Effects of hyperthermia on the peripheral nervous system: a review.

The present paper overviews the current knowledge about effects of hyperthermia at temperatures used in clinical oncology on the peripheral nervous system. From the experimental studies it may be concluded that the heat sensitivity of the nerve is determined by the sensitivity of the nerve vasculature. These studies show that in order to avoid induction of severe neuropathy, application of heat to the peripheral nerves should not be in excess of doses of 30 min at 44 degrees C or equivalent. Using modern equipment for application of loco-regional hyperthermia the incidence of even mild neurological complications is very low. In hyperthermic isolated limb perfusion (HILP) neurotoxicity is an often-mentioned side effect, this is in spite of the fact that in all studies a relatively mild hyperthermic temperature is used that, based on the experimental studies, should be well tolerated by the nerves and other normal tissues in the limbs. It seems that the neurotoxicity observed after HILP results from thermal enhancement of drug toxicity, very probably combined with effects of a high tourniquet pressure that is used to isolate the blood flow in the leg. Whole body hyperthermia (WBH), using anesthesia and appropriate monitoring to avoid cardiovascular stress is at present considered a safe procedure. Still in the recent past cases of neuropathy after treatment have been described. When chemotherapy, and notably cisplatin, is administered before or during hyperthermia there are several clinical and experimental observations that indicate a limited tolerance of the peripheral nervous tissue in such case. Also previous radiotherapy may limit the tolerance of nerves to hyperthermia, notably when radiation is applied with a large field size. Experimental studies show that combined treatment with radiation and heat leads to enhancement of effects of radiation (enhancement ratio approximately 1.5 at 60 min at 44 degrees C). A clear contraindication for the application of hyperthermia in patients is the presence of a neurodegenerative disease, such as multiple sclerosis. Vigilance is also required in the treatment of diabetic patients with hyperthermia, this based on experimental animal studies, but so far no clear clinical data are available.

Ultrastructural changes in the rat sciatic nerve after local hyperthermia.

The rat sciatic nerve was heated over a length of 5 mm for 30 min at 43, 44 or 45 degrees C. Morphological changes were not observed after heating at 43 degrees C. Treatment at 44 degrees C resulted in endoneurial oedema and mild vascular changes, such as contraction and vacuolization of endothelial cells and thickening of the media of the larger vessels. Within 1 week several demyelinated axons were observed. The first changes after heating at 45 degrees C included oedema, blood vessel occlusion and severe endothelial cell damage. Axonal changes, e.g. the accumulation of cell organelles, appeared 8 h after treatment; 24 h after treatment most axons and myelin sheaths showed degenerative changes. Absence of blood flow in the heated area of the nerve was shown 2 h after heating at 45 degrees C. We conclude that hyperthermic treatment directly affects endothelial cells and myelin sheaths in the rat sciatic nerve. Axons degenerate most probably as a consequence of ischaemia.

Heat shock proteins (HSP-72 kd) in thermotolerant rat sciatic nerves.

Localized heating of the rat sciatic nerve over a length of 5 mm for 30 min at 43 degrees C resulted in the production of heat shock protein 72 kd in every nucleated cell and in the induction of thermotolerance in the heated area. HSP-72 kd was never detected in axons. Heat treatment (30 min, 45 degrees C) of thermotolerant nerves, 24 h after pretreatment, led to histopathological changes in the nerve, similar to those in non-thermotolerant nerves after a less strong treatment, i.e. heating for 30 min at 44 degrees C. Although axons did not contain HSPs after treatment at 43 degrees C, these structures tolerated treatment at 45 degrees C. Therefore we conclude that axons in the rat sciatic nerve are relatively heat-resistant and therefore we assume that axons do not need protection by HSPs; this is in contrast to endothelial cells and Schwann cells. Axons can be damaged indirectly as a consequence of vascular damage leading to ischaemia. Development of thermotolerance of the vasculature, ensuring a sufficient blood flow in the heated area, prevents this indirect damage.

Influence of cisplatin on the sensitivity of the rat sciatic nerve to local hyperthermia.

The influence of cisplatin on the sensitivity of the rat sciatic nerve to local hyperthermia was investigated. Rats received 1.7 mg/kg cisplatin i.p., twice a week for 6 weeks, up to a cumulative dose of 20.4 mg/kg. After termination of cisplatin treatment, a 5 mm segment of the nerve was locally heated at a temperature of 45 degrees C (5-30 min). Loss of motor function was assessed by means of the toe-spreading test, 24 h post heating. The calculated ED50 for control nerves was significantly (p < 0.01) larger than the ED50 for cisplatin treated rats; 16.3 +/- 1.1 min vs. 10.9 +/- 1.1 min. This indicates that nerves from cisplatin treated rats were more sensitive to heat than nerves from control rats (dose modifying factor = 1.5 +/- 0.2). Histopathological investigation of nerves after heat alone or after heat preceded by cisplatin confirmed these differences and showed that edema, vascular damage and axonal degenerative changes of axons and myelin sheaths occurred at lower heat doses when compared to control nerves. Recovery studies showed that cisplatin treatment before hyperthermia caused a delay in recovery from motor function loss of about 6 days. Cisplatin treatment after hyperthermia had no influence on recovery from motor function loss.

Hyperthermic injury versus crush injury in the rat sciatic nerve: a comparative functional, histopathological and morphometrical study.

Functional and morphological changes of the rat sciatic nerve after local hyperthermia (30 min, 45 degrees C) and crush treatment were compared. After hyperthermic injury nerve function loss developed in a time period of about 7 h. Nerve crush led to an immediate loss of nerve function. Nerve function loss was assessed by a motor and a sensory function test. Recovery from function loss took place in both treatment groups and was complete in 4-5 weeks. Early (within 8 h post-treatment) histopathological changes in the nerve after heating included edema, possible blood stasis and changes in the blood vessel wall, like swelling of the media. During this period some axonal changes were observed. Immediate after crushing axons were severely damaged, while many blood vessels remained normal. Within one week after both treatments, degeneration of axons and myelin was observed at the site and distal from the site of the lesion (Wallerian degeneration). Three weeks after treatment a major part of the axons had regenerated and remyelinated. Vascular changes at the site of lesion could still be observed in the heat-treated nerves. Twelve weeks after both treatments, blood vessels appeared to be normal again. Morphometrical analysis of the treated nerves confirmed the histological observations. Three and 12 weeks after treatment average axon diameters were significant smaller and average myelin sheaths were significant thinner compared to untreated nerves. These parameters did not differ significantly when the two treatment groups were compared.