Chapter 21 Nerve thermal injury

Chapter 21 Nerve thermal injury

H.S. Sharma and J. Westman (Eds.) h g r t . v s in Brain Rc.rrarch. Vol 1 15 Q IYYX Elsevicr Science BV. All rights reserved. CHAPTER 21 Nerve therm...

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H.S. Sharma and J. Westman (Eds.) h g r t . v s in Brain Rc.rrarch. Vol 1 15 Q IYYX Elsevicr Science BV. All rights reserved.

CHAPTER 21

Nerve thermal injury C.D.P. Lynch and M. Pollock* Department of Neurologv, Department of Medicine, Vniwrsity of Otago Medical School, P.O. Box 913, Dunedin, New Zealand

Introduction

The clinical syndromes of nerve thermal injury have been described since the time of Hippocrates. They have commanded particular attention during military exercises including the Crusades, Napolean’s Russian Campaign, the Crimean War, the First and Second World Wars, the Korean conflict and the Falklands War. Spurred on by clinicians, basic investigators have shown that nerve structure and function are critically dependent on ambient temperature and if nerve temperature falls outside a relatively narrow range, neural function becomes sub-optimal or fails. There has been considerable research, both experimental and clinical, on nerve injury following cold exposure but by contrast that of heat injured nerve has been largely neglected. This is surprising given the clinical importance of hyperthermic nerve injury in a variety of specialties. Pertinent to the subject of nerve thermal injury in general is the considerable body of evidence that suggests that important underlying pathogenetic mechanisms are a breakdown of the blood-nerve barrier and impairment of endothelial synthetic function. In addition, blood coagulation dynamics and platelet physiology show ther-

*Corresponding author. Tel: +64 3 4740999; fax: +64 3 4747641; e-rnail:[email protected]

ma1 sensitivity. These factors culminate in focal angiopathy that is central to the genesis of nerve thermal injury. Here we review the clinical aspects of nerve thermal injury and discuss the experimental studies that illuminate these conditions. Nerve heat injury

Experience of nerve thermal injury in the peripheral nervous system is largely restricted to Emergency and Military Physicians and to those practitioners residing in environments with extremes of ambient temperature (Table 1) (Smith et al., 1915; Ungley and Blackwood, 1942; Malamud et al., 1946; Yaqub et al., 1986; Yaqub, 1987; Zhi-Cheng and Yi-Tang, 1991). However, Neurologists, Psychiatrists, Oncologists, Geriatricians, Paediatricians, and Sports Medicine doctors also need to be cognizant of these disabling and sometimes life threatening conditions (King et al., 1981; Gerad et al., 1984; Emami, 1991; Oshima et al., 1992; Marquez et al., 1993). There have been significant advances in the pathogenesis and treatment of heat stroke and related disorders since they were reviewed by Stefanini (1975) and Goetz and Klawans (1979). In particular, research into malignant hyperthermia and neuroleptic syndrome has provided new insights into our understanding of thermogenesis and thermoregulation (Blatteis, 1992; Zeis-

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TABLE 1 Clinical syndromes of nerve thermal injury Heat Hyperthermic syndromes 1. Heat stroke 2. Malignant hyperthermia 3. Neuroleptic malignant syndrome Burns Whole body hyperthermia Cold Trench foot Immersion limb Frost bite

berger and Merker, 1992; Kao et al., 1994; Lin et al., 1995; Parada et al., 1995). Peripheral nerve injury is a rare complication of hyperthermic syndromes (Garvey et al., 1940; Bull et al., 1979; Adam et al., 1987) with cases of peripheral neuropathy falling into two groups: a Guillain-Barre, syndrome (Garvey et al., 1940; Wijesundene, 19921, and a multifocal sensorimotor polyradiculoneuropathy (Mehta and Baker, 1970; Dhopesh et al., 1976; Bouges et al., 1987). It is possible that the Guillain-Barre, syndrome is a consequence of antigens from heat damaged neural tissue initiating a secondary immunological injury. Neuropathy in burn patients is more common, but frequently not diagnosed even in burns units (Henderson et al., 1971; Helm et al., 1977; Helm et al., 1985; Marquez et al., 1993). Most burn patients exhibit a mononeuritis multiplex (69%), but mononeuropathy, radiculopathy and generalised axonal polyneuropathy have all been described (Marquez et al., 1993). These axonal neuropathies have a predilection for burnt areas. Both burn thickness and total burn surface area correlate with the number of nerves affected. Long term follow up of burn patients has demonstrated that 75% have moderate to severe clinical and electrophysiological deficits relating to their neuropathy (Marquez et al., 1993). A small group

of burn patients have neuropathy in areas distant to the site of burn, unrelated to pressure areas or escharotomy sites. An unknown 'humoral' or toxic mediator has been proposed to explain these rare phenomena (Sepulchre et al., 1979; Bouges et al., 1987). Occasionally neuropathies have been reported following whole body hyperthermia (WBH) for cancer treatment. Bull et al. (1979) described multifocal conduction block in four patients, three of whom presented within 24 h of exposure to 42.8"C. All patients recovered although two affected patients continued to have WBH. Gerad et al. (1984) documented transient paraesthesias in three of 11 patients and a further patient developed wrist drop. Adam et al. (1987) report a case of weakness, patchy sensory loss, and areflexia following three treatments of WBH at 41.8"C. Onset was rapid, progressed over 10 days and had incompletely resolved at 6 months. On investigation there was widespread sensorimotor conduction abnormalities with evidence of denervation. The electrical response of large myelinated Afibres to a 'low grade' hyperthermic injury (47°C) is preferentially abolished over 2 h (Lele, 1963; Klumpp and Zimmermann, 1980; Xu and Pollock, 1994) (Fig. 1). This correlates morphologically with a loss of myelinated fibres (Fig. 2), leaving the unmyelinated fibre population intact. Boykin et al. (1980) has provided evidence that platelet microthrombi are responsible for this post-heat injury. The subsequent loss of large medullated nerve fibres arises from their sensitivity to ischaemia and hypoxia (Dahlin et al., 1989; Fujimura et al., 1991; Xu and Pollock, 1994). The vulnerability of unmyelinated fibres to higher temperatures is revealed by an immediate, selective abolition of C-fibre potentials at 58°C with a corresponding degeneration of unmyelinated nerve fibres (Xu and Pollock, 1994) (Figs. 3 and 4). Nerve cold injury

Peripheral nerve injury in hypothermic disorders is far more common than nerve heat injury. Cases

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I C-fibres I

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m Iv Fig. 1. Early changes in compound action potentials following low grade heating. The left and right columns show C- and A-fibre compound potentials. In I, I1 and 111 the cumulative time following nerve thermal injury is shown. IV shows a typical C-fibre compound potential, 6 h after abolition of the A-fibre compound action potential [from Xu and Pollock (19941, with kind permission of Oxford University Press].

of cold-induced neuropathy are not limited to military exercises (Smith et al., 1915; Ungley and Blackwood, 1942; Ungley et al., 1943) but may be seen in civilian practise. They are prevalent among mountaineers (Carter et al., 1988), arise as a complication of cryotherapy (Bassett et al., 1992), or open heart surgery (Efthimiou et al., 1991) and are familiar to seafarers (Semsarian, 1994). If one uses the traditional nomenclature there is a continuum of severity in cold-induced neuropathy from Trench Foot to Cold Immersion Syndrome to Frostbite. Trench Foot is characterised by paralysis, anaesthesia and swelling of the lower extremities (Smith et al., 1915). It usually begins in wet, non-freezing conditions, often associated with relative immobility and an upright posture. Initially numbness and tightness of the feet are noted, later pain, and weakness on walking. While sensory disturbances last for weeks, complete recovery is possible, though many have persistent paraesthesiae.

Cold Immersion Syndrome has a more acute onset, and is usually characterised by four stages; cold exposure, pre-hyperaemia (hours), hyperaemia (2-48 h) and post-hyperaemia. Within minutes of exposure to non-freezing sea water [0-SOC], numbness and weakness ensue. While severe neurological injury may result within 14 h, pain is rare, but cramps or tenderness are common. After removal from the water, such patients are unable to walk or use their hands due to a dense numbness. Within 2-5 h the limbs become hyperaemic and very painful. A burning, throbbing sensation peaks in intensity within 36 h but may continue for weeks. Mueller et al. (1993) suggest it is reperfusion that produces major nerve damage following hypothermia. Up to 10 days later, lancinating pains may occur, particularly with warmth, exertion or dependency. Sensory symptoms may abate over 6-14 weeks, but occasionally, they recur intermittently. Autonomic dysfunction is common, manifest by anhydrosis in anaesthetic areas and hyperhydrosis at the border

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Fig. 2. An electron micrograph of a rat sciatic nerve, 2 days after low grade nerve heating, showing preserved unmyelinated fibres but degenerating myelinated fibres. Bar = 1 p m [from Xu and Pollock (1994) with kind permission of Oxford University Press].

with normally innervated skin. Muscle wasting in the feet only becomes evident as leg swelling diminishes.

Frost-bite results in freezing and necrosis of tissues. While tissues freeze at - 2.5"C, seawater freezes at - 1.9"C. It is therefore more likely that immersed body parts will not be 'frost bitten' unless a 'cold vasculopathy' is severe enough to cause infarction (Ungley and Blackwood, 1942). The spectrum of symptoms is similar to other cold syndromes but with more severe tissue loss. Sensorimotor changes, similar to the cold immersion syndrome are found proximal to gangrenous areas. Permanent sequelae always result from 'frost-bite'. Conduction velocity in hypothermic nerve is progressively reduced as temperature falls (Basbaum, 1973) (Fig. 5). Myelinated fibres show a differential sensitivity, with Type 2 ([email protected])fibres failing first followed by type 3 (C) and then type 1 (Aa).These changes may be attributed to both energy dependent and physical factors. Physical changes in cell lipid membranes (Tomity and Csillik, 19641, and a reduction of electrical conductance in artificial lipid membranes (Goudeau, 1968) have been described with cold. With increasing cold, there is an arrest of axo-

C-fibres 1

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I1 Fig. 3. Changes induced in compound action potentials by high grade nerve heating. The left and right columns show C- and A-fibre compound action potentials, respectively. 1 shows a control record. Note in 11, the disappearance of the C-fibre compound action potential but persistence of the A-fibre compound action potential, immediately after thermal injury [from Xu and Pollock (1994)with kind permission of Oxford University Press].

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plasmic transport (Figs. 6 and 7). Successive populations of peripheral nerve fibres subsequently undergo axonal degeneration. This begins with a low grade thermal loss of large myelinated axons, followed by small myelinated fibres. Finally in very severe cold lesions unmyelinated axons also degenerate (Basbaum, 1973; Nukada et al., 1981). Pathogenic mechanisms in nerve thermal injury

Fig. 4. An electron micrograph of a rat sciatic nerve, after high grade nerve heating, confirming extensive degeneration of unmyelinated fibres and of a small myelinated fibre, but preservation of the large myelinated fibre. Bar = 1 pm [from Xu and Pollock (1994), with kind permission of Oxford University Press].

The vasa nervorum arc particularly sensitive to nerve thermal injury. Blood nerve barrier function is impaired after both hyper and hypothermic nerve injury (Basbaum, 1973; Nukada et al., 1981; Xu and Pollock, 1994) (Fig. 8). Histological analysis of thermally injured nerve shows thromboses in endoneurial, perineurial, and epineurial (Denny-Brown et al., 1945; Lele, 1963; Xu and Pollock, 1994) (Fig. 9).

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Fig. 6. Block of fast axoplasmic transport by cold. A typical example is shown (filled circles) in which cold (5°C)was applied for 2 h to the rat sciatic nerve (filled arrow: proximal end of cooled nerve segment). The contralateral sciatic nerve (open circles) was ligated just prior to cooling contralateral nerve (open arrow: point of ligation) [from Nukada et al. (1981), with kind permission of Oxford University Press].

Synthesis of proteins that mediate thrombosis and fibronolysis are an integral function of endothelial cells. These products include von Willebrand Factor (vWF), thrombospondin (TSP), Tissue Plasminogen Activator (tPA) and Plasminogen Activator Inhibitor-1 (PAI-1). In an in vitro human endothelial model, levels of tPA, vWF, TSP and PAI-1 were measured between 37-43°C (Strother et al., 1986). TSP and vWF levels increased after 3 h at 41-43°C. PAI-1 levels rose and tPA decreased with increasing temperature. Prolonged exposure to 43°C reduced levels of both PAI-1 and tPA. These changes result in a prothrombotic tendency with heat injury. Clinical correlation of these observations was reported by Mustafa et al. (1985) in patients with heat stroke. In these patients activation of the coagulation

Fig. 7. Electron micrograph of transverse section from rat sciatic nerve 3 days after cold injury. The swollen axoplasm is filled with large membranous bodies suggesting arrest of axoplasmic flow. Bar = 0.5 p m [from Nukada et al. (19811,with kind permission of Oxford University Press].

system was evident as a disseminated intravascular coagulation syndrome. Endothelial integrity fails with heat injury (Ang and Dawes, 1994). This was illustrated using permeability to albumin and low density lipoprotein in an human endothelial model. That endothelial cells are critical in tissue injury should not be surprising since endothelial structural and synthetic integrity are correlated with tissue graft survival and reperfusion tissue damage (Nanney et al., 1983; Gao et al., 1991). Recent work in humans by Rydholm et al. (19951, concentrating on second messenger mechanisms for tPA and PAI-1 production in heat injury, suggests that catecholamines are not in-

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Fig. 8. Electron micrograph of transverse section through endoneural vessels of rat sciatic nerve. A, control. B, 7 days after cold injury. Note swelling of endothelial cell bodies, retraction of endothelial peripheral processes and lateral displacement of pericyte. Interstitial oedema separates a degenerating myelinated fibre from the endoneural capillary. Bars = 1.5 pm. BM = basement membrane. E = endothelial cell. P = pericyte. RBC = red blood cell [from Nukada et al. (1981).with kind permission of Oxford University Press].

volved in stimulation of these factors. However, thrombin has been shown to stimulate endothelial production of both tPA and PAI-1. This work suggests that physiological mechanisms explain thromboses and ischaemia in nerve thermal injury. comparable studies with cold injury using this model have not been reported, although Ungley and Blackwood (1942) observed no difficulty in obtaining venous or arterial blood from hypothermic limbs. Platelet abnormalities are well described in heat injury. In hyperthermic syndromes, thrombocytopenia may occur within 24 h and platelet microthrombi may be seen histologically in neural tissues (Stefanini, 1975; Chao et al., 1981). Early platelet changes are thought to be due to in-

travascular activation, and persistent changes to marrow injury and to the disseminated intravascular syndrome. In hypothermia, platelet numbers are reduced, due to sequestration in splanchnic areas, such as spleen and liver. This appears to be largely reversible with rewarming (Villalobos et al., 1958). In addition, platelets progressively lose their ability to aggregate, with none evident between 2 and 4°C (Kattlove et al., 1970). This state is also reversible and is likely to be due to the temperature sensitivity of platelet microtubules (Behnke, 1967). Thrombocytopenia may be found within an hour of birth in hypothermic neonates ( < 34°C) (Chadd and Gray, 1972). A coagulopathy is also evident in these children who have a high risk of haemorrhage, particularly into lung or brain, with a mortality greater than 50%. Yoshihara et al. (1985) have demonstrated increased fibrinolytic activity in this setting. The coagulation cascade is strikingly inhibited below 35"C, with prothrombin time and activated partial thromboplastin time more sensitive than thrombin time below 33°C (Reed et al., 1990). Johnston et al. (1994) calculated that hypothermia around 29"C, is equivalent to a major clotting disorder. They suggested that enzyme failure accounts for the differential sensitivity of the activated partial thromboplastin time to cold in view of the greater number of enzymes involved. Thermal injury may also alter the metabolic demand for oxygen. In heated tissue, metabolic rate increases proportionately (Goetz and Klawans, 1979; Simon, 1993) and this combined with the increased avidity of oxyhaemoglobin for oxygen may result in an hypoxic potential. Chemical mediators of tissue damage in thermal injury have been extensively debated. It is likely that a range of chemical substances are involved (Boykin et al., 1980; Wahl et al., 1988; Sharma et al., 1994). Mediators in brain, skin, and spinal cord have been reported (Sharma et al., 1992, 1994). Histamine, 5-hydroxytryptamine (5 HT), and prostaglandins exacerbate clinical and

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Fig. 9. A transverse section of rat sciatic nerve 2 days after low grade nerve heating showing widespread endoneural and epineural vascular thromboses. Bar = 800 p m [from Xu and Pollock (1994), with kind permission of Oxford University Press].

histological manifestations of heat injury in neural and vascular tissue. This appears to be via histamine-2 (H-2) and 5 HT-2 receptors. The clinical and histological effects of thermal injury are attenuated by prior administration of the specific inhibitors, cimetidine and ketaserine (Sharma et al., 1994). Boykin et al. (1980) suggest histamine mediates the delayed distant effects of heat injury via H-2 receptors. They demonstrated that histamine depletion or cold, applied immediately to a heated area, have a similar effect, both locally and at a distance, to that of an H-2 antagonist. Thus the above evidence suggests a variety of mediators are responsible for nerve thermal injury. Analysis of these principal chemical mediators is awaited in peripheral nerve, but there is considerable encouragement from work already accomplished in heat injured brain and spinal cord (Wahl et al., 1988; Sharma et al., 1992, 1993, 1994). Immediate effects pertain to conformational alterations of nerve structure. Later ischaemic

changes are mediated by injured endothelium and the inflammatory cascade. In clinical cold injury, the temporal course of symptoms and histological change suggests a breakdown in the blood-nerve barrier and possibly re-perfusion injury. This response is seen in organ transplantation and tissue allografts where survival and successful function is closely correlated to endothelial integrity (Nanney et al., 1983; Gao et al., 1991). In contrast, activation of the coagulation-platelet-endothelial system is more likely in heat injury. There is an underlying theme in the literature of thermal injury that despite a diversity of syndromes there is a single unifying pathological entity of nerve ischaemia. This is the result of the exquisite sensitivity of the vasa nervorum to variations in temperature. Future research into nerve thermal injuries should therefore be directed at strategies which protect endothelial cells or reverse intimal damage. If successful, such strategies are likely to greatly advance treatment options for these disabling disorders.

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