma rather than whole blood due to these microcirculatory events. With pressurized oxygen, the plasma is able to carry the oxygen into the damaged brain tissues which improves the metabolism of the damaged neurons. The oxygen helps to immediately decrease the brain swelling that is causing compression and disruption of blood flow in the surrounding tissues and this "ischemic penumbra" begins immediately to return to normal. When this technique is combined with conventional stroke therapy such as methylprednisolone, dextran, mannitol and some of the emerging techniques such as the use of SOD and other anti-oxidants to neutralize free radicals, spectacular results can be achieved with very little risk involved.

Hyperbaric oxygen treatments are done every few hours during the first 24 to 48 hours of a stroke. This repetitive method of giving hyperbaric oxygen is necessary in order to prevent oxygen toxicity which would occur if the therapy is given continuously. Intermittent pressurized oxygen does work, however, and gives the damaged tissue enough oxygen to stay alive while the blood clot dissolving enzymes are working to re-open the clogged artery.

If these techniques of acute brain repair are not utilized, permanent functional losses will often occur to the stroke victim. At the present time, two million stroke victims fall into this category and have had virtually no therapies made available to them that will help heal and repair the damaged parts of the brain.

In general, physical therapy is offered sporadically for between one to six months to the stroke victim after the onset of the stroke..

In the future these unfortunate people will be able to have their brains repaired close to home by a combination of therapies most of which are present and available at the present time. This combination of therapies will be relatively simple, safe, effective and moderately priced (as compared to years of nursing home care). In other words, the future of brain repair is here already and in the future we will see these techniques become more widespread and generally much more accepted and available.

During the daily treatments of high pressure oxygen, the nonfunctioning ischemic neurons begin to function once again while they are receiving oxygen. After the person is removed from the hyperbaric oxygen chamber, the damaged but still alive neurons begin to sense that they are no longer receiving enough oxygen. This re-occurrence of ischemia turns on genes such as GAP 43 and P53 which are involved with neuron regeneration and angiogenesis. Certain nutrients can contribute to neuronal regenerative gene transcription and other therapies will gradually become available for this purpose. For example Duke University’s Professor of Surgery and Genetics Bruce A. Sullenger has developed a "splicing ribozyme" that cuts RNA at a specific location and attaches a new piece in place of the old one. Dr. Sullenger and colleagues are "trying to develop ribozymes that can change the genetic instructions at the RNA level." (Rawls, 1996)

At this time alternatives to the use of human fetal tissue are available for immunodeficient disorders (e.g., Bone marrow transplants) and diabetes (e.g. adult islet-cell and whole pancreas transplants) and in the future, alternatives to human embryonic fetal tissue cells will be developed and become clinically useful.(JAMA) Already there are firms that have developed human brain fetal cells in culture and are doing the basic science necessary in order to obtain FDA approval for clinical use. It is safe therefore to assume that in the future the use of fetal brain cells will become more widespread as these types of cells and procedures become recognized scientifically and by the FDA.

Recently articles have been published about the lack of effectiveness of growth hormone in reversing age related decline. Premature discarding of growth hormone therapy, however, should be avoided since aging causes cells to lose responsiveness to growth factors despite the presence of respective receptors.(Phillips et al, Amtmann, E. et al) which can be restored by the use of embryonic cell extracts.(Amtmann, E. et al). Thus in the older individual it would appear that growth factors such as human growth hormone must be combined with fetal cell extracts in order to produce beneficial results. Other growth factors in various stages of development include: Brain-derived Neurotrophic Factor, Ciliary Neurotrophic factor, endothelial growth factor, fibroblast growth factors, glially derived neurotrophic factors, glial growth factors, hepatocyte growth factors, insulin-like growth factors, kerantiocyte growth factors, platelet-derived growth factors, stem cell factors, transforming growth factors and vascular endothelial growth factor(Wrotnowski, Cort). It will be many years if ever before these get to the marketplace and many more years before we will know which combination of these is best for neuron and glial cell repair in the setting of chronic stroke and traumatic brain injury. Already, however, nerve growth factor and vascular growth factors are being used clinically in Europe for spinal cord repair with good results.

The discovery of safe and effective methods of administering these to the injured brain site is a challenge that is being actively worked on. In our hands the use of fetal cells or fetal cell extracts appear to give clinically positive results thus indicating that the blood-brain-barrier is not intact in the brain injured individual. Hyperbaric oxygen also has been shown to open this barrier which apparently allows these neurotrophic agents to pass into the brain where they can induce neuronal re-growth. The combination of hyperbaric oxygen, human growth hormone, fetal cell extracts, biofeedback and physical therapy has a positive, synergistic effect on brain repair of chronically brain damaged individuals. Increased degrees of success should come as other tools such as cranial electrostimulation, ultraviolet blood irradiation and proteolytic enzymes are incorporated into the healing program since each of these has already demonstrated clinical success in the treatment of chronic brain injured individuals.

The overall treatment program of the brain injured individual will evolve over the next 50 to 100 years to include the use of hyperbaric oxygen to pre-condition the brain by cleaning up the debris, stimulating formation of extracellular matrix and turning on neuronal genes involved with regeneration and angiogenesis. As this is done, the neurons and glial cells will be stimulated to regrow, elongate and reconnect by a combination of growth factors and anti-inhibitor administration. The specific combination of growth factors that will give the most successful results and the best techniques for their administration still needs to be determined. Tissue culture and animal studies should facilitate these studies and the optimum type and mode of delivery of neurotrophic factors and anti-inhibitors should be known within the next 20 years. Failing these non-invasive techniques, the use of stereotactic needle placement into the sites of injury will be utilized to deliver a powerful combination of primed human fetal brain cells along with a combination of growth factors, angiogenesis stimulators, and anti-inhibitors. Hyperbaric oxygen will be used prior to the operation and for 40 to 60 days afterwards to facilitate the take of the cellular transplant.

Rawls, Rebecca. Splicing ribozyme can ‘edit’ mammalian RNA. C&EN.page 7, June 3, 1996.

Edwards, R. H., Sarmenta, S.S., and Hass, G.M.: A.M.A. Arch. Path. 69:296, 1960.

JAMA. Medical Applications of Fetal Tissue Transplantation. Council on Scientific Affairs and Council on Ethical and Judicial Affairs. Vol. 263, No.4 January 26, 1990.

Phillips, P.D., Kuhnle, E., and Cristofalo, V.J. J.Cell Physiol 114, 311, 1983.

Amtmann, Eberhard, Eli Edde, Gerhard Sauer and Otto Westphal. Restoration of the Responsiveness to Growth Factors in Senescent Cells by an Embryonic Extract. Exp. Cell Research 189, 202-207, 1990.

Wrotnowski, Cort. R&D Trends and the Recent Surge of Interest in Growth Factors and Cytokines. Genetic Engineering News p.6 June 15, 1996.

National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. Tissue Plasminogen Activator for Acute Ischemic Stroke. NEJM 333, No. 24, Dec 14, 1995.