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Paresthesia: the clinical syndrome.

Nerve cells carry information to the brain via the spinal cord. After SCI, some neurons produce abnormal protein molecules that generate nerve impulses. Production of inappropriate electrical currents can ultimately cause pain and "phantom sensations." Scientists studying this subject are finding encouraging results in their search for answers.

In addition to weakness and paralysis following injury to the spinal cord, patients experience a number of poorly understood and debilitating symptoms called paresthesia. "Paresthesia" is a medical term referring to sensation with out stimulus and may include burning, coldness, wetness, pins-and-needles, electricity, numbness, swelling, or perception of movement.

Such symptoms are often referred to as "phantom sensations" because they occur without any actual touching or burning. People have these abnormal sensory experiences in limbs that have little or no feeling. The injury may be no more than a spinal-cord concussion or contusion (bruise) or as severe as complete transection. Such symptoms develop over days or weeks--or longer.

Not all patients develop phantom symptoms. Symptoms differ greatly among affected individuals and maybe short-lived or last months or even years. People are often incapacitated or even terrified (as if paralysis following SCI didn't cause enough suffering and disability).

Although medical history has for centuries documented the existence of such symptoms, only now can scientists even begin to study the pathways and mechanisms that cause paresthesia due to injured spinal cords. This is in part because of advances in understanding the chemical messengers (neurotransmitters) released by nerve cells and voltage-generating proteins (ionic channels) housed on nerve-cell membranes that participate in the transmission of normal sensation.

Attempts to explain paresthesia lead inevitably to a discussion of ectopic-impulse generation--for example, signals that travel along a nerve arise from an abnormal location and at inappropriate times (that is, without a suitable stimulus). Following is a review of some basic neuroanatomy and neurophysiology and current theories on how nerve cells may behave abnormally.


The nervous system is made up of cells, called neurons, which consist of a main cell body and one or several branches (processes) known as axons and dendrites (see Figure 1). Neurons have a small but definite internal electric potential (voltage), which at rest (the resting potential) is approximately-70 millivolts (seventy thousandths of one volt).

The resting potential may be agitated by chemical neurotransmitters that traverse a synapse and make contact with the dendrites of the receiving neuron. This occurs following release from terminal processes of other neurons. Such changes in a neuron's resting potential may be excitatory (voltage moves positively) or inhibitory (voltage moves negatively). These are further explained in the section about synapses and ionic channels.

Cells communicate information to all others connected to them. If inhibitory input is not excessive and excitatory input is adequate, a sequence of impulses, or action potentials, may be transmitted down the axon. The terminal at the end of this axon in turn contains another chemical messenger, whose release into the next synapse depends on these transmitted impulses.

The central nervous system (CNS) consists of the spinal cord and brain. The peripheral nervous system, made up of nerves that emanate from the spinal cord, carries information to and from skin, muscles, joints, and viscera. Spinal-cord and brain neurons are interconnected in a logical fashion; the peripheral nervous system transmits sensory signals coherently to the CNS and the brain, where conscious perception occurs.

The spinal cord consists of gray matter (neuronal cell bodies) and white matter (axons). The peripheral sensory system contains many receptor types, each electrically communicating directly with an axon, which ultimately forms a synapse in the dorsal horn of the spinal cord see (Figure 2). The cell body of the spinal sensory neuron is connected to this axon via a process that does not normally send sensory information.

These cell bodies are grouped together next to the spinal cord in the form of the dorsal root ganglion (DRG) with intertwining, closely approximated processes. Each sensory fiber (mediating touch, pain, heat, cold, pressure, static limb position, kinesthesia, etc.) is associated with a unique receptor and fiber type.

Information from these sensory fibers enters the spinal cord at the dorsal-root entry zone and follows any one of several pathways (see Figure 2). Sensory axons that mediate pain generally form a synapse promptly within the spinal cord in the dorsal horn. The receiving neuron's axon crosses the spinal cord and then ascends in the spinal cord within a column of axons destined to connect with the thalamus, the part of the brain often referred to as the "sensory relay station." Nerves conveying information about touch or pressure enter the spinal cord and ascend promptly in the so-called posterior columns without crossing the middle of the spinal cord.

In addition to these pathways, those descending from the brain inhibit or modulate painful sensation (see Figure 2). A number of neurotransmitters participate in pain modulation; scientists have the best understanding about the workings of opioids, serotonin, and norepinephrine. Peripheral hormones and other chemical substances have various excitatory and inhibitory effects on pain sensation.


What can o wrong once an axon is injured? Studies on dorsal-root-ganglion neurons and peripheral axons have imparted the most information. Scientists may infer by analogy what can happen to spinal-cord axons.

The white matter of the spinal cord consists of axons whose cell bodies are situated either in the dorsal-root ganglion or higher up in the brain. Thus, SCI results largely in the injury of spinal-cord axons.

When an axon is injured, the connected cell body initiates a massive production of proteins, including receptors and ion channels that are delivered to the neuronal membrane, presumably as part of the repair process. The axon, in the meantime, may try to regrow along its prior path. Unfortunately, the site of injury is often too disrupted, and the original target of the axon is too far away.

The failed attempt to regrow leads to formation of a neuroma--a tangled mass of axon sprouts unable to appropriately regenerate along the path of the distal peripheral nerve to the original target tissue. The membranes of all these axon sprouts are enriched with ionic channels and various forms of receptors that make the neuroma excitable. The neuroma, therefore, becomes a source of ectopic impulses.

Even if a neuroma does not form, the injured axon may generate ectopic impulses (see Figure 3). In this way, the site of injury may be a source of inappropriate signals that pass into the spinal cord and ultimately signal pain. Researchers suspect that neuromas are responsible for the form of paresthesia called "pins and needles." When these sensations become persistent, they are generally interpreted as uncomfortable and painful.

While the neuronal cell body produces numerous ion channels and receptors destined for the axon under repair, a substantial fraction of these proteins ends up on the membrane of the cell body. Consequently, during the process of axonal repair, the cell body itself becomes a second hyperexcitable source of ectopic impulses that can cause pain.

Studies at the PVA/EPVA Center for Neuroscience and Regeneration Research have found that, following injury, some spinal sensory neurons turn off the production of certain molecules (sodium channels) that act as molecular batteries producing nerve impulses, and turn on production of still other types of sodium channels. As a result, the neurons produce different kinds of sodium channels. We have also found that these spinal sensory-neurons switch on genes for sodium channels previously silent.

We have hypothesized that the newly produced mixture of sodium channels after injury causes spinal sensory neurons to be hyperexcitable--they produce abnormal activity that could be sensed as pain. Since the newly produced sodium channels are different from the original ones, it is possible that researchers can develop drugs specifically to block them. This will provide new treatments for post-SCI pain.

In the dorsal-horn gray matter of the spinal cord, sensory nerve terminals corresponding to damaged axons might also become overly enriched with chemical receptors and make them excessively sensitized. This in turn makes normal pain-suppressing pathways (that is, the body's own opioids, serotonin, etc.) ineffective.

Paresthetic-pain signals arising either from the spinal cord or from DRG neurons are not suppressed, and it is possible that they are inappropriately amplified. In the spinal cord, axonal regeneration either fails entirely or is not initiated; we can only speculate how an injured spinal-cord axon becomes a source of ectopic impulses.


Based on this information, the most effective medical treatments for neuropathic pain are those known to reduce neuronal excitability, including benzodiazepines (diazepam, lorazepam, etc.), anticonvulsants (phenytoin, carbamazepine), and tricyclic antidepressants. Narcotic medications are partially but temporarily effective; since most of the syndromes result from permanent injury of the spinal cord, exposing patients not only to the dependency of narcotic medication but also to the many potential adverse effects is often impractical.

The benzodiazepine family of drugs inhibits neurons by sensitizing the so-called GABA (gamma-amino butyric acid, an inhibitory neurotransmitter) receptors residing in sensory-nerve terminals. Phenytoin and carbamazepine block the sodium channel, therefore disallowing sodium ions from entering neurons. Phenytoin, carbamazepine, and other similar medications have the peculiar property of blocking sodium channels only when they are excessively active. If excessive trains of ectopic impulses are generated in, for example, a neuroma, these drugs can selectively (although partially) suppress that activity without suppressing neural activity in the whole body.

Unfortunately, these medications are difficult for patients to tolerate at the high doses necessary to significantly lessen symptoms. Tricyclic antidepressants inhibit the metabolism of chemical messengers such as norepinephrine and serotonin; this prolongs and bolsters inhibitory activity.

The Yale Center research team is exploring development of new drugs to provide more effective treatment for pain and paresthesia after SCI. By finding those that block only the sodium channels produced by spinal sensory-neurons after injury, selectively silencing nerve cells responsible for the pain may be possible. This research, ongoing at the PVA/EPVA Research Center Sensory Neuron Laboratory, is moving along rapidly.


Many electrical and metabolic changes occur in chronically injured axons and their neuronal cell bodies of origin. One of these changes is the synthesis of chemical receptors and ionic channels. The repair process is sometimes complicated by neuroma formation.

Painful paresthesia results from ectopic impulse generation, which may arise at one or several sites in the nervous system. Current treatments are specific but often incompletely effective due to (1) the many-faceted underlying causes and (2) the toxicity of medication.

Continued research is aimed at specific medical treatments affecting known impulse-generating and -modulating mechanisms in the spinal cord and peripheral nerves. In the future, new drugs that block specific sodium channels may provide new, more effective treatments for pain.


* Kocsis, J. D. and S G. Waxman. "Long-term regenerated nerve fibers retain sensitivity to potassium channel blocking agents." Nature (London) 304: 640-642.1983.

* Rizzo, M. A. et al. "Selective loss of slow and enhancement of fast sodium currents in cutaneous afferent dorsal root ganglion neurons following axotomy." Neurobiology of Disease, 2:87-96. 1995.

* Rizzo, M. A., et al. "Mechanisms of paresthesiae, dysesthesiae, and hyperesthesiae: role of Na channel heterogenity." European Neurology, in press. 1995.

* Waxman, S. G. et al. "Type Ill sodium channel mRNA is expressed in embryonic but not adult spinal sensory neurons, and is reexpressed following axotomy." Journal of Neurophysiology, 72:466-470. 1994.


* ectopic not in the normal place

* neuroanatomy the study of the nervous system/nerve structure

* neurons

nerve cells

* neuropathic of a diseased condition of nerves

* neurophysiology study of the function of the nervous system

* sodium channels protein molecules that generate nerve impulses

* synapse a region where nerve inpulses are transmitted and received

* transection


* viscera internal organs


About the Author

Dr. Rizzo graduated from Brandeis University (Waltham, Mass.) with high honors in physics. His M.D. and Ph.D. (in physiology and biophysics) are from the University of Miami School of Medicine. He is assistant professor of neurology at Yale and a research physiologist at the PVA/EPVA Neuroscience Research Center. He cares for patients at the West Haven VA Neurology Clinic and the Yale School of Medicine. For more information about the studies mentioned in this article, contact him c/o the Neuroscience Research Center, 127A, VA Medical Center, Building 34, West Haven, CT 06516.


Of the types of pain described below, 2, 3, and 4 are most relevant to the information in this article.

1 Mechanical instability of spine. Sometimes due to imcomplete healing of a fracture. Worsens with sitting or moving. Usually treatable with external or internal stabilization.

2 Mechanical compression of a nerve root at the injury site. Due to a piece of bone or part of spinal disc pressing on nerve. Produces radiating pain that worsens with movement. MRI can often identify location of pressure; surgery can remove the cause of the pressure and relieve the pain.

3 Pain in paralyzed part of the body, below the level of injury. Pain may be a burning, aching, or throbbing and seems to be in lower part of the body. Is difficult to treat. Drugs may or may not decrease this form of pain.

4 Chronic pain in body area that has partial sensation. Also difficult to treat. Drugs may or may not be effective. Surgery to cut a specific nerve root may help.

5 Pain due to overuse injuries of joints and muscles. These in juries are usually in upper limbs because of overuse for mobility. Can include calcium spurs in shoulders, tendinitis, carpal tunnel syndrome. This group of overuse injuries may be treated with a wide variety of therapies: exercise, massage, immobilization, medications, or surgery.

Source: Chronic Pain After Spinal Cord Injury, World Wide Web site http://weber.u.washington .edu/-rehab/sci/5-2/as published in The Spinal Cord Injury Newsletter, Volume 1, Number 1, Winter 1995. For information about this resource, contact Medical News Publishing, P.O. Box 99702, San Diego, CA 92169-9702.
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Author:Rizzo, Marco A.
Publication:PN - Paraplegia News
Date:Apr 1, 1996
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