Multiple Sclerosis Cooling Foundation

Providing Information on Cooling for those with MS

HYPOTHERMIA: A SIMPLE THERAPEUTIC TOOL FOR MULTIPLE SCLEROSIS David G. Baker, Ph.D. MSQR MULTIPLE SCLEROSIS QUARTERLY REPORT VOLUME 17 NUMBER 4, DECEMEBER 1998  Many people with multiple sclerosis, myself included, live with the sometimes distressing but always frustrating phenomenon that small alterations in body temperature produce dramatic changes in symptoms. We live with this phenomenon every day; it impacts all aspects of our lives - careers, families, and relationships; tears at our confidence; and undoubtedly contributes to the disease’s early name, “faker’s disease”. The waffling of symptoms as body temperature rises and falls is certainly a source of great frustration. Symptoms like spasticity, fatigue, visual acuity, and cognitive abilities come and go but always worsen in the afternoon, just when the body’s temperature reaches its daily peak. Symptoms always worsen with hot weather, especially hot muggy weather when sweating is inefficient, with fever when the body’s thermostat resets to higher levels, and with exercise, as heat generated by working muscles increases body temperature, transforming a limping gait into no gait at all. Fortunately, heat-induced worsening is only transient, and symptoms improve when temperature returns to normal levels. Indeed symptoms improve dramatically for many when temperature is reduced to hypothermic levels. For me, leg spasticity decreases after swimming in the San Francisco Bay or after wearing a “cooling garment”, enabling me to play catch with my son, mow the lawn, walk unaided through a museum, or enjoy dinner with my wife. The underlying mechanism, how temperature alters symptoms of multiple sclerosis, has been known for many years, although temperature’s ameliorating effect has not always been appreciated by the clinician nor has it adequately been discussed by clinicians with their patients. In 1959 in the New England Journal of Medicine, Watson noted hypothermia’s effect in a number of MS patients and commented on the “apparent lack of awareness on the part of physicians of the beneficial effect of cold” (12). Unfortunately, these words are still true today. The physiology was elucidated in the 1970s by several investigators in different laboratories, using in vitro preparations of demyelinated nerves (3,4,13). In these isolated experiments, it was possible to carefully control temperature while simultaneously monitoring activity of individual demyelinated nerves. Small increases (0.5o F) blocked conduction in some demyelinated nerves, still active at baseline temperature. Conversely, small decreases restored conduction in other demyelinated nerves, previously blocked at baseline temperature. Understanding exactly how temperature affects nerve conduction in demyelinated nerves will require courses in neurophysiology, but just a little additional knowledge will provide you with a much better appreciation of what is going on. In myelinated nerves, action potentials, momentary reversals of membrane potential, propagate along the axon, hoping from node of Ranvier to node of Ranvier. Depolarizing currents, generated by the action potential, spread in advance and down the interior of the axon, exiting and exciting the axonal membrane at the next node of Ranvier. The insulation provided by the layers of myelin prevents current from escaping, and it is only at the bare sites, the nodes of Ranvier, that escape is possible. Here, the depolarizing current, passing out through the axonal membrane, regenerates the action potential (Fig 1A). Increasing temperature shortens the duration of the action potential and, as a result, less current is available to excite the node of Ranvier. Decreasing temperature has the opposite effect. The duration of the action potential is prolonged and more current is available over time to depolarize the next node Ranvier. Normally, changes in temperature, certainly those experienced in our daily lives, have no effect, there is more than enough current to depolarize the nodal membrane or hop over any small lesion. However, in the severely demyelinated nerve, currents escape over the entire denuded region of demyelination, and there is not always enough current remaining to excite the next node of Ranvier (Fig 1B). Fig 1. Schematic diagram shows depolarizing currents in myelinated (top) and demyelinated axons (bottom). Arrows and broken lines indicate flow of depolarizing current from action potential (cross-hatching) down the interior of the axon and out through node of Ranvier or region of demyelination. Normally high resistance and low capacitance myelin prevents shunting, except at the node of Ranvier. In multiple sclerosis, however, inflammation destroys myelin. Conduction block occurs when the action potential no longer conducts through the demyelinated region or hops directly over the lesion to the next node of Ranvier (for further explanation, see ref. 13). We can present these ideas in a much simpler way, by considering the safety factor for conduction, which is defined as, current available to depolarize a node / current necessary to depolarize the node. In the healthy myelinated axon, the safety factor can be as high as 5-7. In the demyelinated axon, however, leakage reduces the safety factor and the ratio may be closer to 1. When it is less than 1, conduction stops. When it is just above 1, conduction continues. Nerves are composed of populations of axons. In MS, individual axons are demyelinated to varying degrees and when the safety factor of a large proportion innervating a specific muscle group falls below 1, symptoms emerge. If the safety factor is just above 1, symptoms remain hidden. However, if the safety factor varies about 1, for example, in response to changes in body temperature, symptoms waffle. A good example, one that is a bit sobering, is the pilot whose vision blurred when his temperature rose but improved when it fell to its daily low, and his symptoms even improved by simply drinking ice water (9). With an understanding of the exact mechanisms, the stage was set for search of pharmacological agents that would, likewise, raise the safety factor for conduction and ameliorate heat-related symptoms (5). The result was the identification of the potassium channel blockers, in particular, 4-aminopyridine (1). However, the simple use of hypothermia to restore activity in heat blocked nerves has not caught on, and it has remained on the research bench and out of the reach of many. Why? I am not sure. Perhaps the benefits of hypothermia are deemed too transient or the means of cooling too inefficient or too uncomfortable for the patient. It is also possible that scientific assessment and study of hyothermia's effect is too difficult in view of other interacting factors that also raise and lower the safety factor (6,11). Despite all, many folks with MS are acutely aware that small decreases in body temperature produce improvements in symptoms. Posting queries on the Internet in the past, I was amazed at the ingenious ways that cooling had been incorporated into lives of those with MS; I was not alone. A man in New York built his house over a deep water-filled quarry to take a daily cold swim; a Canadian built his house next to a lake, in which to swim when not frozen-over, a longshoreman ingested large quantities of ice before his labors inside a ship’s hot-hole; a woman in Texas, who couldn’t move her house, sat in a nearby stream, beating the summer heat. Finally, a teacher of the disabled in California who took cold showers between lessons. For my own summers, I stayed put. Why? Mark Twain understood: “I never was so cold as the summer I spent in San Francisco”. Although our understanding of the exact mechanisms has been of considerable theoretical importance, responsible, in part, for spurring the search for blockers of potassium channels, the simple use of cooling as a therapeutic tool has had little practical clinical value, no doubt because benefits appear so transient. Nevertheless, a chance for short term benefits - a little physical exercise, a good night’s sleep, a short escape from the overwhelming fatigue of MS – can have great rejuvenating benefits. More significantly, long-term benefits that were not previously appreciated or widely discussed are emerging. First, by lowering body temperature 1-2o F (not enough to shiver) conduction is restored in previously blocked nerves and the individual with MS is able to exercise to his/her maximum, thereby gaining the most of aerobic conditioning and physiotherapy programs. It is recognized that exercising and achieving the best physical health is one of the best preventative treatments for individuals with MS. In a recent study, regular exercise improved fitness and strength and reduced fat and also “improved such quality of life indices as depression, anger and social interaction” (8). Swimming in cool water is a convenient way to provide such an exercise program. The buoyancy effect of water and the diminished effect of gravity minimize spasticity and maximize body movement. But aquatic programs are made difficult by water temperatures that are frequently too warm. Several years ago, I swam regularly at a local recreational pool, maintained at 79-80oF. I usually swam 500 yards; my distance was limited by neuronal fatigue. My concern was getting to the shower without slipping. On one occasion, the heater broke and temperature fell 2-3o each day; and, as water temperature fell, I felt stronger, swam faster and further, and my swimming time increased. On the final day, when the water temperature was 65oF, I swam 1500 yards and enjoyed a dip in the hot tub afterward. However, the temperature of local swimming pools cannot be set to the appropriate temperature for each individual with MS to offset the debilitating effects of exercise-generated heat. It is an unreasonable expectation. Fortunately, effective and reliable cooling garments are now available*. These garments are efficient enough to lower body temperature, even while exercising and comfortable enough to wear while on a stationary bicycle or rowing machine, and all this can be done in a cost-effective manner at home. The second long-term benefit - clearly justifying use of hypothermia, especially for the newly diagnosed - involves the body’s own repair and remyelination processes. Demyelination leads to conduction block and disuse, and, finally to programmed cell death (7). However, cell suicide can be prevented by neuronal activity, and if the safety factor is near 1, cooling may raise the ratio just enough to spark that activity. Furthermore, restored neuronal activity may release GG2, (neuregulin glial growth factor) which may work in collaboration with other growth factors released from other cell types to induce proliferation, migration, and maturation of oligodendrocytes, the myelin-producing cells (1,10). Laboratory studies are just beginning to unravel the underlying mechanisms of myelinogenesis, and axonal-glial signaling. Nevertheless, these studies are the basis for future clinical studies, as they raise the promising possibility that cooling and restoration of nerve activity, perhaps together with exercise and other growth factors preserves demyelinated neurons and creates the best environment for remyelination. And any remyelination at all will have profound effects on the lives of individuals directly or indirectly affected by MS. References 1. Barres, B. A. and M. C. Raff. Proliferation of oligodendrocyte precursor cells depends on electrical activity in axons. Nature. 361(6409): 258-260, 1993. 2. Bever, C. T. The current status of aminopyridines in patients with multiple sclerosis. Annals of Neurol. 36: S118-S121, 1994. 3. Bostock, H., R. M. Sherratt, and T. A. Sears. Overcoming conduction failure in demyelinated nerve fibers by prolonging action potentials. Nature . 274: 385-387, 1978. 4. Davis, F. A. and S. Jacobson. Altered thermal sensitivity in injured and demyelinated nerve - a possible model of the temperature effect in multiple sclerosis. J. Neurol. Neurosurg. Psychiatry . 34: 551-561, 1971. 5. Davis, F. A and C. L. Schauf. Approaches to the development of pharmacological interventions in multiple sclerosis. In: Demyelinating Disease: Basic and Clinical Electrophysiology. Waxman, S. G. and Ritchie, eds. New York, Raven Press, 1981. 6. Gutherie, T. and D. A. Nelson. Influence of temperature changes on multiple sclerosis: critical review of mechanisms and research potential. J. of the Neurol. Sci.129:1-8, 1995. 7. Jacobson, M.D., M. Weil, and M. C. Raff. Programmed cell death in animal development. Cell. 88(3): 347-354, 1997. 8. Patajan, J. H., E. Gappmaier, A. T. White, M. K. Spencer, L. Mino, and R. W. Hicks. Impact of aerobic training on fitness and quality of life in multiple sclerosis. Annals of Neuro. 39(4): 432-441, 1996. 9. Scherokman, B. J., J. B. Selhorst, E. A. Waybright, B. Jabbari, G. E. Bryan, and C. G. Maitland. Improved optic nerve conduction with ingestion of ice water. Lancet. 17: 418-419, 1985. 10. Shi, J., A. Marinovich, and B. A. Barres. Purification and characterization of adult oligodendrocyte precursor cells from the rat optic nerve. J. of Neurosci. 18(12): 4627-4636, 1998. 11. Smith, K. J. Conduction properties of central demyelinated and remyelinated axons, and their relation to symptom production in demyelinated disorders. Eye. 8:224-237, 1994. 12. Watson, C. W. Effect of lowering of body temperature on the symptoms and signs of multiple sclerosis. N. Engl. J. Med. 261(25): 1253-1259, 1959. 13. Waxman, S. G. Membranes, myelin and the pathophysiology of multiple sclerosis. N. Engl. J. Med. 306: 1529-1533, 1982.