Early investigations into sensory conduction are reviewed and related to recent and ongoing research, specifically with relation to the early detection of nerve disorders. Current study on entrapment neuropathies and on the assessment of minor sensory conduction changes is presented. It is concluded that, in the early recognition of nerve disease, the clinical orientation of the electromyographer is essential to proper test interpretation. MUSCLE 81 NERVE
1:352-359
1978
SENSORY CONDUCTION STUDIES IN THE EARLY RECOGNITION OF NERVE DISORDERS R. W. GILLIA’IT, DM
M a n y of the most exciting advances in medicine arise from chance observations that are made when people are attempting to do something else, and the story of sensory conduction studies and their development for clinical use is no exception. The story begins in the years immediately following World War 11, when G . D. Dawson was working at the National Hospital in London in a unit supported by the Medical Research Council. His interest being in myoclonic epilepsy, he was particularly concerned with the cerebral activity which could be recorded in the EEG immediately before a myoclonic jerk. EARLY HISTORY OF SENSORY CONDUCTION STUDIES
In one of Dawson’s patients, a tendon tap or electrical stimulation of a peripheral nerve regularly produced a small positive-going cortical response from the rolandic region, which was sometimes followed by a run of spikes and by a myoclonic jerk.6 To record the small initial cortical response, Dawson required high amplification and extremely low amplifier noise levels. In addition, he used photographic superimposition of a number of faint traces to improve his signal-to-noise ratio, an innovation that arose from discussions with Dr. John Bates, another neurophysiologist in the MRC unit. Subsequently, it was found that Galambos and Davis13had already used pho-
From the Institute of Neurology, Queen Square, London, England. Address reprint requests to Dr. Gilliatt at the Institute of Neurology, Queen Square, London WCIN 3BG. England. 0148-639XlO10510352$OO.OO/O 1978 Houghton Mifflin Professional Publishers @
352
Early Nerve Disorders
tographic superimposition in their study of auditory nerve action potentials in cats, but Dawson and Bates apparently introduced the technique into their own work quite independently. Thus, two technical points that later proved so important for peripheral conduction studies (i.e., the use‘ of high-gain, low-noise amplifiers and of photographic superimposition) were in fact developed for investigations of the central nervous system. Later, Dawson was able to show that, in healthy sub jects, similar but smaller cerebral responses could be recorded from the scalp over the postrolandic cortex following peripheral nerve stimulation. The results were demonstrated at a rneeting of the Physiological Society at Queen Square (London) in December 1946, and were published the following year.’ As part of this program, Dawson needed to record action potentials from peripheral nerves. When the median or ulnar nerve was to be stimulated at the wrist, surface electrodes were placed over the course of the nerve at a higher level in the arm, so that the growth of the ascending nerve action potential with increasing stimulus strength could be compared with that of the cerebral evoked response recorded from the scalp (fig. 1). In their 1949 paper on the technique of recording nerve action potentials, Dawson and Scott” noted that among their subjects were two who had previously suffered peripheral nerve damage. One of these subjects had no residual defcct of power or sensation; but in both cases, nerve action potentials were absent or of small amplitude. Commenting on this, the authors made the suggestion that “the recording of nerve action potentials may be a delicate means of detecting minor degrees of damage.” I n the context of our present theme, it is particularly interesting that the possibility of detecting minor or subclinical nerve damage by electrophysiological
MUSCLE & NERVE
SeptlOct 1978
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Figure 1 . Simultaneous recordings obtained by Dawson from the median nerve above the elbow and the contralateral cerebral hemisphere, showing the effect of varying the intensity of the stimulus to the median nerve at the wrist. Fifty sweeps superimposed. Calibration (10 pV for trace 2 and 20 pV for trace 3 ) shown in B. For further details, see Dawson.
.1
3
studies was raised at this early stage. (To maintain historical accuracy I should, however, add that Dawson was not the first to record human nerve action potentialsthis had been done by Eichler at the Physiological Institute of the University of Freiburg, and results had been published in 1937,” a precedent that Dawson himself was subsequently glad to acknowledge.)
Having mentioned our early studies on conduction in ischemic nerve under or distal to an arterial cuff, I should like to clarify the different ways in which experiments with arterial cuffs have been used to study function in pathological nerves. These are summarized as follows: 1. Motor and sensory changes in hypocalcemic patientsZ,24,Z9,35
EXPERIMENTS INVOLVING AN ARTERIAL
CUFF
The decision to stimulate digital fibers in the fingers rather than a mixed nerve trunk at the wrist came soon afterward; it arose from experiments in which Peter Nathan and I collaborated with Dawson in 1954. We wished to study conduction in sensory fibers compressed by an arterial cuff or clamp, and to correlate the failure of sensory conduction through the compressed ischemic zone with the sensation experienced. This kind of correlation was later studied with much greater precision by Professor Buchthal and Dr. R~senfalck,~ and I mention it only to explain why Dawson needed to produce a pure sensory volley. Our ischemia experiments were never published (except the study quoted by Nathanz6),but finger stimulation was then used by Dawson to study relative conduction velocities of sensory and motor fibers in the median and ulnar nerves. These results appeared in the Journal of Physiology in 1956.9
Early Nerve Disorders
2. Motor and sensory changes in carpal tunnel patientsl’lz’z0’21
3. Exaggeration of sensory loss due to central lesionslg 4. Changes in nerve resistance to ischemia in diabetic patients5,Z2,30,3Z
The effect of a tourniquet in producing muscular spasm in hypocalcemia has been known for many years and forms the basis of Trousseau’s and Von Bonsdorff s sign^.^,^^ K ~ g e l b e t - 2made ~ a detailed study of accoinmodation during and after ischemia in healthy subjects, and subsequently Robinsonz9showed that both ischemic and postischemic paresthesiae of patients with hypocalcemia were grossly increased. Studies on the carpal tunnel syndrome showed something rather different.z0I n carpal tunnel patients suffering from frequent spontaneous attacks of pain in the hand. a cuff inflated around the arm to arrest the blood
MUSCLE & NERVE
SeptIOct 1978
353
A l f
Figure 2 . Ascending action potentials recorded from the median and ulnar nerves of a patient with a mild ulnar lesion at the elbow. (Reprinted with permission from Gilliatt RW, Sears TA: Sensory nerve action potentials in patients with peripheraal nerve lesions. J Neurol Neurosurg Psychiatry 27:709-778, 7958.)
supply not only increased the paresthesiae but sometimes produced pain in the hand of such severity that the cuff had to be released. Conduction studies during this procedure were subsequently carried out by Fullerton,” who showed that conduction in motor fibers to the thenar muscles might fail within a few minutes of the onset of circulatory arrest, whereas in healthy subjects motor conduction survives for a much longer period. Of particular interest was the fact that, in Fullerton’s results, patients with this premature failure of conduction during ischemia were not those with a severe carpal tunnel syndrome in terms of motor or sensory deficit or conduction delay at the wrist. O n the contrary, this test was more often positive in patients with relatively short histories, but who were having frequent spontaneous attacks of pain at the time it was carried out. Many other simpler and less exacting methods are available for confirming the diagnosis of carpal tunnel syndrome in ordinary clinical practice, but the results cited are of particular interest in that they revealed an abnormality o f the nerve fibers that was not brought out by routine clinical examination or by nerve conduction studies without ischemia. In patients with central lesions affecting sensory pathways, ischemia produced by a cuff around the arm may also bring out a sensory deficit that was not apparent beforehand.19 I t seems that distortion of the peripheral input by ischemia can have a marked effect on sensation in an individual with a minimal lesion of the
354
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CASE
A
G.S.
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sensory pathway at a higher level, and it would be most interesting to know what effect a peripheral cuff of this kind would have on spinal or cerebral evoked potentials in such a patient. The fourth group of cuff experiments shown in the list above are those in which diabetic nerves have been shown to withstand ischemia better than normal nerve^,^^**^^^^^* a phenomenon that is particularly remarkable in that the increased resistance to ischemia was best seen in poorly controlled diabetes and tended to disappear with good diabetic control. DEVELOPMENT OF SENSORY CONDUCTION TESTS FOR CLINICAL USE
Returning to the subject of sensory conduction, the first studies o n patients were carried out in 1955 at Queen Square, where, of course, Dawson’s work was well known; and within a year the work on motor conduction by Lambert and his colleagues4~z3~z5 and by Simpson31 became available, so that clinical neurophysiologists were presented with two powerful new tools for investigating patients with local or generalized neuropathy. In the next decade, an intense effort was made to apply these techniques to different clinical situations. Although laboratories all over the world participated, the lead was undoubtedly taken by Professor Buchthal’s group in Copenhagen, where rnany of the basic studies determining stimulating and recording conditions and the range o f normal variation were carried out. In addition to the
MUSCLE & NERVE
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Figure 3 . Sensory action potentials recorded from the ulnar nerve following stimulation of the fiffh digit in a normal subject (left) and in a patient with a minimal ulnar lesion at the elbow (right). The bottom trace in each case shows averaging with the stimulus switched off. The figures above the other traces indicate velocity (mlsec) in each case. (Modified with permission from Payan J: Electrophysiological localisation of ulnar nerve lesions. J Neurol Neurosurg Psychiatry 32208-220, 7969.j
work on sensory conduction undertaken by Dr. Rosenfalck and Professor Buchthal, which was finally reported in extenso in a special issue of Brain Research published in 1966,3important papers on motor conduction were contributed by others in the laboratory, in particular by Trojaborg and Gasse1.14-18*33,34 As a measure of the technical improvements introduced by Professor Buchthal, one has only to compare the early pictures of sensory action potentials recorded through surface electrodes in London with those later obtained by the Copenhagen group using an active recording electrode close to the nerve trunk, a special input transformer, and a digital averager. Figure 2, for example, illustrates early records from Queen Square of ascending action potentials in a patient with an ulnar nerve lesion. T h e patient, a man of 56 years, had noticed numbness of the fourth and fifth fingers for about a month, without obvious weakness of the hand. On examination he was able to detect cotton wool and pinprick normally, but he made occasional errors to compass points on the fifth finger. In contrast to the
Early Nerve Disorders
very mild clinical deficit, nerve action potentials were clearly abnormal, the ascending action potential above the elbow being delayed in comparison with the median and markedly reduced in amplitude. At the time, this seemed a relatively sensitive method of detecting a mild lesion. Compare it, however, with the more recent records shown in figure 3. These are from a paper by Dr. Payan,28published when he was working with Professor Buchthal. Tracings on the left are from a normal subject, and those o n the right are from the patient. T h e stimulus in each case was to the fifth finger, and it can be seen that, in this patient, the sensory action potentials were small at all three levels, the velocity of the fastest components being normal between finger and wrist and as far proximally as the distal end of the ulnar groove. Across the sulcus, however, the velocity was reduced, and the proximal response shows temporal dispersion. T h e interesting aspect of these tracings is that this nerve was clinically nomnal and was only examined because the patient had an ulnar lesion in his opposite arm. So
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Sept/Oct 1978
355
Figure 5. Single teased fibers from a clinically normal median nerve just proximal to the flexor retinaculum. Three fibers with bulbous swellings to show (a) normal myelin thickness proximal to the node of Ranvier, (b) demyelination proximal to the node, and (c) remyelination proximal to the node. Bar = 1 mm. (Reprinted with permission from Neary D, Ochoa J, Gilliatt RW: Subclinical entrapment neuropathy In man. J Neurol Sci 24:283-298, 7975.) Figure 4. Localized fascicular enlargement at the elbow in a clinically normal ulnar nerve. The transverse sections were taken (a) 6 cm proximal to the elbow, (b) in the ulnar groove, and (c) 4 cm distal to the elbow. Bar = 1 mm. (Reprinted with permission from Neary D, Ochoa J, Gilliatt RW: Sub-clinical entrapment neuropathy in man. J Neurol Sci 24:283-298, 7975.)
we have, in this instance, electrophysiological evidence of subclinical neuropathy. It was, in fact, this type of result that encouraged us in London to look for anatomical evidence of subclinical entrapment in patients without symptoms or signs. SUBCLINICAL ENTRAPMENT NEUROPATHY
We decided that the ulnar nerve at the elbow and the median nerve at the wrist were likely sites for subclinical entrapment, and proceeded to obtain these nerves from patients coming to autopsy for other reasons. Patients with known disease of the peripheral nervous system were excluded; nevertheless, convincing evidence of localized nerve fiber damage was found at the two entrapment sites in approximately 40% of cases.27Our total series was relatively small, consisting only of about 25 nerves, because of the difficulty of obtaining autopsy material within a few hours of death. When patients died
356
Early Nerve Disorders
in hospital and nerves could be obtained within six hours, examination by both electron and light microscopy was possible. Striking connective tissue changes had occurred in some of the nerves obtained at autopsy. Neuromatous thickening of the ulnar nerve in the distal part of the ulnar groove had resulted from enlargment of individual fascicles, with or without perineurial thickening (fig. 4).In the median nerve under the carpal ligament, fascicular enlargement was less conspicuous than perineurial and epineurial thickening. At both sites, accumulations of Renaut bodies were observed. All of these changes could occur in the absence of significant alterations in nerve fibers. Apparently, only in more advanced entrapment lesions is one likely to find both connective tissue and nerve fiber changes occurring together. Features characteristic of nerve fiber damage in the median and ulnar nerves were distorted internodes with club-shaped swellings at one end, with or without demyelination (fig. 5 ) . Demyelination was limited to the paranodal region and often affected several successive internodes on the same fibers. The site of entrapment could be predicted from the orientation of these distorted internodes, since the bulbar swellings were always at the end of the internode further from the center of
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SepVOct 1978
the lesion. It was much easier to recognize the presence of nerve damage from these changes in teased fibers than from examination of transverse sections. The scarcity of pathological fibers in transverse sections can, perhaps, be explained on a simple mathematical basis. If a bulbous swelling or short length of demyelinated fiber occupies a length of only 50 pm, if the full length of the internodal segment is 1000 pm, and if every large myelinated fiber is affected, a transverse section would reveal this change in only one fiber in 20. If only one fiber in 20 were involved, then a transverse section would show the change in one fiber in 400.
Mrs AC 19-4-77
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ASSESSMENT OF MINOR CHANGES IN SENSORY CONDUCTION
The frequent presence of subclinical entrapment neuropathy in healthy asymptomatic subjects has important practical implications for clinicians performing electrodiagnostic tests. It emphasizes the danger of overinterpretation when minor abnormalities are found by very sensitive electrophysiological techniques. A clinical neurophysiologist must decide whether he is looking at minimal evidence of meaningful disease, or whether he is being misled by minor pathologic changes of the type that I have just illustrated. One context in which this difficulty may arise is when nerve conduction studies are used to survey an industrial population for possible neurotoxic damage. In this situation, conduction across entrapment sites may be misleading, and the choice of nerves to be examined becomes important. I f conduction studies are used to search for minimally affected relatives of patients with hereditary neuropathy, the situation is reversed; in this case, conduction across entrapment sites should be tested, as this may provide the earliest evidence of abnormality. In routine electrodiagnostic practice, a very sensitive technique is just as likely to yield too much information as too little. I, myself, find it helpful to regard each electrophysiological measurement on each nerve as a physical sign to be weighed in relation to the rest of the clinical picture and either accepted or discarded, in the same way that one would evaluate a doubtful physical sign during examination at the bedside. T o illustrate this concept in relation to a particular patient, figure 6 shows somewhat low-amplitude action potentials recorded through surface electrodes from the ulnar nerve in the right arm. N o slowing of conduction in the elbow region and no disproportionate fall in amplitude across the elbow occurred to suggest a local block at this level-not a very significant abnormality, one might say. However, the patient was a young woman, and the corresponding action potentials on the contralateral side were much larger. Further, her median sensory action potentials were normal, and she had localized muscle wasting in the thenar region on the right side (fig. 7). X-rays of her neck subsequently revealed a long down-curving C7 transverse process on the left, and a rudimentary cervical rib on the right (fig. 8). Thus, the small ulnar sensory action potentials, in themselves,
Early Nerve Disorders
Figure 6. Low-amplitude sensory action potentials recorded from the ulnar nerve through conventional (saddle-type) surface electrodes. Sixteen responses averaged in each case. Conduction velocity between the two recording sites was 52 mlsec. (Modified with permission from Gilliatt RW, Willison RG, Dietz V, et a/: Peripheral nerve conduction in patients with a cervical rib and band. Ann Neurol 4:124-129, 1978.)
Figure 7. Right hand of the patient whose tracings are illustrated in figure 6, showing the presence of partial thenar atrophy.
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357
Figure 8. A radiograph of the cervical spine from the same patient as in figures 6 and 7, showing a long, down-curving C7 transverse process on the left and a rudimentary cewical rib on the right.
meant very little, but gained importance when considered in conjunction with the complete clinical and electrophysiologic picture. O n surgical exploration she was found to have a sharp fibrous band passing forward from the tip of a rudimentary cervical rib on the right; the band was angulating to C8 and T1 roots, the latter being translucent and swollen at the site of damage.
SUMMARY
My conclusion is in a sense a paradoxical one: the more sensitive and refined the technique, the more difficult it may be to interpret the results correctly. For the early recognition of nerve disease, the clinical orientation of the electromyographer is therefore as important as the sensitivity of his tests.
REFERENCES 1. Bharucha EP: Ischaemic paralysis and acroparaesthesia. Clin Sci 11:235-239, 1952. 2. Bonsdorff von B: Nagra fall av tetani bland varnpliktiga. Fiiiska lak sallsk hand1 72: 108-134, 1930. 3. Buchthal F, Rosenfalck A: Evoked action potentials and conduction velocity in human sensory nerves. Bruin Res 3:l-122, 1966. 4. Carpendale MTF: Conduction time in the terminal portion of the motor fibers of the ulnar, median and peroneal nerves in healthy subjects and in patients with neuropathy. MS (Phys Med) Thesis, University of Minnesota, 1956. 5. Castaigne P, Cathala HP, Dry J, Mastropaolo C: Les reponses des nerfs et des muscles a des stimulations electriques au cours d u n e epreuve de garrot ischemique chez l'homme normal et chez le diabetique. REVNeurol (Paris) 115:61-66, 1966. 6. Dawson GD: Investigations o n a patient subject to myoclonic seizures after sensory stimulation.J Neurol Neurosurg Psychzatry 10:141-162, 1947. 7 . Dawson GD: Cerebral responses to electrical stimulation of peripheral nerve in man. J Neural Neurosurg Psychiatiy 10:134-140, 1947. 8. Dawson GD: Cerebral responses to nerve stimulation in man. Br Med Bull 63326-329, 1950. 9. Dawson GD: The relative excitability and conduction velocity of sensory and motor nerve fibres in man. J Physiol 13 1 :436-451, 1956. 10. Dawson GD, Scott JW: T h e recording of nerve action po-
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tentials through the skin in man. J Neurol Neurosurg Psychiatry 12:259-267, 1949. 1 1 . Eichler W: Uber die Ableitung der Aktionspontentiale vom menschlichen Nerven in situ. Z Biol 98:182-214, 1937. 12. Fullerton PM: T h e effect of ischaemia o n nerve conduction in the carpal tunntl syndrome. J Neurol Neurosurg Psychiatry 26~385-397, 1963. 13. Galambos R, Davis H: T h e response of single auditory nerve fibers to acoustic stimulation. J Neurophysiol 6:39-58, 1943. 14. Gassel MM: A study of femoral nerve conduction time. Arch Neurol 9:607--614, 1963. 15. Gassel MM: A test of nerve conduction to muscles of the shoulder girdle as a n aid in the diagnosis of proximal neurogenic and muscular disease. J Nmrol Nmrosurg Psychiatry 27:200-205, 1964. 16. Gassel MM: Sources of error in motor nerve conduction studies. Neurology (,Minneap) 14:825-835, 1964. 17. Gassel MM, Diamantopoulos E: Pattern of conduction times in the distribution of the radial nerve. Neurology (Minneap) 14:222-231, 1964. 18. Gassel MM, Trojaborg W: Clinical and electrophysiological study of the pattern of conduction times in the distribution of the sciatic nerve. J Neural Neurosurg Psychiatry 27:351357, 1964. 19. Gilliatt RW: Ischaemic sensory loss in patients with spinal and cerebral lesions. J Neural Neurosurg Psychiatry 18: 145154, 1955.
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20. Gilliatt RW, Wilson TG: A pneumatic-tourniquet test in the carpal tunnel syndrome. Lancet 2:595-597, 1953. 21. Gilliatt RW, Wilson TG: Ischaemic sensory loss in patients with peripheral nerve lesions. J Neurol Neurosurg Psychiatry 17~104-114. 1954. 22. Gregersen G: A study of the peripheral nerves in diabetic subjects during ischaemia. J Neurol Neurosurg Psychiatry 31:175-181, 1968. 23. Henriksen JD: Conduction velocity of motor nerves in normal subjects and patients with neuromuscular disorders. MS (Phys Med) Thesis, University of Minnesota, 1956. 24. Kugelberg E: Neurologic mechanism for certain phenomena in tetany. Arch Neurol Psychiatr?, (Chic) 56:507-521, 1946. 25. Lambert EH: Electromyography and electric stimulation of peripheral nerves and muscle. In Clinical Exam'iiatioris in Neurology. Philadelphia, Mayo Clinic, 1956. 26. Nathan P: Ischaemic and post-ischaemic numbness and paraesthesiae. J Neurol Neurosurg Psychiatr?, 21: 12-23,1958. 27. Neary D, Ochoa J, Gilliatt RW: Sub-clinical entrapment neuropathy in man./ Neurol Sci 24:283-298, 1975.
Early Nerve Disorders
28. Payan J: Electrophysiological localisation of ulnar nerve lesions. J Neurol Neurosurg Psychiatry 32:208-220, 1969. 29. Robinson PK: Sensory changes in the upper limb during ischaemia in tetany. Neurology (Minneap) 5:460-467. 1955. 30. Seneviratne KN. Peiris OA: T h e effect of ischaemia o n the excitability of sensory nerves in diabetes mellitus. J Neurol Neurosurg Psyc.hzatly 31:348-353, 1968. 31. Simpson JA: Electrical signs in the diagnosis of' carpal tunnel and related syndromes. J Neural Neurosurg Psychiatiy 191275-280, 1956. 32. Steiness I: Influence of diabetic status on vibratory perception during ischaemia. Acta Med Scand 170:319-338, 1961. 33. Trojaborg W: Motor nerve conduction electromyography and strength-duration curves. Electroencephalogr Clin Nrurophysiol (Suppl) 22:45-48, 1962. 34. Trojaborg W: Motor nerve conduction velocities in normal subjects with particular reference to the conduction in proximal and distal segments of median and ulnar nerve. Electroencephalogr Clin Neurophysiol 17:314-321, 1964. 35. Trousseau A: Clinigice MMicale, 3rd ed. Paris, JB Balliere, 1868.
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1:352-359
1978
SENSORY CONDUCTION STUDIES IN THE EARLY RECOGNITION OF NERVE DISORDERS R. W. GILLIA’IT, DM
M a n y of the most exciting advances in medicine arise from chance observations that are made when people are attempting to do something else, and the story of sensory conduction studies and their development for clinical use is no exception. The story begins in the years immediately following World War 11, when G . D. Dawson was working at the National Hospital in London in a unit supported by the Medical Research Council. His interest being in myoclonic epilepsy, he was particularly concerned with the cerebral activity which could be recorded in the EEG immediately before a myoclonic jerk. EARLY HISTORY OF SENSORY CONDUCTION STUDIES
In one of Dawson’s patients, a tendon tap or electrical stimulation of a peripheral nerve regularly produced a small positive-going cortical response from the rolandic region, which was sometimes followed by a run of spikes and by a myoclonic jerk.6 To record the small initial cortical response, Dawson required high amplification and extremely low amplifier noise levels. In addition, he used photographic superimposition of a number of faint traces to improve his signal-to-noise ratio, an innovation that arose from discussions with Dr. John Bates, another neurophysiologist in the MRC unit. Subsequently, it was found that Galambos and Davis13had already used pho-
From the Institute of Neurology, Queen Square, London, England. Address reprint requests to Dr. Gilliatt at the Institute of Neurology, Queen Square, London WCIN 3BG. England. 0148-639XlO10510352$OO.OO/O 1978 Houghton Mifflin Professional Publishers @
352
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tographic superimposition in their study of auditory nerve action potentials in cats, but Dawson and Bates apparently introduced the technique into their own work quite independently. Thus, two technical points that later proved so important for peripheral conduction studies (i.e., the use‘ of high-gain, low-noise amplifiers and of photographic superimposition) were in fact developed for investigations of the central nervous system. Later, Dawson was able to show that, in healthy sub jects, similar but smaller cerebral responses could be recorded from the scalp over the postrolandic cortex following peripheral nerve stimulation. The results were demonstrated at a rneeting of the Physiological Society at Queen Square (London) in December 1946, and were published the following year.’ As part of this program, Dawson needed to record action potentials from peripheral nerves. When the median or ulnar nerve was to be stimulated at the wrist, surface electrodes were placed over the course of the nerve at a higher level in the arm, so that the growth of the ascending nerve action potential with increasing stimulus strength could be compared with that of the cerebral evoked response recorded from the scalp (fig. 1). In their 1949 paper on the technique of recording nerve action potentials, Dawson and Scott” noted that among their subjects were two who had previously suffered peripheral nerve damage. One of these subjects had no residual defcct of power or sensation; but in both cases, nerve action potentials were absent or of small amplitude. Commenting on this, the authors made the suggestion that “the recording of nerve action potentials may be a delicate means of detecting minor degrees of damage.” I n the context of our present theme, it is particularly interesting that the possibility of detecting minor or subclinical nerve damage by electrophysiological
MUSCLE & NERVE
SeptlOct 1978
.-
I-
-7
- r v
”>-,-.-,
3
A
A
I
.\ .
.
.
-
E
7
Figure 1 . Simultaneous recordings obtained by Dawson from the median nerve above the elbow and the contralateral cerebral hemisphere, showing the effect of varying the intensity of the stimulus to the median nerve at the wrist. Fifty sweeps superimposed. Calibration (10 pV for trace 2 and 20 pV for trace 3 ) shown in B. For further details, see Dawson.
.1
3
studies was raised at this early stage. (To maintain historical accuracy I should, however, add that Dawson was not the first to record human nerve action potentialsthis had been done by Eichler at the Physiological Institute of the University of Freiburg, and results had been published in 1937,” a precedent that Dawson himself was subsequently glad to acknowledge.)
Having mentioned our early studies on conduction in ischemic nerve under or distal to an arterial cuff, I should like to clarify the different ways in which experiments with arterial cuffs have been used to study function in pathological nerves. These are summarized as follows: 1. Motor and sensory changes in hypocalcemic patientsZ,24,Z9,35
EXPERIMENTS INVOLVING AN ARTERIAL
CUFF
The decision to stimulate digital fibers in the fingers rather than a mixed nerve trunk at the wrist came soon afterward; it arose from experiments in which Peter Nathan and I collaborated with Dawson in 1954. We wished to study conduction in sensory fibers compressed by an arterial cuff or clamp, and to correlate the failure of sensory conduction through the compressed ischemic zone with the sensation experienced. This kind of correlation was later studied with much greater precision by Professor Buchthal and Dr. R~senfalck,~ and I mention it only to explain why Dawson needed to produce a pure sensory volley. Our ischemia experiments were never published (except the study quoted by Nathanz6),but finger stimulation was then used by Dawson to study relative conduction velocities of sensory and motor fibers in the median and ulnar nerves. These results appeared in the Journal of Physiology in 1956.9
Early Nerve Disorders
2. Motor and sensory changes in carpal tunnel patientsl’lz’z0’21
3. Exaggeration of sensory loss due to central lesionslg 4. Changes in nerve resistance to ischemia in diabetic patients5,Z2,30,3Z
The effect of a tourniquet in producing muscular spasm in hypocalcemia has been known for many years and forms the basis of Trousseau’s and Von Bonsdorff s sign^.^,^^ K ~ g e l b e t - 2made ~ a detailed study of accoinmodation during and after ischemia in healthy subjects, and subsequently Robinsonz9showed that both ischemic and postischemic paresthesiae of patients with hypocalcemia were grossly increased. Studies on the carpal tunnel syndrome showed something rather different.z0I n carpal tunnel patients suffering from frequent spontaneous attacks of pain in the hand. a cuff inflated around the arm to arrest the blood
MUSCLE & NERVE
SeptIOct 1978
353
A l f
Figure 2 . Ascending action potentials recorded from the median and ulnar nerves of a patient with a mild ulnar lesion at the elbow. (Reprinted with permission from Gilliatt RW, Sears TA: Sensory nerve action potentials in patients with peripheraal nerve lesions. J Neurol Neurosurg Psychiatry 27:709-778, 7958.)
supply not only increased the paresthesiae but sometimes produced pain in the hand of such severity that the cuff had to be released. Conduction studies during this procedure were subsequently carried out by Fullerton,” who showed that conduction in motor fibers to the thenar muscles might fail within a few minutes of the onset of circulatory arrest, whereas in healthy subjects motor conduction survives for a much longer period. Of particular interest was the fact that, in Fullerton’s results, patients with this premature failure of conduction during ischemia were not those with a severe carpal tunnel syndrome in terms of motor or sensory deficit or conduction delay at the wrist. O n the contrary, this test was more often positive in patients with relatively short histories, but who were having frequent spontaneous attacks of pain at the time it was carried out. Many other simpler and less exacting methods are available for confirming the diagnosis of carpal tunnel syndrome in ordinary clinical practice, but the results cited are of particular interest in that they revealed an abnormality o f the nerve fibers that was not brought out by routine clinical examination or by nerve conduction studies without ischemia. In patients with central lesions affecting sensory pathways, ischemia produced by a cuff around the arm may also bring out a sensory deficit that was not apparent beforehand.19 I t seems that distortion of the peripheral input by ischemia can have a marked effect on sensation in an individual with a minimal lesion of the
354
Early Nerve Disorders
CASE
A
G.S.
17.10. 56
sensory pathway at a higher level, and it would be most interesting to know what effect a peripheral cuff of this kind would have on spinal or cerebral evoked potentials in such a patient. The fourth group of cuff experiments shown in the list above are those in which diabetic nerves have been shown to withstand ischemia better than normal nerve^,^^**^^^^^* a phenomenon that is particularly remarkable in that the increased resistance to ischemia was best seen in poorly controlled diabetes and tended to disappear with good diabetic control. DEVELOPMENT OF SENSORY CONDUCTION TESTS FOR CLINICAL USE
Returning to the subject of sensory conduction, the first studies o n patients were carried out in 1955 at Queen Square, where, of course, Dawson’s work was well known; and within a year the work on motor conduction by Lambert and his colleagues4~z3~z5 and by Simpson31 became available, so that clinical neurophysiologists were presented with two powerful new tools for investigating patients with local or generalized neuropathy. In the next decade, an intense effort was made to apply these techniques to different clinical situations. Although laboratories all over the world participated, the lead was undoubtedly taken by Professor Buchthal’s group in Copenhagen, where rnany of the basic studies determining stimulating and recording conditions and the range o f normal variation were carried out. In addition to the
MUSCLE & NERVE
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Figure 3 . Sensory action potentials recorded from the ulnar nerve following stimulation of the fiffh digit in a normal subject (left) and in a patient with a minimal ulnar lesion at the elbow (right). The bottom trace in each case shows averaging with the stimulus switched off. The figures above the other traces indicate velocity (mlsec) in each case. (Modified with permission from Payan J: Electrophysiological localisation of ulnar nerve lesions. J Neurol Neurosurg Psychiatry 32208-220, 7969.j
work on sensory conduction undertaken by Dr. Rosenfalck and Professor Buchthal, which was finally reported in extenso in a special issue of Brain Research published in 1966,3important papers on motor conduction were contributed by others in the laboratory, in particular by Trojaborg and Gasse1.14-18*33,34 As a measure of the technical improvements introduced by Professor Buchthal, one has only to compare the early pictures of sensory action potentials recorded through surface electrodes in London with those later obtained by the Copenhagen group using an active recording electrode close to the nerve trunk, a special input transformer, and a digital averager. Figure 2, for example, illustrates early records from Queen Square of ascending action potentials in a patient with an ulnar nerve lesion. T h e patient, a man of 56 years, had noticed numbness of the fourth and fifth fingers for about a month, without obvious weakness of the hand. On examination he was able to detect cotton wool and pinprick normally, but he made occasional errors to compass points on the fifth finger. In contrast to the
Early Nerve Disorders
very mild clinical deficit, nerve action potentials were clearly abnormal, the ascending action potential above the elbow being delayed in comparison with the median and markedly reduced in amplitude. At the time, this seemed a relatively sensitive method of detecting a mild lesion. Compare it, however, with the more recent records shown in figure 3. These are from a paper by Dr. Payan,28published when he was working with Professor Buchthal. Tracings on the left are from a normal subject, and those o n the right are from the patient. T h e stimulus in each case was to the fifth finger, and it can be seen that, in this patient, the sensory action potentials were small at all three levels, the velocity of the fastest components being normal between finger and wrist and as far proximally as the distal end of the ulnar groove. Across the sulcus, however, the velocity was reduced, and the proximal response shows temporal dispersion. T h e interesting aspect of these tracings is that this nerve was clinically nomnal and was only examined because the patient had an ulnar lesion in his opposite arm. So
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Figure 5. Single teased fibers from a clinically normal median nerve just proximal to the flexor retinaculum. Three fibers with bulbous swellings to show (a) normal myelin thickness proximal to the node of Ranvier, (b) demyelination proximal to the node, and (c) remyelination proximal to the node. Bar = 1 mm. (Reprinted with permission from Neary D, Ochoa J, Gilliatt RW: Subclinical entrapment neuropathy In man. J Neurol Sci 24:283-298, 7975.) Figure 4. Localized fascicular enlargement at the elbow in a clinically normal ulnar nerve. The transverse sections were taken (a) 6 cm proximal to the elbow, (b) in the ulnar groove, and (c) 4 cm distal to the elbow. Bar = 1 mm. (Reprinted with permission from Neary D, Ochoa J, Gilliatt RW: Sub-clinical entrapment neuropathy in man. J Neurol Sci 24:283-298, 7975.)
we have, in this instance, electrophysiological evidence of subclinical neuropathy. It was, in fact, this type of result that encouraged us in London to look for anatomical evidence of subclinical entrapment in patients without symptoms or signs. SUBCLINICAL ENTRAPMENT NEUROPATHY
We decided that the ulnar nerve at the elbow and the median nerve at the wrist were likely sites for subclinical entrapment, and proceeded to obtain these nerves from patients coming to autopsy for other reasons. Patients with known disease of the peripheral nervous system were excluded; nevertheless, convincing evidence of localized nerve fiber damage was found at the two entrapment sites in approximately 40% of cases.27Our total series was relatively small, consisting only of about 25 nerves, because of the difficulty of obtaining autopsy material within a few hours of death. When patients died
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in hospital and nerves could be obtained within six hours, examination by both electron and light microscopy was possible. Striking connective tissue changes had occurred in some of the nerves obtained at autopsy. Neuromatous thickening of the ulnar nerve in the distal part of the ulnar groove had resulted from enlargment of individual fascicles, with or without perineurial thickening (fig. 4).In the median nerve under the carpal ligament, fascicular enlargement was less conspicuous than perineurial and epineurial thickening. At both sites, accumulations of Renaut bodies were observed. All of these changes could occur in the absence of significant alterations in nerve fibers. Apparently, only in more advanced entrapment lesions is one likely to find both connective tissue and nerve fiber changes occurring together. Features characteristic of nerve fiber damage in the median and ulnar nerves were distorted internodes with club-shaped swellings at one end, with or without demyelination (fig. 5 ) . Demyelination was limited to the paranodal region and often affected several successive internodes on the same fibers. The site of entrapment could be predicted from the orientation of these distorted internodes, since the bulbar swellings were always at the end of the internode further from the center of
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the lesion. It was much easier to recognize the presence of nerve damage from these changes in teased fibers than from examination of transverse sections. The scarcity of pathological fibers in transverse sections can, perhaps, be explained on a simple mathematical basis. If a bulbous swelling or short length of demyelinated fiber occupies a length of only 50 pm, if the full length of the internodal segment is 1000 pm, and if every large myelinated fiber is affected, a transverse section would reveal this change in only one fiber in 20. If only one fiber in 20 were involved, then a transverse section would show the change in one fiber in 400.
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ASSESSMENT OF MINOR CHANGES IN SENSORY CONDUCTION
The frequent presence of subclinical entrapment neuropathy in healthy asymptomatic subjects has important practical implications for clinicians performing electrodiagnostic tests. It emphasizes the danger of overinterpretation when minor abnormalities are found by very sensitive electrophysiological techniques. A clinical neurophysiologist must decide whether he is looking at minimal evidence of meaningful disease, or whether he is being misled by minor pathologic changes of the type that I have just illustrated. One context in which this difficulty may arise is when nerve conduction studies are used to survey an industrial population for possible neurotoxic damage. In this situation, conduction across entrapment sites may be misleading, and the choice of nerves to be examined becomes important. I f conduction studies are used to search for minimally affected relatives of patients with hereditary neuropathy, the situation is reversed; in this case, conduction across entrapment sites should be tested, as this may provide the earliest evidence of abnormality. In routine electrodiagnostic practice, a very sensitive technique is just as likely to yield too much information as too little. I, myself, find it helpful to regard each electrophysiological measurement on each nerve as a physical sign to be weighed in relation to the rest of the clinical picture and either accepted or discarded, in the same way that one would evaluate a doubtful physical sign during examination at the bedside. T o illustrate this concept in relation to a particular patient, figure 6 shows somewhat low-amplitude action potentials recorded through surface electrodes from the ulnar nerve in the right arm. N o slowing of conduction in the elbow region and no disproportionate fall in amplitude across the elbow occurred to suggest a local block at this level-not a very significant abnormality, one might say. However, the patient was a young woman, and the corresponding action potentials on the contralateral side were much larger. Further, her median sensory action potentials were normal, and she had localized muscle wasting in the thenar region on the right side (fig. 7). X-rays of her neck subsequently revealed a long down-curving C7 transverse process on the left, and a rudimentary cervical rib on the right (fig. 8). Thus, the small ulnar sensory action potentials, in themselves,
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Figure 6. Low-amplitude sensory action potentials recorded from the ulnar nerve through conventional (saddle-type) surface electrodes. Sixteen responses averaged in each case. Conduction velocity between the two recording sites was 52 mlsec. (Modified with permission from Gilliatt RW, Willison RG, Dietz V, et a/: Peripheral nerve conduction in patients with a cervical rib and band. Ann Neurol 4:124-129, 1978.)
Figure 7. Right hand of the patient whose tracings are illustrated in figure 6, showing the presence of partial thenar atrophy.
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Figure 8. A radiograph of the cervical spine from the same patient as in figures 6 and 7, showing a long, down-curving C7 transverse process on the left and a rudimentary cewical rib on the right.
meant very little, but gained importance when considered in conjunction with the complete clinical and electrophysiologic picture. O n surgical exploration she was found to have a sharp fibrous band passing forward from the tip of a rudimentary cervical rib on the right; the band was angulating to C8 and T1 roots, the latter being translucent and swollen at the site of damage.
SUMMARY
My conclusion is in a sense a paradoxical one: the more sensitive and refined the technique, the more difficult it may be to interpret the results correctly. For the early recognition of nerve disease, the clinical orientation of the electromyographer is therefore as important as the sensitivity of his tests.
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tentials through the skin in man. J Neurol Neurosurg Psychiatry 12:259-267, 1949. 1 1 . Eichler W: Uber die Ableitung der Aktionspontentiale vom menschlichen Nerven in situ. Z Biol 98:182-214, 1937. 12. Fullerton PM: T h e effect of ischaemia o n nerve conduction in the carpal tunntl syndrome. J Neurol Neurosurg Psychiatry 26~385-397, 1963. 13. Galambos R, Davis H: T h e response of single auditory nerve fibers to acoustic stimulation. J Neurophysiol 6:39-58, 1943. 14. Gassel MM: A study of femoral nerve conduction time. Arch Neurol 9:607--614, 1963. 15. Gassel MM: A test of nerve conduction to muscles of the shoulder girdle as a n aid in the diagnosis of proximal neurogenic and muscular disease. J Nmrol Nmrosurg Psychiatry 27:200-205, 1964. 16. Gassel MM: Sources of error in motor nerve conduction studies. Neurology (,Minneap) 14:825-835, 1964. 17. Gassel MM, Diamantopoulos E: Pattern of conduction times in the distribution of the radial nerve. Neurology (Minneap) 14:222-231, 1964. 18. Gassel MM, Trojaborg W: Clinical and electrophysiological study of the pattern of conduction times in the distribution of the sciatic nerve. J Neural Neurosurg Psychiatry 27:351357, 1964. 19. Gilliatt RW: Ischaemic sensory loss in patients with spinal and cerebral lesions. J Neural Neurosurg Psychiatry 18: 145154, 1955.
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20. Gilliatt RW, Wilson TG: A pneumatic-tourniquet test in the carpal tunnel syndrome. Lancet 2:595-597, 1953. 21. Gilliatt RW, Wilson TG: Ischaemic sensory loss in patients with peripheral nerve lesions. J Neurol Neurosurg Psychiatry 17~104-114. 1954. 22. Gregersen G: A study of the peripheral nerves in diabetic subjects during ischaemia. J Neurol Neurosurg Psychiatry 31:175-181, 1968. 23. Henriksen JD: Conduction velocity of motor nerves in normal subjects and patients with neuromuscular disorders. MS (Phys Med) Thesis, University of Minnesota, 1956. 24. Kugelberg E: Neurologic mechanism for certain phenomena in tetany. Arch Neurol Psychiatr?, (Chic) 56:507-521, 1946. 25. Lambert EH: Electromyography and electric stimulation of peripheral nerves and muscle. In Clinical Exam'iiatioris in Neurology. Philadelphia, Mayo Clinic, 1956. 26. Nathan P: Ischaemic and post-ischaemic numbness and paraesthesiae. J Neurol Neurosurg Psychiatr?, 21: 12-23,1958. 27. Neary D, Ochoa J, Gilliatt RW: Sub-clinical entrapment neuropathy in man./ Neurol Sci 24:283-298, 1975.
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28. Payan J: Electrophysiological localisation of ulnar nerve lesions. J Neurol Neurosurg Psychiatry 32:208-220, 1969. 29. Robinson PK: Sensory changes in the upper limb during ischaemia in tetany. Neurology (Minneap) 5:460-467. 1955. 30. Seneviratne KN. Peiris OA: T h e effect of ischaemia o n the excitability of sensory nerves in diabetes mellitus. J Neurol Neurosurg Psyc.hzatly 31:348-353, 1968. 31. Simpson JA: Electrical signs in the diagnosis of' carpal tunnel and related syndromes. J Neural Neurosurg Psychiatiy 191275-280, 1956. 32. Steiness I: Influence of diabetic status on vibratory perception during ischaemia. Acta Med Scand 170:319-338, 1961. 33. Trojaborg W: Motor nerve conduction electromyography and strength-duration curves. Electroencephalogr Clin Nrurophysiol (Suppl) 22:45-48, 1962. 34. Trojaborg W: Motor nerve conduction velocities in normal subjects with particular reference to the conduction in proximal and distal segments of median and ulnar nerve. Electroencephalogr Clin Neurophysiol 17:314-321, 1964. 35. Trousseau A: Clinigice MMicale, 3rd ed. Paris, JB Balliere, 1868.
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