Fall 1996 Volume 5, Number 4

After Neurotrauma

Brain and Spinal Cord Repair

BY JOSEPH R. MADSEN, M.D.

At a vacation resort last summer, an 11-month-old child fell a few feet onto a floor. He remained conscious, cried, and was consoled by his parents. A few hours later, he started vomiting and was somewhat lethargic; four hours after the fall, he was seen in a local emergency room, where the medical staff felt he was a little sleepy, but neurologically intact. However, a CT scan they performed showed an epidural hematoma (bleeding between the dura, the tissue covering the brain, and the skull).

When the helicopter arrived to airlift the child to a pediatric neurosurgical center, doctors found that his left pupil had become dilated

This implied that the hematoma was pushing the brain beyond its normal confines on the side of the injury and beginning to press upon the brainstem and the nerve that controls light reflex in the pupil.

The child was placed on a mechanical ventilator and medicines were given to try to draw fluid out of the brain tissue to decrease the pressure. He was immediately loaded into the helicopter. As the aircraft raced against a thunderstorm, also headed for Boston, the child's other pupil dilated and became fixed. The airborne team alerted the hospital of the gravity of the situation and arranged to bring the child directly from the helipad to the operating room, where he would be met by a neurosurgeon.

Within nine minutes of touchdown of the helicopter and about one hour from leaving the other hospital, the blood clot was out. The child's pupillary responses returned to normal on the operating table, and he was neurologically intact the following morning.

He returned home with his family six days later.

Anatomy of a Neurotrauma CAT scans of a brain of an 11-month-old boy injured in a seemingly harmless fall.
Lighter-shade area shows life-threatening pressure on the brain from bleeding dura and skull.	After surgery, scan shows the pressure relieved.
(Scans coutesy of J. Madsen.)

The neurotrauma epidemic
The technical term for the boy's injury is "neurotrauma," traumatic injury to either the brain or spinal cord. Neurotrauma is an epidemic based on accidents and violence. Neurological trauma causes thousands of deaths and devastating irreversible tragedies annually. Because it afflicts many perfectly healthy young people, the productive years lost as a result of its ravages are particularly high. About half of the 150,000 trauma-caused deaths in the United States each year are due to fatal brain injuries.

An additional 10,000 persons sustain spinal cord injuries each year, resulting in loss of motor control, sensation, and bowel and bladder control. An estimated 200,000 survivors of severe central nervous system injuries in the United States live with their neurological disabilities, and often, with little hope (see related story).

Rescue: preventing delayed injuries.
Human brains and spinal cords tolerate the usual shock of bumps from playground falls, soccer balls, and unexpected low doorways fairly well. Concussion --temporary alteration in neurological function without structural damage --probably results from momentary change in the chemical surroundings of the brain cells. This would include disruptions in release of neurotransmitters, some of which are excitatory (speeding up electrical firing in the neurons they signal) and others inhibitory (slowing firing down).

More severe impacts to the brain can disrupt neurons' fine filaments, called axons, that travel through the brain; such disruption can interrupt communications between cells and shut down the machineries of consciousness and even the life-sustaining control of breathing. Death or a vegetative state may result. Disruption of the integrity of the bony armor of the spinal cord can tear the cables connecting voluntary activity in the brain to the muscles of the limbs, causing paralysis.

The physical impact causing trauma can be over in less than a second, but the damage to central nervous system (CNS) tissue can worsen over hours or days. Some neurons may die at the moment of trauma, but not all; others survive but are weakened by the initial insult plus a lack of nutrients or oxygen, or the presence of toxins produced by the first neurons killed.

Prevention and treatment of the effects of these various delayed insults or "secondary injuries" to the brain and spinal cord at cellular and biochemical levels has added much to the therapeutic armamentarium. The urgency to limit ongoing damage --and its costly long term consequences --makes trauma one of the most aggressively-managed of neurological diseases.

In the field, the emergency room, and the first hours of treatment, "optimization of the neuronal environment" is the watchword and the motivation for all of the standard goals of resuscitation: maintenance of blood pressure and oxygenation, correction of acid-base balance, normalization of electrolyte status, control of the electrical storms of seizure activity, and optimization of nutritional support. These steps contribute to keeping the sick neurons alive.

One treatable crisis, increased intracranial pressure (ICP), unique to head injury, occurs because the soft tissues of the brain are enclosed in the inelastic skull. Elevated ICP occurs whenever cellular swelling or leakage of fluid through blood vessels overfills the limited capacity of the skull, as it did with the child treated last summer. Traditional neurosurgical treatment, such as removal of blood clots outside of the brain (epidural or subdural hematomas) or within the brain (contusions or parenchymal hemorrhages), aims to decrease intracranial pressure and thereby allows metabolic conditions more favorable to neuronal survival.

A mainstay of neurosurgical treatment has become the insertion of small temporary devices called ICP monitors, which directly measure intracranial pressure, allowing an optimal approach to resuscitative fluid management, respirator settings, and the use of osmotic agents to try to draw fluid out of the brain. The results of unchecked ICP have been known for decades: loss of consciousness, loss of regulated circulation to the brain, and ultimately loss of life.

A recent observation about the death of individual neurons in culture has suggested an additional possibility for intervention to limit damage. Partially-injured neurons become sensitive to normal excitatory neurotransmitters, such as glutamic acid. Some neuronal death after trauma is a result of this phenomenon of excitoxicity, and specific blockers of the nerve cell receptors for the transmitter can limit this death in the culture dish. So far, this strategy has not reached routine clinical use, but it is part of a larger trend toward highly specific approaches to treatment based on our increasingly sophisticated understanding of the neurobiology of trauma. Another such strategy might take advantage of neurotrophic factors, naturally-occurring peptides that keep neurons alive in development. These may also sustain injured neurons and prevent the march toward cell death. It seems virtually inevitable that specific neurotrophins and/or excitotoxicity blockers will one day be used to limit secondary injury.

In a broader sense, however, all non-specific interventions currently used (such as minimizing ICP, maximizing cerebral perfusion, and mechanically stabilizing the spine) ultimately work because they limit secondary damage and cell death.

Repair: Future strategies
While current efforts are targeted toward the optimal physical and chemical nature of the neuronal milieu, the instantaneous disruption of axons and resulting disability requires its own strategic response, and there is hope that regeneration-promoting biological manipulations will become available. New approaches to improving axonal regeneration in the CNS have generated hope for finding such strategies. Particular interest in this area has involved spinal cord injury, because disruption of the long, cable-like nerve fiber tracts is the major cause of disability. The same biological principles would apply to the brain.

In the peripheral nervous system, and when the central nervous system first develops, nerve cell axons, long threadlike projections through which neurons send their signals, grow out over long distances and form functionally appropriate connections. But once the CNS of higher vertebrates becomes mature, this capability is turned off. Thus, strategies for CNS repair might seek to alter the environment to recapitulate early development stages, or to supply conditions similar to those for peripheral nerves.

Proposed strategies for spinal cord repair include blocking the molecules (called endogenous neurite outgrowth inhibitors) that prevent CNS neurons from regrowing, and using non-CNS tissue to build "bridges" to promote outgrowth of axons (see CNS Repair). These approaches, which show great promise in animal studies, would be particularly important for survivors of neurotrauma with fixed deficits.

The latest dramatic study was published in the journal, Science, in July. Henrich Cheng, Yihai Cao, and Lars Olson at the Karolinska Institute in Stockholm reported a procedure in which they used multiple peripheral nerve grafts to replace an excised portion of the spinal cord in rats and stabilized the grafts in a protein gel framework laced with a growth factor called acidic fibroblast growth factor.

With this combination, they saw evidence of genuine bridging of long tracks of neurons across a gap, with recovery of function that seems to require all these aspects of the treatment. Promotion of regeneration, using multiple modalities of neurobiological knowledge, seems an imaginable goal.

While waiting for regeneration . . .
As a result of neuroscientific research, better physical health after trauma need not await biological implants to promote regeneration. Because some electrical signals to nerves and muscle and some neurotransmitter signals in the damaged brain and cord are understood, computer-driven interim solutions seem reasonable and are being tested in clinical trials. Functional electrical stimulation, for example, attempts to provide electrical impulses to the peripheral nerves to maintain tone and, hopefully, function, in the muscle groups isolated from the functioning CNS by a spinal cord injury. However, the requirements of standing and walking without aid of an intact spinal cord have so far eluded satisfactory computational solutions.

Another computer-assisted approach has hinged on the identification of specific neurotransmitters that help damp down involuntary movement that may result from brain and spinal cord injury. Baclofen, a drug that closely resembles one inhibitory neurotransmitter, GABA, can now be delivered by a programmable, microchip directed pump implanted under the skin. The result is control of potentially severe spasticity and painful spasms, which may plague survivors of CNS injury and cause joint deformity and destruction. Although a far cry from restoration of voluntary function, in certain patients these implantable bionic devices can be a veritable godsend. Although a mere dream a decade ago, they are FDA-approved and available now.

The challenge for basic scientists and clinicians alike is clear: Can the rescue be made robust, and the possibility of repair be made real? Tens of thousands await the answers --some who have had a split-second of neurotrauma, and some who have not. *