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Peripheral neuropathy caused by severe hypothermia
Clinical Neurophysiology 124 (2013) 1019–1024
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Peripheral neuropathy caused by severe hypothermia S. Løseth a,b,⇑, A. Bågenholm c, T. Torbergsen a, E. Stålberg d a
Department of Neurology and Neurophysiology, University Hospital of North Norway, 9038 Tromsø, Norway Department of Clinical Medicine, University of Tromsø, Norway c Department of Radiology, University Hospital of North Norway, Tromsø, Norway d Department of Clinical Neurophysiology, Institute of Neurosciences, Uppsala University, Sweden b
a r t i c l e
i n f o
Article history: Accepted 5 November 2012 Available online 7 December 2012 Keywords: Hypothermia Neuropathy Cold injury Peripheral nerves Critical illness
h i g h l i g h t s A victim of deep accidental deep hypothermia developed a severe sensorimotor neuropathy with mainly involvement of large diameter nerve fibers. There was a dramatic clinical improvement over the first years, leading to a good restitution. Eleven years of follow-up studies have shown improvement of neurophysiological parameters especially during the first 5 years.
a b s t r a c t Objective: To report follow-up data in the evaluation of peripheral neuropathy in a 29-year old female after accidental deep hypothermia (13.7 °C) in 1999. Methods: Nerve conduction studies (NCS) and electromyography (EMG) were performed 20 days after the accident and again after 5 months and 1, 3, 5 and 11 years. Macro EMG was performed after 3, 5 and 11 years. To evaluate small fiber function, RR-interval, sympathetic skin response, quantitative sensory testing and skin biopsy for quantification of intra-epidermal nerve fiber density were performed in 2009. Results: In the intensive care unit sensory and motor responses were absent except for the tibial nerves, and EMG showed profuse denervation. Improvement of amplitudes and conduction velocities was seen during the first 5 years. Muscular atrophy of hand muscles persisted. Large fibers were involved more extensively than small fibers. Conclusions: A severe axonal sensorimotor polyneuropathy developed in the intensive care unit following severe hypothermia. The mechanism was most likely cold injury to peripheral nerves. Significance: The clinical picture and the laboratory findings indicate that even multi-organ dysfunction and, of specific interest in this study, a severe axonal degeneration may come to a good restitution after long time. Ó 2012 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.
1. Introduction There are different types of neuropathies caused by cold. Frostbite is a local cold injury that occurs in dry conditions at temperature below freezing point. Ice crystals form in and between cells, and tissue necrosis occurs as a result of direct cellular injury and vascular impairment (Heggers et al., 1987; Goertz et al., 2011). Mountaineers are one of the major groups at risk (Harirchi et al., 2005), but the condition is also seen in soldiers and civilians (Ward, 1974).
⇑ Corresponding author. Address: Department of Neurology and Neurophysiology, University Hospital of North Norway, 9038 Tromsø, Norway. Tel.: +47 776 27106; fax: +47 776 27074. E-mail address: [email protected] (S. Løseth).
Non-freezing local cold injury is reported in individuals after prolonged exposure (most often of the lower limbs) to a wet environment just above freezing point. The condition, also called ‘‘trench foot’’ or ‘‘immersion foot’’, is classically seen in soldiers, but is also reported in sportsmen and the homeless (Irwin et al., 1997). Peripheral neuropathy is a prominent feature, and axonal degeneration has been demonstrated in animal experiments (Irwin, 1996). Symptoms and clinical signs of peripheral neuropathy following generalized deep hypothermia (core temperature <28 °C) have been reported in only a few cases (Winegard, 1997; Walpoth et al., 1997). However, electrophysiological findings in these individuals have not been described. We describe a woman with accidental very deep hypothermia who developed pronounced peripheral axonal neuropathy. Results
1388-2457/$36.00 Ó 2012 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.clinph.2012.11.002
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from neurophysiologic follow-up studies for more than 10 years are presented. 2. Subject and methods 2.1. Subject In May 1999, a 29 year old female junior medical registrar fell through a frozen river waterfall gully when skiing. She became trapped in the ice-cold water with her head submerged in the water and her skis on the surface of the frozen river. Her friends tried in vain to pull her out with a rope tied around her left ankle. She stopped moving after 40 min. She was eventually successfully pulled out of the water through a hole which was cut in the ice after 80 min. She was found to be clinically dead, and resuscitation was immediately started. On admission to hospital, approximately 2 h later, she was connected to a cardiopulmonary bypass machine, and slowly warmed. Her lowest rectal temperature measured at the hospital was 13.7 °C (56.7 °F), which to our knowledge is the lowest temperature reported in a surviving patient. (Lampe and Becker, 2011). She had cardiac arrest for approximately 3 h and developed transitory multi-organ failure. A more detailed description of the resuscitation and treatment in the intensive care unit has been reported previously (Gilbert et al., 2000). All sedation was stopped after 2 weeks, and she mentally made a full recovery. However, she had almost complete paralysis in both arms and legs with weak proximal movements. Her EEG was normal, and an MRI of the brain showed only minimal frontal white matter abnormalities. She required respiratory assistance for the next 35 days. Her physical condition gradually improved, especially during the first 1½ years. After 4 months she had regained some strength in her truncal and in the proximal muscles of both arms and legs. However, the distal muscles, especially in the arms (thenar, hypothenar, intrinsic hand muscles, wrist extensors and flexors) were very weak with symmetrical atrophy. She could walk without aid, but had a bilateral drop-foot which was most pronounced on the left side. Stretch reflexes were absent. She had considerably reduced touch and pressure sensibility distally in the upper limbs and to a much lesser degree in her feet. Pain and temperature sensibility were almost normal. She was able to ski 6 months after the accident, but she had to tape her hands to the ski poles. Her skiing boots gave her excellent stability, but she had great difficulty putting them on. In June 2000 there was still pronounced atrophy and weakness of hand and distal arm muscles, but in the lower limbs there was only a slight drop-foot on the left side. She complained of cold intolerance and had hyperesthesia for light touch distally in both arms and legs (a feeling of ‘‘sparkling water running down the skin’’). Stretch reflexes were now present, but reduced. She
started to work again part time from January 2001 and full-time from February 2002. She had, however, to change medical specialty from surgery to radiology because the strength of her hand grip and wrist extension/flexion was still severely reduced. Three years after the accident the strength of her hand grip had improved. In the following years she has felt progressively stronger, but clinical neurological findings have been almost unchanged. There remains a clear difference between findings in the upper and lower limbs and as there is still severe muscle atrophy of the hand muscles (Fig 1). She is now very active in sports but complains of reduced endurance and reduced capacity to withstand cold temperatures, especially in her hands. Cardiopulmonary function has been evaluated several times and showed that she has developed a mild asthma. Echocardiography has been normal. Blood pressure (BP) was low during the first 2–3 years (e.g. 95/60 in 2001), and she complained of orthostatic symptoms. A 24 h ECG recording in 2003 showed bradycardia (40/ min) with episodic sinus tachycardia (179/min). Her BP and heart rate have subsequently been normal. She also developed some gastrointestinal problems with episodes of diarrhea and a slight anal sphincter dysfunction which lasted for 2 years after the accident. 2.2. Methods Nerve conduction studies (NCS) and electromyography (EMG) were performed on Keypoint equipment (Medtronic, Copenhagen) in the intensive care unit (day 20) and at several follow-up studies (in 1999, 2000, 2002, 2004 and 2010). Motor and sensory nerves in at least one leg and one arm were tested using surface electrodes for stimulation and recording. The following parameters were measured: compound muscle action potential (CMAP) amplitude and shape, sensory nerve action potential (SNAP) amplitude, motor and sensory conduction velocities (CV), F-wave minimal latencies and late components after the CMAP. EMG investigation included analysis of spontaneous activity, quantitative motor unit potential (MUP) analysis and interference patterns in several muscles. Macro EMG was performed in 2002, 2004 and 2010 in the right tibialis anterior and vastus lateralis muscles according to published description (Stålberg, 1980). To evaluate small fiber involvement, the following tests were performed in 2009: sympathetic skin response (SSR) with recordings in both hands and feet and stimulations with loud sounds, RR-interval (during normal and deep breathing), quantitative sensory testing (QST) with detection of warmth and cold perception thresholds on the dorsum of the foot, distal part of the leg and laterally on the thigh (right side) and skin biopsy obtained from the right leg for quantification of intra-epidermal nerve fiber (IENF) density. The methods for QST and IENF density have been described in detail elsewhere (Løseth et al., 2006). For all quantitative parameters, reference values used in the laboratory routine have been used. The patient has given her acceptance to this publication, and is one of the co-authors. 3. Results 3.1. NCS
Fig. 1. Atrophy of hand muscles 11 years after the accident.
3.1.1. Motor NCS Data of amplitudes and MCVs in motor nerves at different time points are presented in Table 1. At the first investigation (day 20), no responses were obtained except for a response of 8 mV CMAP and 50 m/s motor conduction velocity (MCV) from the tibial nerve (left side investigated). The amplitudes increased during the first 5 years. MCVs were on the order of 15–45 m/s. The stimulation
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S. Løseth et al. / Clinical Neurophysiology 124 (2013) 1019–1024 Table 1 Serial changes of compound muscle action potential amplitudes (mV) and conduction velocities (m/s). NCS of the tibial nerves have been normal are and not included. 1 month
5 months
1 year
3 years
5 years
11 years
0
0
0
0.3 27
0.6 28
1.1 27
0.01 31
0.2 24
1.7 25
3.5 31
0.1 36
1.5 26
3.4 28
3.7 38
0.2 49
3.2 48
5.1 30
5.1 46
0.5 42
0.4 44
0.7 46
0.7 47
0.01 16
0.1 19
0.4 29
0.3 26
Medianus dx
Amp CV
Medianus sin
Amp CV
Ulnaris dx
Amp CV
0
Ulnaris sin
Amp CV
0
Fibularis dx
Amp CV
Fibularis sin
Amp CV
0
0.01 30
0
Amp, amplitude; CV, conduction velocity.
thresholds were considerably increased (data not shown), and there were abundant late responses. Some of these were A-waves, i.e. indirect double discharges (Fig. 2a), others were probably slow conducting individual axons, seen as CMAP satellites both with distal and proximal stimulation (Fig. 2b). They moved with the main CMAP at different stimulation sites. Distal latencies, especially in median nerves, were initially on the order of 10–15 ms, improving until 2010 to 4–5 ms. No F-waves were obtained in studies performed during the first 5 years except in the tibial nerves. In later studies, F-waves were seen, particularly in the median and ulnar nerves, but still A-waves were present. All the time NCS of both tibial nerves have been normal (amplitudes, MCV and F-responses).
(a)
3.1.2. Sensory NCS Ulnar, median, radial and sural nerves were studied either unilaterally or bilaterally, and data are presented in Table 2. No responses were obtained until after 10 months when a small response was seen in the left sural nerve and after 26 months in the left radial nerve. The ulnar and median responses reappeared after 3 years. The sensory conduction velocities were initially on the order of 30 m/s with a partial recovery over 5 years. 1 div
3.2. EMG
0.5 mV/Div, 5.0 ms/Div
(b)
wrist
below elbow
above elbow
Fig. 2. Stimulating the right ulnar nerve and recording from the abductor digiti minimi muscle. (a) Late components with distal stimulation. When the stimulation electrode is moved 25 mm proximally, CMAP latency is increased (small arrows), but some of the late components appear with shorter latency (large arrows) indicating that they are generated proximal to the stimulation site – A waves (indirect double discharges). (b) NCS showing slowing of CV, late components also at proximal stimulation and dispersion of the main CMAP complex.
3.2.1. Concentric needle EMG At the first investigation (day 20) there was abundant spontaneous activity (fibrillation potentials and positive sharp waves, psws) in all tested muscles: extensor digitorum (ED), interosseus dorsalis I (IOD I), vastus lateralis (VL), tibialis anterior (TA) and gastrocnemius medialis (GM) bilaterally. There was no voluntary activity except in VL and GM (GM was only tested again in 2010). At day 30 there were a few MUPs in ED and TA, but not in IOD I. After 4.5 months there was still denervation activity in all muscles (this time also the right deltoideus was investigated). There was re-innervation activity with instability and polyphasia, especially in TA (only a few MUPs in TA with low amplitude, mean amplitude 200 lV). After 10 months there was less spontaneous activity in ED, and the MUPs were more stable with higher amplitudes. For the first time a few MUPs could be recorded in IOD I on the right side, and after 26 months also on the left side. There were still fibrillation potentials and psws in hand muscles in all needle positions, and the interference pattern was severely reduced. After 3 years (in 2002) there was less spontaneous activity in most muscles, and the MUPs were more stable. In 2004 fibrillation potentials and psws were only present in IOD I and distal part of TA, and not in ED, VL and deltoideus. MUPs
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Table 2 Serial changes of sensory nerve action potential amplitudes (lV) and conduction velocities (m/s). 1 month
5 months
1 year
3 years
5 years
11 years
0
0
0
13 32
22 38
46 44
0
3 28
19 38
9 47
0
3 26
5 35
11 40
0
1 20
7 36
5 43
0
3 39
3 44
0.6 39
5 41
3 45
0
0
4 32
0
0
3 36
Medianus dx
Amp CV
Medianus sin
Amp CV
Ulnaris dx
Amp CV
0
Ulnaris sin
Amp CV
0
Radialis dx
Amp CV
0
Radialis sin
Amp CV
Suralis dx
Amp CV
Suralis sin
Amp CV
0
0
0
0
0.7 39
Amp, amplitude; CV, conduction velocity.
3.2.2. Macro EMG Median amplitudes of macro potentials in the right TA and VL were normal in 2002 and 2004, but considerably increased in 2010 (Table 3). 3.3. Small diameter nerve fiber testing SSR and RR-interval were normal. QST showed borderline thresholds for warmth and cold, especially at the leg (warm perception threshold 40.3 °C and cold perception threshold 26.2 °C). The quality of the temperature sensations was normal. IENF density was borderline (6.0 fibers/mm). 4. Discussion
Fig. 3. Changes in MUP amplitudes over time. Values are given as the mean amplitude of approximately 20 MUPs in each muscle. ED, extensor digitorum; IOD I, interosseus dorsalis I; TA, tibialis anterior; VL, vastus lateralis.
were polyphasic. MUP amplitudes (especially in distal muscles) could vary in different sites of the muscle from below the normal limit to high, while the mean amplitudes in these muscles were increased (Fig 3). With time the interference pattern became denser. In 2010 fibrillation potentials and positive sharp waves were still seen in all needle positions in IOD I, and some instability in MUPs was still present in this muscle and in TA. EMG in VL and deltoideus in 2004 and 2010 and in GM in 2010 was almost normal (slight increased polyphasia). In 2010 the highest MUP amplitude in IOD I was 12 mV, in ED 4 mV and in TA 6 mV.
Table 3 Amplitudes of 20 macro potentials at different times (years after the accident). Median lV (times normal).
Tibialis ant dx Vastus lat dx
3 years
5 years
11 years
178 (1.12) 196 (1.25)
202 (1.27) 244 (1.56)
1856 (8.97) 536 (3.55)
We describe clinical and neurophysiological studies in this unique patient with very deep accidental hypothermia who developed a severe neuropathy. She has now been followed for 11 years. At the ICU she woke up almost paralyzed in her arms and legs, with only some movements in proximal muscles. She recovered clinically especially during the first 1–2 years. The most serious sequela has been persistent weakness and atrophy of her hand muscles. NCS and EMG were performed several times during the first year, and after 3, 5 and 11 years. Initial EMG showed profuse amount of fibrillation potentials and psws, interpreted as signs of denervation. No motor or sensory responses were obtained on NCS except for a normal motor response from the tibial nerve. These findings were consistent with a pronounced axonal sensorimotor polyneuropathy, but with almost sparing of the tibial nerves. Both motor and sensory amplitudes increased during the first 5 years, but have not normalized. Distal latencies and MCVs also improved, but are still abnormal in most nerves. Slow velocity indicates dysmyelination and probably also axonal atrophy, expected in recovery after severe axonal degeneration. The time–course and pattern of recovery are probably not specific to cold injury, and are also seen in severe axonal neuropathy due to other causes (Tamura et al., 2007). CMAP-responses have shown abundant late components, some of which were generated in the nerve, so called indirect double discharges. Other late components were CMAP satellites, due to slowly conducting axons distally. Nerve excitability tested as stimulus response amplitude curve was severely reduced initially, and was not tested at later visits.
S. Løseth et al. / Clinical Neurophysiology 124 (2013) 1019–1024
During the first 5 years concentric needle EMG showed increasing MUP amplitudes, and the interference pattern became denser but did not normalize. Recovery progressed from proximal to distal sites. Reinnervation potentials in some muscles (especially TA) or in some muscle sites had initially very low amplitude indicating axonal re-growth, rather than collateral sprouting (Stålberg et al., 2010). Still after 11 years spontaneous activity was present in hand muscles but the motor units that could be activated were enlarged due to the reinnervation process. Macro EMG, measuring the size of the motor unit (size and number of muscle fibers) performed in VL and TA showed median amplitudes within normal limits in 2002 and 2004. Later the macro amplitudes increased and were up to 9 times normal in 2010 in TA and more than 3 times normal in VL. This could indicate incomplete reinnervation and persistence of atrophic muscle fibers in 2002 and 2004. Later continued reinnervation and possibly increase in muscle fiber diameters give large macro MUPs signals in 2010, corresponding to improved muscle strength. There could be at least two possible mechanisms for developing neuropathy in this patient: critical illness and cold injury with axonal damage. In addition local injuries due to traction of nerves in connection with the rescue and resuscitation could also be present as a separate local cause. Critical illness polyneuropathy (CIP) is an acute diffuse primarily axonal sensorimotor neuropathy commonly seen in critically ill patients with sepsis or multiple organ failure. The condition can be seen alone or in combination with critical illness myopathy (Hund, 2001; Zink et al., 2009). The distribution of CIP is symmetrical, and mainly nerves of the lower limbs are affected. The pathophysiology is complex and still not fully understood, but includes disturbed microcirculation and toxic effects of cytokines in sepsis (Zink et al., 2009). The prognosis depends on the severity of the critical illness. Follow-up studies have shown that persisting motor and sensory disabilities are common (Fletcher et al., 2003; Guarneri et al., 2008). Our patient had risk factors for developing CIP since she suffered from multi-organ failure and needed prolonged ventilatory support. However, she did not develop sepsis which is known as one of the major risk factors (Zink et al., 2009). The other alternative to the condition is a cold induced axonal damage. A few findings point to cold induced damage, rather than a systemic CIP. The lower limbs were involved to a lesser degree than the upper, and persistent weakness and atrophy are mostly present in the hands. Secondly, there is a variation between nerves. Both tibial nerves were almost spared (normal NCS including F-responses), although EMG at the ICU showed spontaneous activity in the gastrocnemius muscles indicating some axonal damage. These patchy patterns of nerve involvements could be explained by cold induced neuropathy rather than CIP. More involvement of the upper limbs could be caused by her body posture in the river. Her feet and legs were partially above the ice during the effort to rescue her, while her hands/arms were constantly submersed in the ice-cold running water. The reason for the very limited affection of the tibial nerves could be their deeper location in the legs compared to the fibular nerves. This could also be an explanation for the lesser involvement of proximal nerves. She developed bilateral drop-foot which clinically was most pronounced on the left side. One reason for this asymmetry could be a traction injury. Her friends tried to pull her up with a rope tied around her left ankle, and the left knee was sometimes squeezed against the edge of the ice. Despite the fact that the degrees of abnormalities of the fibular nerves on EMG and NCS examinations were symmetrical a superimposed traction trauma cannot be excluded. There are only a few literature reports on neurophysiologic findings in accidental generalized hypothermia-induced neuropathy. One report describes serial electrophysiological studies in a child with accidental hypothermia (body temperature 32.2 °C) (Afifi
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et al., 1988). He was found asystolic on ice covered water lying with his face down. Spontaneous pulse and respiration recurred after 1½ h, and he was weaned from the respirator after 30 h. Due to difficulties in walking and weakness in the arms NCS was performed on day 9. There were no responses in the median, tibial or fibular nerves. On EMG examination there were a few motor unit potentials in proximal muscles and some fibrillation potentials. Muscle strength gradually improved, and after 10 months he had recovered completely, and NCS and EMG were normal. The authors’ conclusion was a full recovery from severe axonopathy. We would like to add the following comment. In some muscles they found no fibrillation potentials and psws (e.g. IOD after 9 days) combined with absent voluntary activity. At 10 months EMG was normal in this muscle without reinnervation activity. This combination of findings could indicate conduction block rather than axonal degeneration in this nerve. In our case, reduced excitability is compatible with hypomyelination and probably also axonal abnormality. Collier et al. (2012) report a similar case. A 6-year old girl was successfully resuscitated after drowning in an ice-covered stock pond. The lowest body temperature measured at the hospital was 28.9 °C (84 °F). The condition was considered to be cold induced axonal polyneuropathy rather than critical illness neuropathy. She was followed for 1 year. Initially EMG showed fibrillation potentials and psws and reduced recruitment. Signs of reinnervation were seen after 28 weeks. NCS demonstrated absent motor and sensory responses until 1 year after the accident when small responses in some nerves were noted. Although EMG and NCS remained abnormal, her clinical outcome was excellent. Still another report describes a 26 year-old man who was found unconscious 3 h after a car accident in a ditch filled with icy water (Peyronnard et al., 1978). He was hypothermic (body temperature not reported). He developed weakness and atrophy of small muscles of hands and feet and distal hypoesthesia. Initially sensory action potentials were absent, but motor CVs were within normal ranges although distal latencies were prolonged (amplitudes not reported). On EMG there was spontaneous activity predominantly in hand and foot muscles, and after some months there were signs of reinnervation. Sural biopsy showed findings consistent with an axonal neuropathy with greatest loss of large diameter nerve fibers. He had recovered almost fully after 19 months and had only some hyperesthesia in fingers and feet. In one study of 15 patients with deep hypothermia, clinical signs of focal nerve lesions or plexus lesions were present in 3, but NCS or EMG results are not reported (Walpoth et al., 1997). Other more recent reports regarding outcome after severe hypothermia do not focus on complications from the peripheral nervous system (Vassal et al., 2001; Silfvast and Pettila, 2003; Van Der Ploeg et al., 2010). The mechanisms of cold injury to peripheral nerves are mostly studied in non-freezing cold injury (‘‘trench foot’’). The basic mechanism is thought to be direct axonal damage due to ischemia– reperfusion injury (Irwin, 1996). Animal experiments on rabbit hind limbs exposed 16 h to cold water immersion at temperature just above freezing concluded that large myelinated nerve fibers were preferentially damaged (Irwin, 1996). Others have also shown almost selective involvement of large diameter nerve fibers (Peyronnard et al., 1978; Nukada et al., 1981; Kennett and Gilliatt, 1991). However, cold hypersensitivity and cold allodynia are frequent symptoms, but mechanisms are not fully understood (Irwin, 1996; Namer et al., 2008). In our patient the major symptoms and findings were motor impairment and to a much lesser extent sensory symptoms consistent with large fiber dysfunction (paresthesia, hypoesthesia). However, she also developed symptoms and signs of small fiber involvement. During the first years she had autonomic dysfunction with arrhythmia, sweating and gastrointestinal dysfunction. She also reported cold intolerance, but no neuropathic pain. Small fiber tests (QST and IENF density) were
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not performed until 10 years after the accident. These showed borderline values in contrast to signs of more abnormal large fiber function (motor and sensory NCS recorded from the same area). RR-interval and SSR were normal while the patient had autonomic symptoms. In conclusion the patient has a sensorimotor axonal neuropathy with secondary dysmyelination after severe hypothermia. This is probably due to a direct effect of cold on the axons, but a component of critical illness polyneuropathy cannot be excluded. Her physical recovery has been good although weakness and atrophy have persisted in distal muscles. Neurophysiological investigations have shown findings suggestive of an on-going reinnervation process during a period of at least 5 years. References Afifi AK, Kimura J, Bell WE. Hypothermia-induced reversible polyneuropathy: electrophysiologic evidence of axonopathy. Pediatr Neurol 1988;4:49–53. Collier T, Patel A, Rinaldi R. Hypothermia-induced peripheral polyneuropathy after an episode of drowning. PM R 2012;3:230–3. Fletcher SN, Kennedy DD, Ghosh IR, Misra VP, Kiff K, Coakley JH, et al. Persistent neuromuscular and neurophysiologic abnormalities in long-term survivors of prolonged critical illness. Crit Care Med 2003;31:1012–6. Gilbert M, Busund R, Skagseth A, Nilsen PA, Solbo JP. Resuscitation from accidental hypothermia of 13.7 °C with circulatory arrest. Lancet 2000;355:375–6. Goertz O, Baerreiter S, Ring A, Jettkant B, Hirsch T, Digeler A, et al. Determination of microcirculatory changes and angiogenesis in a model of frostbite injury in vivo. J Surg Res 2011;168:155–61. Guarneri B, Bertolini G, Latronico N. Long-term outcome in patients with critical illness myopathy or neuropathy: the Italian multicentre CRIMYNE study. J Neurol Neurosurg Psychiatry 2008;79:838–41. Harirchi I, Arvin A, Vash JH, Zafarmand V. Frostbite: incidence and predisposing factors in mountaineers. Br J Sports Med 2005;39:898–901. Heggers JP, Robson MC, Manavalen K, Weingarten MD, Carethers JM, Boertman JA, et al. Experimental and clinical observations on frostbite. Ann Emerg Med 1987;16:1056–62. Hund E. Neurological complications of sepsis: critical illness polyneuropathy and myopathy. J Neurol 2001;248:929–34. Irwin MS. Nature and mechanism of peripheral nerve damage in an experimental model of non-freezing cold injury. Ann R Coll Surg Engl 1996;78:372–9.
Irwin MS, Sanders R, Green CJ, Terenghi G. Neuropathy in non-freezing cold injury (trench foot). J R Soc Med 1997;90:433–8. Kennett RP, Gilliatt RW. Nerve conduction studies in experimental non-freezing cold injury: II. Generalized nerve cooling by limb immersion. Muscle Nerve 1991;14:960–7. Lampe JW, Becker LB. State of the art in therapeutic hypothermia. Annu Rev Med 2011;62:79–93. Løseth S, Lindal S, Stålberg E, Mellgren SI. Intraepidermal nerve fibre density, quantitative sensory testing and nerve conduction studies in a patient material with symptoms and signs of sensory polyneuropathy. Eur J Neurol 2006;13:105–11. Namer B, Kleggetveit IP, Handwerker H, Schmelz M, Jørum E. Role of TRPM8 and TRPA1 for cold allodynia in patients with cold injury. Pain 2008;139:63–72. Nukada H, Pollock M, Allpress S. Experimental cold injury to peripheral nerve. Brain 1981;104:779–811. Peyronnard JM, Pedneault M, Aguayo AJ. Neuropathies due to cold: quantitative studies of structural changes in human and animal nerves. In: Den Hartog Jager WA, Bruyn GW, Heijstee APJ, editors. Neurology. International congress series No. 434. Amsterdam: Excerpta Medica; 1978. p. 308–29. Silfvast T, Pettila V. Outcome from severe accidental hypothermia in southern Finland: a 10-year review. Resuscitation 2003;59:285–90. Stålberg E, Macro EMG. A new recording technique. J Neurol Neurosurg Psychiatry 1980;43:475–82. Stålberg E, Trontelj J, Sanders D. Neurogenic disorders. In: Stålberg E, Trontelj J, Sanders D, editors. Single fiber EMG. 3rd ed. Fiskebäkskil, Sweden: Edshagen Publishing House; 2010. p. 195–217. Tamura N, Kuwabara S, Misawa S, Kanai K, Nakata M, Sawai S, et al. Time course of axonal regeneration in acute motor axonal neuropathy. Muscle Nerve 2007;35:793–5. Van Der Ploeg GJ, Goslings JC, Walpoth BH, Bierens JJ. Accidental hypothermia: rewarming treatments, complications and outcomes from one university medical centre. Resuscitation 2010;81:1550–5. Vassal T, Benoit-Gonin B, Carrat F, Guidet B, Maury E, Offenstadt G. Severe accidental hypothermia treated in an ICU: prognosis and outcome. Chest 2001;120:1998–2003. Walpoth BH, Walpoth-Aslan BN, Mattle HP, Radanov BP, Schroth G, Schaeffler L, et al. Outcome of survivors of accidental deep hypothermia and circulatory arrest treated with extracorporeal blood warming. New Engl J Med 1997;337:1500–5. Ward M. Frostbite. Br Med J 1974;1:67–70. Winegard C. Successful treatment of severe hypothermia and prolonged cardiac arrest with closed thoracic cavity lavage. J Emerg Med 1997;15:629–32. Zink W, Kollmar R, Schwab S. Critical illness polyneuropathy and myopathy in the intensive care unit. Nat Rev Neurol 2009;5:372–9.
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Clinical Neurophysiology journal homepage: www.elsevier.com/locate/clinph
Peripheral neuropathy caused by severe hypothermia S. Løseth a,b,⇑, A. Bågenholm c, T. Torbergsen a, E. Stålberg d a
Department of Neurology and Neurophysiology, University Hospital of North Norway, 9038 Tromsø, Norway Department of Clinical Medicine, University of Tromsø, Norway c Department of Radiology, University Hospital of North Norway, Tromsø, Norway d Department of Clinical Neurophysiology, Institute of Neurosciences, Uppsala University, Sweden b
a r t i c l e
i n f o
Article history: Accepted 5 November 2012 Available online 7 December 2012 Keywords: Hypothermia Neuropathy Cold injury Peripheral nerves Critical illness
h i g h l i g h t s A victim of deep accidental deep hypothermia developed a severe sensorimotor neuropathy with mainly involvement of large diameter nerve fibers. There was a dramatic clinical improvement over the first years, leading to a good restitution. Eleven years of follow-up studies have shown improvement of neurophysiological parameters especially during the first 5 years.
a b s t r a c t Objective: To report follow-up data in the evaluation of peripheral neuropathy in a 29-year old female after accidental deep hypothermia (13.7 °C) in 1999. Methods: Nerve conduction studies (NCS) and electromyography (EMG) were performed 20 days after the accident and again after 5 months and 1, 3, 5 and 11 years. Macro EMG was performed after 3, 5 and 11 years. To evaluate small fiber function, RR-interval, sympathetic skin response, quantitative sensory testing and skin biopsy for quantification of intra-epidermal nerve fiber density were performed in 2009. Results: In the intensive care unit sensory and motor responses were absent except for the tibial nerves, and EMG showed profuse denervation. Improvement of amplitudes and conduction velocities was seen during the first 5 years. Muscular atrophy of hand muscles persisted. Large fibers were involved more extensively than small fibers. Conclusions: A severe axonal sensorimotor polyneuropathy developed in the intensive care unit following severe hypothermia. The mechanism was most likely cold injury to peripheral nerves. Significance: The clinical picture and the laboratory findings indicate that even multi-organ dysfunction and, of specific interest in this study, a severe axonal degeneration may come to a good restitution after long time. Ó 2012 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.
1. Introduction There are different types of neuropathies caused by cold. Frostbite is a local cold injury that occurs in dry conditions at temperature below freezing point. Ice crystals form in and between cells, and tissue necrosis occurs as a result of direct cellular injury and vascular impairment (Heggers et al., 1987; Goertz et al., 2011). Mountaineers are one of the major groups at risk (Harirchi et al., 2005), but the condition is also seen in soldiers and civilians (Ward, 1974).
⇑ Corresponding author. Address: Department of Neurology and Neurophysiology, University Hospital of North Norway, 9038 Tromsø, Norway. Tel.: +47 776 27106; fax: +47 776 27074. E-mail address: [email protected] (S. Løseth).
Non-freezing local cold injury is reported in individuals after prolonged exposure (most often of the lower limbs) to a wet environment just above freezing point. The condition, also called ‘‘trench foot’’ or ‘‘immersion foot’’, is classically seen in soldiers, but is also reported in sportsmen and the homeless (Irwin et al., 1997). Peripheral neuropathy is a prominent feature, and axonal degeneration has been demonstrated in animal experiments (Irwin, 1996). Symptoms and clinical signs of peripheral neuropathy following generalized deep hypothermia (core temperature <28 °C) have been reported in only a few cases (Winegard, 1997; Walpoth et al., 1997). However, electrophysiological findings in these individuals have not been described. We describe a woman with accidental very deep hypothermia who developed pronounced peripheral axonal neuropathy. Results
1388-2457/$36.00 Ó 2012 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.clinph.2012.11.002
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from neurophysiologic follow-up studies for more than 10 years are presented. 2. Subject and methods 2.1. Subject In May 1999, a 29 year old female junior medical registrar fell through a frozen river waterfall gully when skiing. She became trapped in the ice-cold water with her head submerged in the water and her skis on the surface of the frozen river. Her friends tried in vain to pull her out with a rope tied around her left ankle. She stopped moving after 40 min. She was eventually successfully pulled out of the water through a hole which was cut in the ice after 80 min. She was found to be clinically dead, and resuscitation was immediately started. On admission to hospital, approximately 2 h later, she was connected to a cardiopulmonary bypass machine, and slowly warmed. Her lowest rectal temperature measured at the hospital was 13.7 °C (56.7 °F), which to our knowledge is the lowest temperature reported in a surviving patient. (Lampe and Becker, 2011). She had cardiac arrest for approximately 3 h and developed transitory multi-organ failure. A more detailed description of the resuscitation and treatment in the intensive care unit has been reported previously (Gilbert et al., 2000). All sedation was stopped after 2 weeks, and she mentally made a full recovery. However, she had almost complete paralysis in both arms and legs with weak proximal movements. Her EEG was normal, and an MRI of the brain showed only minimal frontal white matter abnormalities. She required respiratory assistance for the next 35 days. Her physical condition gradually improved, especially during the first 1½ years. After 4 months she had regained some strength in her truncal and in the proximal muscles of both arms and legs. However, the distal muscles, especially in the arms (thenar, hypothenar, intrinsic hand muscles, wrist extensors and flexors) were very weak with symmetrical atrophy. She could walk without aid, but had a bilateral drop-foot which was most pronounced on the left side. Stretch reflexes were absent. She had considerably reduced touch and pressure sensibility distally in the upper limbs and to a much lesser degree in her feet. Pain and temperature sensibility were almost normal. She was able to ski 6 months after the accident, but she had to tape her hands to the ski poles. Her skiing boots gave her excellent stability, but she had great difficulty putting them on. In June 2000 there was still pronounced atrophy and weakness of hand and distal arm muscles, but in the lower limbs there was only a slight drop-foot on the left side. She complained of cold intolerance and had hyperesthesia for light touch distally in both arms and legs (a feeling of ‘‘sparkling water running down the skin’’). Stretch reflexes were now present, but reduced. She
started to work again part time from January 2001 and full-time from February 2002. She had, however, to change medical specialty from surgery to radiology because the strength of her hand grip and wrist extension/flexion was still severely reduced. Three years after the accident the strength of her hand grip had improved. In the following years she has felt progressively stronger, but clinical neurological findings have been almost unchanged. There remains a clear difference between findings in the upper and lower limbs and as there is still severe muscle atrophy of the hand muscles (Fig 1). She is now very active in sports but complains of reduced endurance and reduced capacity to withstand cold temperatures, especially in her hands. Cardiopulmonary function has been evaluated several times and showed that she has developed a mild asthma. Echocardiography has been normal. Blood pressure (BP) was low during the first 2–3 years (e.g. 95/60 in 2001), and she complained of orthostatic symptoms. A 24 h ECG recording in 2003 showed bradycardia (40/ min) with episodic sinus tachycardia (179/min). Her BP and heart rate have subsequently been normal. She also developed some gastrointestinal problems with episodes of diarrhea and a slight anal sphincter dysfunction which lasted for 2 years after the accident. 2.2. Methods Nerve conduction studies (NCS) and electromyography (EMG) were performed on Keypoint equipment (Medtronic, Copenhagen) in the intensive care unit (day 20) and at several follow-up studies (in 1999, 2000, 2002, 2004 and 2010). Motor and sensory nerves in at least one leg and one arm were tested using surface electrodes for stimulation and recording. The following parameters were measured: compound muscle action potential (CMAP) amplitude and shape, sensory nerve action potential (SNAP) amplitude, motor and sensory conduction velocities (CV), F-wave minimal latencies and late components after the CMAP. EMG investigation included analysis of spontaneous activity, quantitative motor unit potential (MUP) analysis and interference patterns in several muscles. Macro EMG was performed in 2002, 2004 and 2010 in the right tibialis anterior and vastus lateralis muscles according to published description (Stålberg, 1980). To evaluate small fiber involvement, the following tests were performed in 2009: sympathetic skin response (SSR) with recordings in both hands and feet and stimulations with loud sounds, RR-interval (during normal and deep breathing), quantitative sensory testing (QST) with detection of warmth and cold perception thresholds on the dorsum of the foot, distal part of the leg and laterally on the thigh (right side) and skin biopsy obtained from the right leg for quantification of intra-epidermal nerve fiber (IENF) density. The methods for QST and IENF density have been described in detail elsewhere (Løseth et al., 2006). For all quantitative parameters, reference values used in the laboratory routine have been used. The patient has given her acceptance to this publication, and is one of the co-authors. 3. Results 3.1. NCS
Fig. 1. Atrophy of hand muscles 11 years after the accident.
3.1.1. Motor NCS Data of amplitudes and MCVs in motor nerves at different time points are presented in Table 1. At the first investigation (day 20), no responses were obtained except for a response of 8 mV CMAP and 50 m/s motor conduction velocity (MCV) from the tibial nerve (left side investigated). The amplitudes increased during the first 5 years. MCVs were on the order of 15–45 m/s. The stimulation
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S. Løseth et al. / Clinical Neurophysiology 124 (2013) 1019–1024 Table 1 Serial changes of compound muscle action potential amplitudes (mV) and conduction velocities (m/s). NCS of the tibial nerves have been normal are and not included. 1 month
5 months
1 year
3 years
5 years
11 years
0
0
0
0.3 27
0.6 28
1.1 27
0.01 31
0.2 24
1.7 25
3.5 31
0.1 36
1.5 26
3.4 28
3.7 38
0.2 49
3.2 48
5.1 30
5.1 46
0.5 42
0.4 44
0.7 46
0.7 47
0.01 16
0.1 19
0.4 29
0.3 26
Medianus dx
Amp CV
Medianus sin
Amp CV
Ulnaris dx
Amp CV
0
Ulnaris sin
Amp CV
0
Fibularis dx
Amp CV
Fibularis sin
Amp CV
0
0.01 30
0
Amp, amplitude; CV, conduction velocity.
thresholds were considerably increased (data not shown), and there were abundant late responses. Some of these were A-waves, i.e. indirect double discharges (Fig. 2a), others were probably slow conducting individual axons, seen as CMAP satellites both with distal and proximal stimulation (Fig. 2b). They moved with the main CMAP at different stimulation sites. Distal latencies, especially in median nerves, were initially on the order of 10–15 ms, improving until 2010 to 4–5 ms. No F-waves were obtained in studies performed during the first 5 years except in the tibial nerves. In later studies, F-waves were seen, particularly in the median and ulnar nerves, but still A-waves were present. All the time NCS of both tibial nerves have been normal (amplitudes, MCV and F-responses).
(a)
3.1.2. Sensory NCS Ulnar, median, radial and sural nerves were studied either unilaterally or bilaterally, and data are presented in Table 2. No responses were obtained until after 10 months when a small response was seen in the left sural nerve and after 26 months in the left radial nerve. The ulnar and median responses reappeared after 3 years. The sensory conduction velocities were initially on the order of 30 m/s with a partial recovery over 5 years. 1 div
3.2. EMG
0.5 mV/Div, 5.0 ms/Div
(b)
wrist
below elbow
above elbow
Fig. 2. Stimulating the right ulnar nerve and recording from the abductor digiti minimi muscle. (a) Late components with distal stimulation. When the stimulation electrode is moved 25 mm proximally, CMAP latency is increased (small arrows), but some of the late components appear with shorter latency (large arrows) indicating that they are generated proximal to the stimulation site – A waves (indirect double discharges). (b) NCS showing slowing of CV, late components also at proximal stimulation and dispersion of the main CMAP complex.
3.2.1. Concentric needle EMG At the first investigation (day 20) there was abundant spontaneous activity (fibrillation potentials and positive sharp waves, psws) in all tested muscles: extensor digitorum (ED), interosseus dorsalis I (IOD I), vastus lateralis (VL), tibialis anterior (TA) and gastrocnemius medialis (GM) bilaterally. There was no voluntary activity except in VL and GM (GM was only tested again in 2010). At day 30 there were a few MUPs in ED and TA, but not in IOD I. After 4.5 months there was still denervation activity in all muscles (this time also the right deltoideus was investigated). There was re-innervation activity with instability and polyphasia, especially in TA (only a few MUPs in TA with low amplitude, mean amplitude 200 lV). After 10 months there was less spontaneous activity in ED, and the MUPs were more stable with higher amplitudes. For the first time a few MUPs could be recorded in IOD I on the right side, and after 26 months also on the left side. There were still fibrillation potentials and psws in hand muscles in all needle positions, and the interference pattern was severely reduced. After 3 years (in 2002) there was less spontaneous activity in most muscles, and the MUPs were more stable. In 2004 fibrillation potentials and psws were only present in IOD I and distal part of TA, and not in ED, VL and deltoideus. MUPs
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Table 2 Serial changes of sensory nerve action potential amplitudes (lV) and conduction velocities (m/s). 1 month
5 months
1 year
3 years
5 years
11 years
0
0
0
13 32
22 38
46 44
0
3 28
19 38
9 47
0
3 26
5 35
11 40
0
1 20
7 36
5 43
0
3 39
3 44
0.6 39
5 41
3 45
0
0
4 32
0
0
3 36
Medianus dx
Amp CV
Medianus sin
Amp CV
Ulnaris dx
Amp CV
0
Ulnaris sin
Amp CV
0
Radialis dx
Amp CV
0
Radialis sin
Amp CV
Suralis dx
Amp CV
Suralis sin
Amp CV
0
0
0
0
0.7 39
Amp, amplitude; CV, conduction velocity.
3.2.2. Macro EMG Median amplitudes of macro potentials in the right TA and VL were normal in 2002 and 2004, but considerably increased in 2010 (Table 3). 3.3. Small diameter nerve fiber testing SSR and RR-interval were normal. QST showed borderline thresholds for warmth and cold, especially at the leg (warm perception threshold 40.3 °C and cold perception threshold 26.2 °C). The quality of the temperature sensations was normal. IENF density was borderline (6.0 fibers/mm). 4. Discussion
Fig. 3. Changes in MUP amplitudes over time. Values are given as the mean amplitude of approximately 20 MUPs in each muscle. ED, extensor digitorum; IOD I, interosseus dorsalis I; TA, tibialis anterior; VL, vastus lateralis.
were polyphasic. MUP amplitudes (especially in distal muscles) could vary in different sites of the muscle from below the normal limit to high, while the mean amplitudes in these muscles were increased (Fig 3). With time the interference pattern became denser. In 2010 fibrillation potentials and positive sharp waves were still seen in all needle positions in IOD I, and some instability in MUPs was still present in this muscle and in TA. EMG in VL and deltoideus in 2004 and 2010 and in GM in 2010 was almost normal (slight increased polyphasia). In 2010 the highest MUP amplitude in IOD I was 12 mV, in ED 4 mV and in TA 6 mV.
Table 3 Amplitudes of 20 macro potentials at different times (years after the accident). Median lV (times normal).
Tibialis ant dx Vastus lat dx
3 years
5 years
11 years
178 (1.12) 196 (1.25)
202 (1.27) 244 (1.56)
1856 (8.97) 536 (3.55)
We describe clinical and neurophysiological studies in this unique patient with very deep accidental hypothermia who developed a severe neuropathy. She has now been followed for 11 years. At the ICU she woke up almost paralyzed in her arms and legs, with only some movements in proximal muscles. She recovered clinically especially during the first 1–2 years. The most serious sequela has been persistent weakness and atrophy of her hand muscles. NCS and EMG were performed several times during the first year, and after 3, 5 and 11 years. Initial EMG showed profuse amount of fibrillation potentials and psws, interpreted as signs of denervation. No motor or sensory responses were obtained on NCS except for a normal motor response from the tibial nerve. These findings were consistent with a pronounced axonal sensorimotor polyneuropathy, but with almost sparing of the tibial nerves. Both motor and sensory amplitudes increased during the first 5 years, but have not normalized. Distal latencies and MCVs also improved, but are still abnormal in most nerves. Slow velocity indicates dysmyelination and probably also axonal atrophy, expected in recovery after severe axonal degeneration. The time–course and pattern of recovery are probably not specific to cold injury, and are also seen in severe axonal neuropathy due to other causes (Tamura et al., 2007). CMAP-responses have shown abundant late components, some of which were generated in the nerve, so called indirect double discharges. Other late components were CMAP satellites, due to slowly conducting axons distally. Nerve excitability tested as stimulus response amplitude curve was severely reduced initially, and was not tested at later visits.
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During the first 5 years concentric needle EMG showed increasing MUP amplitudes, and the interference pattern became denser but did not normalize. Recovery progressed from proximal to distal sites. Reinnervation potentials in some muscles (especially TA) or in some muscle sites had initially very low amplitude indicating axonal re-growth, rather than collateral sprouting (Stålberg et al., 2010). Still after 11 years spontaneous activity was present in hand muscles but the motor units that could be activated were enlarged due to the reinnervation process. Macro EMG, measuring the size of the motor unit (size and number of muscle fibers) performed in VL and TA showed median amplitudes within normal limits in 2002 and 2004. Later the macro amplitudes increased and were up to 9 times normal in 2010 in TA and more than 3 times normal in VL. This could indicate incomplete reinnervation and persistence of atrophic muscle fibers in 2002 and 2004. Later continued reinnervation and possibly increase in muscle fiber diameters give large macro MUPs signals in 2010, corresponding to improved muscle strength. There could be at least two possible mechanisms for developing neuropathy in this patient: critical illness and cold injury with axonal damage. In addition local injuries due to traction of nerves in connection with the rescue and resuscitation could also be present as a separate local cause. Critical illness polyneuropathy (CIP) is an acute diffuse primarily axonal sensorimotor neuropathy commonly seen in critically ill patients with sepsis or multiple organ failure. The condition can be seen alone or in combination with critical illness myopathy (Hund, 2001; Zink et al., 2009). The distribution of CIP is symmetrical, and mainly nerves of the lower limbs are affected. The pathophysiology is complex and still not fully understood, but includes disturbed microcirculation and toxic effects of cytokines in sepsis (Zink et al., 2009). The prognosis depends on the severity of the critical illness. Follow-up studies have shown that persisting motor and sensory disabilities are common (Fletcher et al., 2003; Guarneri et al., 2008). Our patient had risk factors for developing CIP since she suffered from multi-organ failure and needed prolonged ventilatory support. However, she did not develop sepsis which is known as one of the major risk factors (Zink et al., 2009). The other alternative to the condition is a cold induced axonal damage. A few findings point to cold induced damage, rather than a systemic CIP. The lower limbs were involved to a lesser degree than the upper, and persistent weakness and atrophy are mostly present in the hands. Secondly, there is a variation between nerves. Both tibial nerves were almost spared (normal NCS including F-responses), although EMG at the ICU showed spontaneous activity in the gastrocnemius muscles indicating some axonal damage. These patchy patterns of nerve involvements could be explained by cold induced neuropathy rather than CIP. More involvement of the upper limbs could be caused by her body posture in the river. Her feet and legs were partially above the ice during the effort to rescue her, while her hands/arms were constantly submersed in the ice-cold running water. The reason for the very limited affection of the tibial nerves could be their deeper location in the legs compared to the fibular nerves. This could also be an explanation for the lesser involvement of proximal nerves. She developed bilateral drop-foot which clinically was most pronounced on the left side. One reason for this asymmetry could be a traction injury. Her friends tried to pull her up with a rope tied around her left ankle, and the left knee was sometimes squeezed against the edge of the ice. Despite the fact that the degrees of abnormalities of the fibular nerves on EMG and NCS examinations were symmetrical a superimposed traction trauma cannot be excluded. There are only a few literature reports on neurophysiologic findings in accidental generalized hypothermia-induced neuropathy. One report describes serial electrophysiological studies in a child with accidental hypothermia (body temperature 32.2 °C) (Afifi
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et al., 1988). He was found asystolic on ice covered water lying with his face down. Spontaneous pulse and respiration recurred after 1½ h, and he was weaned from the respirator after 30 h. Due to difficulties in walking and weakness in the arms NCS was performed on day 9. There were no responses in the median, tibial or fibular nerves. On EMG examination there were a few motor unit potentials in proximal muscles and some fibrillation potentials. Muscle strength gradually improved, and after 10 months he had recovered completely, and NCS and EMG were normal. The authors’ conclusion was a full recovery from severe axonopathy. We would like to add the following comment. In some muscles they found no fibrillation potentials and psws (e.g. IOD after 9 days) combined with absent voluntary activity. At 10 months EMG was normal in this muscle without reinnervation activity. This combination of findings could indicate conduction block rather than axonal degeneration in this nerve. In our case, reduced excitability is compatible with hypomyelination and probably also axonal abnormality. Collier et al. (2012) report a similar case. A 6-year old girl was successfully resuscitated after drowning in an ice-covered stock pond. The lowest body temperature measured at the hospital was 28.9 °C (84 °F). The condition was considered to be cold induced axonal polyneuropathy rather than critical illness neuropathy. She was followed for 1 year. Initially EMG showed fibrillation potentials and psws and reduced recruitment. Signs of reinnervation were seen after 28 weeks. NCS demonstrated absent motor and sensory responses until 1 year after the accident when small responses in some nerves were noted. Although EMG and NCS remained abnormal, her clinical outcome was excellent. Still another report describes a 26 year-old man who was found unconscious 3 h after a car accident in a ditch filled with icy water (Peyronnard et al., 1978). He was hypothermic (body temperature not reported). He developed weakness and atrophy of small muscles of hands and feet and distal hypoesthesia. Initially sensory action potentials were absent, but motor CVs were within normal ranges although distal latencies were prolonged (amplitudes not reported). On EMG there was spontaneous activity predominantly in hand and foot muscles, and after some months there were signs of reinnervation. Sural biopsy showed findings consistent with an axonal neuropathy with greatest loss of large diameter nerve fibers. He had recovered almost fully after 19 months and had only some hyperesthesia in fingers and feet. In one study of 15 patients with deep hypothermia, clinical signs of focal nerve lesions or plexus lesions were present in 3, but NCS or EMG results are not reported (Walpoth et al., 1997). Other more recent reports regarding outcome after severe hypothermia do not focus on complications from the peripheral nervous system (Vassal et al., 2001; Silfvast and Pettila, 2003; Van Der Ploeg et al., 2010). The mechanisms of cold injury to peripheral nerves are mostly studied in non-freezing cold injury (‘‘trench foot’’). The basic mechanism is thought to be direct axonal damage due to ischemia– reperfusion injury (Irwin, 1996). Animal experiments on rabbit hind limbs exposed 16 h to cold water immersion at temperature just above freezing concluded that large myelinated nerve fibers were preferentially damaged (Irwin, 1996). Others have also shown almost selective involvement of large diameter nerve fibers (Peyronnard et al., 1978; Nukada et al., 1981; Kennett and Gilliatt, 1991). However, cold hypersensitivity and cold allodynia are frequent symptoms, but mechanisms are not fully understood (Irwin, 1996; Namer et al., 2008). In our patient the major symptoms and findings were motor impairment and to a much lesser extent sensory symptoms consistent with large fiber dysfunction (paresthesia, hypoesthesia). However, she also developed symptoms and signs of small fiber involvement. During the first years she had autonomic dysfunction with arrhythmia, sweating and gastrointestinal dysfunction. She also reported cold intolerance, but no neuropathic pain. Small fiber tests (QST and IENF density) were
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not performed until 10 years after the accident. These showed borderline values in contrast to signs of more abnormal large fiber function (motor and sensory NCS recorded from the same area). RR-interval and SSR were normal while the patient had autonomic symptoms. In conclusion the patient has a sensorimotor axonal neuropathy with secondary dysmyelination after severe hypothermia. This is probably due to a direct effect of cold on the axons, but a component of critical illness polyneuropathy cannot be excluded. Her physical recovery has been good although weakness and atrophy have persisted in distal muscles. Neurophysiological investigations have shown findings suggestive of an on-going reinnervation process during a period of at least 5 years. References Afifi AK, Kimura J, Bell WE. Hypothermia-induced reversible polyneuropathy: electrophysiologic evidence of axonopathy. Pediatr Neurol 1988;4:49–53. Collier T, Patel A, Rinaldi R. Hypothermia-induced peripheral polyneuropathy after an episode of drowning. PM R 2012;3:230–3. Fletcher SN, Kennedy DD, Ghosh IR, Misra VP, Kiff K, Coakley JH, et al. Persistent neuromuscular and neurophysiologic abnormalities in long-term survivors of prolonged critical illness. Crit Care Med 2003;31:1012–6. Gilbert M, Busund R, Skagseth A, Nilsen PA, Solbo JP. Resuscitation from accidental hypothermia of 13.7 °C with circulatory arrest. Lancet 2000;355:375–6. Goertz O, Baerreiter S, Ring A, Jettkant B, Hirsch T, Digeler A, et al. Determination of microcirculatory changes and angiogenesis in a model of frostbite injury in vivo. J Surg Res 2011;168:155–61. Guarneri B, Bertolini G, Latronico N. Long-term outcome in patients with critical illness myopathy or neuropathy: the Italian multicentre CRIMYNE study. J Neurol Neurosurg Psychiatry 2008;79:838–41. Harirchi I, Arvin A, Vash JH, Zafarmand V. Frostbite: incidence and predisposing factors in mountaineers. Br J Sports Med 2005;39:898–901. Heggers JP, Robson MC, Manavalen K, Weingarten MD, Carethers JM, Boertman JA, et al. Experimental and clinical observations on frostbite. Ann Emerg Med 1987;16:1056–62. Hund E. Neurological complications of sepsis: critical illness polyneuropathy and myopathy. J Neurol 2001;248:929–34. Irwin MS. Nature and mechanism of peripheral nerve damage in an experimental model of non-freezing cold injury. Ann R Coll Surg Engl 1996;78:372–9.
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