J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.42.5.422 on 1 May 1979. Downloaded from Journal ofNeurology, Neurosurgery, and Psychiatry, 1979, 42, 422435

Sensory functions in chronic neuralgia

ULF LINDBLOM AND RONALD T. VERRILLO From the Department of Neurology, Huddinge University Hospital, Huddinge, Sweden

SUMMARY Eleven patients with sustained neuralgia, in most cases after traumatic nerve lesion, were subjected to quantitative sensory testing with thermal and non-noxious mechanical stimuli. Measurements were made in the pain area and at a homologous site on the contralateral normal side. All patients were hypoaesthetic with raised thresholds for warm and cold or touch, or both. Thermal pain thresholds were also raised in some patients but lowered in others indicat- ing hypersensitivity of the nociceptor system or dysaesthesia for thermal input. In six patients single mechanical stimuli produced a painful response above the touch detection threshold. Reaction time measurements indicated that this painful response was the result of a central dysfunction rather than of peripheral sensitisation. The response to suprathreshold mechanical pulses was measured by magnitude estimation as a function of stimulus amplitude. The results were fitted by power functions, as in normal skin, but with steeper slopes on the abnormal side. Suprathreshold hyperaesthesia (recruitment) may exist in the presence of normal threshold functioning. Protected by copyright.

The symptom of neuralgia which is the centre of be observed and measured on patients and extra- concern for both the patient and the physician is, polate from experimental physiological data. of course, the pain itself. Of secondary importance Among conceivable peripheral mechanisms, which is the hyperalgesia and other sensory abnormalities have been reviewed recently by Wall and Devor which often occur in the painful area. Hyper- (1978), are receptor sensitisation, multiplication of algesia literally indicates exaggerated pain, and afferent discharges at the site of the lesion in the usually includes both abnormally strong pain on nerve, and ectopic impulse generation. These noxious stimulation, such as pinch or heat, and mechanisms are certainly operative in conditions painful responses to tactile or non-noxious thermal such as skin burn and acute nerve compression. stimulation. The skin of the painful area may Regenerated nerve fibres with heterotypic re- also be hyposensitive to one or more types of ceptor connections or pathological excitability are stimuli with raised perception thresholds and re- possible mechanisms for chronic sensory abnor- duced sensation on suprathreshold stimulation. malities (Trotter and Davies, 1909; Weddell et al., This hypoaesthesia, which can occur together 1948; Wall and Gutnick, 1974; Dickhaus et al., http://jnnp.bmj.com/ with hyperalgesia, is usually taken as a sign of 1976; Ochoa, 1977). They may account both for denervation of the afferent pathway. spontaneous pain and for some components of The sensory abnormalities of neuralgic patients the hyperpathic syndrome-for example, hyper- are often still more complex and consist of, in algesia. Other features, such as radiation of sensa- addition to the features already mentioned, loss of tion, seem to presuppose central mechanisms. identification and localisation of stimulus, radia- These could be imbalance of the afferent inflow tion of sensation, abnormal temporal summation, (Foerster, 1927; Zotterman, 1939; Noordenbos, and after-sensations. This state, which is called 1959; Melzack and Wall, 1965), denervation

hyper- on October 2, 2021 by guest. hyperpathia after Foerster (1927), has been sub- activity of interneurones (Anderson et al., 1971; ject to much speculation about the underlying Sunderland, 1976), central "irritation" or dis- mechanism or mechanisms. Since it is difficult to inhibition (Livingstone, 1943; Melzack, 1971; imitate in animals, one has to build on what can Denny-Brown et al., 1973). In the search for the mechanisms of chronic Address for reprint requests: Dr Ulf Lindblom, Department of Neurology, Huddinge University Hospital, Huddinge S-14186, neuralgias, as well as for improved therapeutic Sweden. tools, it may be as important to study the sensory Accepted 6 November 1978 abnormalities as the pain itself. The primary aim 422 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.42.5.422 on 1 May 1979. Downloaded from Sensory functions in chronic neuralgia 423 of the present study was to examine the sensory peripheral nerve injury was not documented. functions in chronic neuralgia with precise The patient underwent operation on the day of methods, and to describe some of the abnormalities the fracture with screw and cerclage fixation. The quantitatively as a basis for further studies of the pain appeared when the effect of the anaesthetic pathophysiology. Detection thresholds for touch, subsided. There was no evidence of nerve injury cold, warmth, and thermal pain were determined, at the operation. After three weeks there was a and sensations evoked by suprathreshold mech- wound infection which healed after antibiotic anical stimulation were quantified. Reaction time therapy. When the final cast was removed, a measurements were made to determine if pain sensory loss with patchy hyperpathia was found resulting from tactile stimulation is the result of which covered the whole foot, except for the peripheral sensitisation of the nociceptive apparatus medial aspect, and extended laterally over the or of a central dysfunction. lower third of the lower leg. The distribution of the sensory loss was not compatible with a particu- Patients and methods lar peripheral nerve lesion. Conduction velocities of the peroneal and sural nerves were within The basic data on the patients are summarised in normal limits. On the other hand, the sensory loss Table 1. Trauma was the single known aetiological remained and did not vary as a hysterical one. factor in eight cases. In case 1 the trauma was a In case 11 the neuralgia and sensory abnormalities neurotomy that had been performed because of a were confined to the lateral border of the foot. common trigeminal neuralgia. After the neur- Because of the irradiating character of the pain otomy the original neuralgia was replaced by a and associated backache, myelography and continuous burning pain with hyperpathia. In laminectomy were performed without pathological case 2 the lateral cutaneous rami of the caudal findings. Neurography of the sural nerve showed

intercostal nerves were cut or crushed in an normal action potential amplitude and conduction Protected by copyright. emergency renal operation. In case 3 trauma in velocity. the form of neurotomy was a contributory cause. The mean age of the patients was 47.2 years, It was performed because of a neuralgia which and the median age 46.0 years with a range of was supposed to be due to entrapment of the 35 to 61 years. The mean and median duration of genitofemoral and lateral femoral cutaneous pain were 7.1 and 4.0 years respectively with a nerves, but the neuralgic condition was worsened range from one to 24 years. The pain region was instead of improved. In case 5 the neuralgia on the right side in six patients and on the left occurred immediately after an intramuscular in- in five. jection which apparently happened to injure the Before quantitative sensory testing, routine lateral femoral cutaneous nerve. In case 10 a neurological interview and examination were con-

Table 1 Summary of details of patients studied

Case Sex Age (y,r) Pain region Injured nerve(s) Aetiology Duration of Principal type(s) pain (yr) ofpain I F 61 Face Infraorbital Trauma 2 Burning (neurotomy) Throbbing http://jnnp.bmj.com/ 2 F 45 Lumbar Intercostal Trauma 2 Aching Abdomen (neurotomy) 3 F 46 Abdomen Genitofemoral Entrapment 20 Aching Thigh Lateral femoral + trauma (neurotomy) 4 F 47 Thigh lliohypogastric Trauma 24 Aching Lateral femoral (childbirth) Burning 5 F 40 Thigh Lateral femoral Trauma 2 Aching (injection) 6 F 43 Knee Saphenous Entrapment 4 Aching

Burning on October 2, 2021 by guest. 7 F 54 Knee Saphenous Trauma 5 Aching (car accident) Stabbing 8 F 56 Lower leg Sciatic Trauma 10 Aching Foot (car accident) Burning 9 F 54 Foot Sural Trauma 4 Burning (malleolar fracture) Throbbing 10 F 35 Foot Undetermined Trauma I Aching (malleolar fracture) Shooting 11 M 38 Foot Undetermined Unknown 4 Burning Aching

D J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.42.5.422 on 1 May 1979. Downloaded from 424 Ulf Lindblom and Ronald T. Verrillo ducted on each patient to ascertain the nature and randomly applied suprathreshold pulses ranging extent of the pain and to determine the gross from 30 to 70 dB which was the maximum output sensory characteristics of the skin in the painful of the stimulator. area. On the basis of this examination, sites and The second method used for mechanical precise procedures were selected for further test- stimulation was a standard set of von Frey hairs ing. The pain level was scored on a visual analogue calibrated independently by two people in the scale before and repeatedly during and after the laboratory. Thresholds at the 50% level of de- tests, and notes were made on the quality of pain tection for touch and pain were determined. and other sensations. Measurements of thermal sensitivity were made Sensory measurements were determined for two using the Marstock apparatus (Fruhstorfer et al., classes of physical stimuli-mechanical and 1976b). It consists of a stimulator constructed of thermal. Mechanical stimulation was provided by elements operating on the Peltier principle bonded two techniques. The first consisted of single pulses to a metal block perfused with circulating water delivered by a Bruel and Kjaer vibrator (model at 300C. It has a surface area of 1250 mm2 (25X 4810). The displacement of the contactor was 50 mm) in contact with the skin. The tempera- monitored by a capacitance meter whose output ture at the surface of the skin was measured by a was displayed and measured on the grid of an thermocouple bonded to the centre of the contact oscilloscope. The displacement of the contactor area and recorded by a pen recorder which was carefully calibrated to the output of the functions like the Bekesy automatic recording capacitance device by measuring the displacement attenuator (Bekesy, 1947). Before testing, the optically under a microscope. The vibrator was skin temperature was measured at the test site in driven by a wave-form generator (Wavetek 112) the painful area and in the homologous contra- which provided single pulses with a half sinusoidal lateral skin area by means of a digital-readout

wave form at 50 Hz. The contactor was plexiglass thermocouple device. Protected by copyright. with a round, flat surface having a diameter of After the stimulator was situated and taped in 2 mm and an area of 0.03 cm2. It was centred place on the desired site of the skin, the patient within a rigid surround with a gap of less than was instructed to depress a hand switch im- 1.0 mm between the contactor and the edge of the mediately upon feeling warm or, alternatively, surround. This prevented the spread of the mech- cold sensations. Switching changes the direction anical disturbance over the surface of the of current flow within the stimulator and conse- skin. The pulses were triggered manually by the quently the temperature at the surface. The tem- experimenter, and the patient responded by press- perature at the skin surface under the stimulator ing a button which operated a light whenever the caused by the alternate switching by the patient is stimulus was perceived. A modified method of automatically recorded on a moving chart. The limits was used for threshold measurements in threshold of detection is defined as the median which a 75% criterion was accepted for "yes", temperature of the warm and cold excursion limits and "no" responses. A displacement value of 50% of the pen. Approximately one to two minutes of of the difference between these measurements recording time was used to establish each thres- was used as the threshold of detection. The patient hold. The difference between the warm and cold was seated comfortably in a reclining examination thresholds-that is, the neutral zone-was also chair in a position where none of the equipment recorded, since an expanded neutral zone has http://jnnp.bmj.com/ was within view (for further details of the stimula- been shown to be a characteristic of neural tion technique, see Lindblom, 1974). pathology (Fruhstorfer et al., 1976a). With this method measurements were made of Measurements were also made of the cold pain touch detection thresholds, pain thresholds when threshold. The patients were instructed to allow the mechanical pulses could elicit pain, and re- the temperature to decrease until the sensation action times to both touch and pain. Reaction times was painful before pressing the switch. When the were measured using a precision electronic timer temperature rose to within the neutral zone, the activated by the onset of the stimulus and stopped experimenter activated a switch which caused on October 2, 2021 by guest. by a switch pressed by the patient as soon as the the temperature to drop again, and the subject stimulus was perceived. The median value of repeated the procedure, usually three times. After seven trials was taken as reaction time. The in- this measurement, a corresponding procedure was tensity of the stimulus was preset at approximately repeated at high temperatures to establish a heat twice the detection threshold for all reaction time pain threshold. Heat pain tolerance levels were measurements. Psychophysical intensity functions measured in five patients. For this measurement were determined with magnitude estimation of the patient was asked to press the switch only J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.42.5.422 on 1 May 1979. Downloaded from Sensory functions in chronic neuralgia 425 when the heat pain became intolerable. The had dorsal column stimulators, which had good median temperatures of the switching points effect. One patient was treated with intermittent recorded by the pen were taken as the cold pain, vibration or heat stimulation. Sympathetic blocks heat pain, and heat pain tolerance levels. had been performed in four patients with only Mechanical and thermal sensory measurements short-lasting effect. Azapetin (Ilidar) reduced the were determined for each patient in the pain area pain in at least three patients, but side effects and also at a homologous site on the contralateral, hindered sustained medication. normal side. Since thresholds can vary consider- On conventional neurological screening exam- ably at different body sites for both mechanical ination, the camel-hair brush and pinprick were and thermal stimulation, the data are expressed felt as either numb, unpleasant, or painful. The both as raw scores and as different levels between hypersensitivity had typically a patchy or spotty the abnormal and normal sides of the body (ab- distribution, and the location of the sensitive spots normal side minus normal side). This permits an could change somewhat over time (cf Noordenbos evaluation of the effect of the dysfunction com- (1959), p. 9). In three patients touch was painful pared with a normal, homologous site independent only on stroking which implies that substantial of the various areas tested on different patients. spatiotemporal summation was a prerequisite for The results are expressed as mean values. eliciting pain. Even when the stimuli were not Measurements were often repeated to gather data painful, the sensations were different from normal for different phases of the study and to provide touch, pinprick, cold or warmth. The abnormal checks on previously obtained data. In order to quality of the sensation was often associated with insure comparability across patients, data from loss of recognition of the stimulus and usually initial test sessions only are reported. All patients with radiation. The sensation produced by a were examined at least twice over a period of six pointed stimulus then had an areal distribution

to 12 months. and might radiate widely, even outside the region Protected by copyright. of pain and sensory skin changes. Most patients Results had a post-stimulation painful after-sensation of 30-60 seconds duration. These qualitative sensory GENERAL CLINICAL DESCRIPTION changes will be referred to as dysaesthesia. The pain was continuous in all cases except for By analogy with the mechanical stimulation, one in which there were periods when it was inter- the response to thermal stimulation yielded both mittent. The pain was aggravated by physical hypo- and hyperphenomena as well as dysaesthesia. activity, negative emotions, and environmental In some cases moderate cold or warmth, or both, changes such as cold weather. The testing pro- was unpleasant or painful, or was felt stronger cedures produced an overall increase of 18%. The than on the normal side. Delay of sensation dominant quality of pain was aching, but most occurred but was not as conspicuous as in patients also experienced burning, stabbing, throb- postherpetic neuralgia (Noordenbos, 1959). bing, shooting, radiating, tearing, or cramping pain The symptoms and the results of the screening together with the aching type or alternating with examination clearly identified the sensory dis- it (Table 1). turbances with the syndrome of hyperpathia. All patients reported that the area was Some of the cases painful could be diagnosed as causalgia, http://jnnp.bmj.com/ numb, but that touch was unpleasant or painful, either major (case 8) or minor (cases 1-7 and 9), at least in certain patches. Temperatures in the but we prefer the descriptive term chronic range which ordinarily do not hurt were often neuralgia for all cases. Causalgia has been taken painful and increased the resting pain. Several to denote partly different syndromes after trau- patients had found that firm pressure in or near matic nerve injury and is, therefore, an ambiguous the painful region temporarily reduced both pain diagnosis, unless it is specifically defined (Mitchell, and hypersensitivity. 1872; Livingstone, 1943; Noordenbos, 1959; Most patients avoided common be- analgesics Richards, 1967). Furthermore, burning pain, which on October 2, 2021 by guest. cause they had experienced more side effects than is the literal meaning of causalgia, was not a pain relief. Three were under controlled non- prominent or constant feature in our cases. narcotic analgesic and sedative therapy and, at the time when they were tested, transcutaneous nerve QUANTITATIVE SENSORY TESTING stimulation (TNS) had been tried by all patients Mean raw values and mean difference values are with varying results. Two had good pain relief presented in the tables. Mean difference values and used it on a long-term basis. In three cases were obtained by first subtracting the normal side the pain was aggravated by TNS. Three patients measurement from that of the abnormal side for J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.42.5.422 on 1 May 1979. Downloaded from 426 Ulf Lindblom and Ronald T. Verrillo each patient and then taking the mean of the difference between normal and abnormal sides differences. The means of the individual differences when the patients were treated as a single group. were evaluated using a t test for correlated means. However, closer examination of the heat and Comparisons between the hypo- and hypersensitive cold pain measurements showed that the total groups were made using a t test for uncorrelated sample was comprised of two distinct groups: one means. Probabilities are based on a two-tailed with a hypersensitivity to thermal pain and another distribution. that was hyposensitive. Hypersensitivity is ex- pressed as lower temperatures to reach heat pain THERMAL STIMULATION thresholds, and as raised temperatures for cold The mean raw score values of thermal sensitivity pain. Hyposensitivity is reflected by the converse measurements (in degrees Celsius) for the normal result. and abnormal sides of all patients are presented in Figure 1 shows the record of a patient who Table 2. The table shows that there was virtually showed hyposensitivity to thermal pain, and Fig. 2 no difference between the two sides with respect shows the typical record of a patient from the to skin temperature which indicates that there hypersensitive group. The sensory anomalies with was no sympathetic reflex dysfunction at the times respect to thermal pain are clearly illustrated by when the examinations were made. By inspection, these examples. it also appears that values for the abnormal side Note first the greater neutral zone (AT) on the relative to the normal side reflect a loss of abnormal sides of both patients. In Fig. 1, AT sensitivity to warmth and cold with an expanded equals 15.5° on the abnormal side compared to neutral zone. Differences between the two sides 6.50 on the normal side. In Fig. 2, A/T equals appear to be slight with respect to measurements 8.50 on the abnormal side and 5.50 on the normal of heat pain, cold pain, and heat pain tolerance side. levels. The hyposensitive patient (Fig. 1) reached aProtected by copyright. cold pain threshold (CP) at 250 on the normal Table 2 Mean values* of thermal measurements side, but did not feel pain on the abnormal side when the temperature had reached the lower limit Measure Normal Abnormal (100) of the record. The hypersensitive patient Skin temperature 31.50 31.30 (Fig. 2) perceived 10.5° as painful on the normal Warm 37.30 40.30 side but on the abnormal side 240 to Cold 31.50 27.00 felt be pain- Neutral zone 5.40 13.1° ful. Heat pain (HP) was felt at 430 on the normal Heat pain 44.40 43.0° side by the hyposensitive patient (Fig. 1), but at Cold pain 16.50 16.80 Heat pain tolerance 46.70 45.90 a raised temperature of 480 on the abnormal side. The hypersensitive patient (Fig. 2), on the other *All values in °C. hand, raised the temperature to 42.50 on the normal side, while on the abnormal side pain was The results shown in Table 3 are expressed as experienced at 390. the means of the individual differences between Figure 3 gives a graphic representation of the the two sides. These values provide an indication individual results showing the comparison of of the effect of the neural pathology or dys- normal (left columns) and abnormal (right function on thermal sensitivity. It is clear from an columns) sides, as well as the differences between http://jnnp.bmj.com/ inspection of the t test and probability values that the hypo- and hypersensitive groups. One patient the effect is significant with regard to warm and (case 8) did not belong clearly in either group. cold thresholds and the expanded neutral zone on The tops of the cross-hatched columns indicate the abnormal side. There was no thermal pain the thresholds for heat pain; the bottoms are the warmth detection thresholds. The tops of the Table 3 Mean difference values* of thermal hatched columns indicate the cold detection measurements thresholds; the bottoms are the thresholds for cold pain. The clear areas between warm and cold on October 2, 2021 by guest. Measure 4 abnormal-normal df t P thresholds represent the neutral zones. Warm +2.950 10 2.81 < 0.02 All hyposensitive patients are characterised by Cold -4.45° 10 2.24 < 0.05 Neutral zone +7.730 10 2.84 <0.02 higher heat pain and lower cold pain thresholds Heat pain -1.41' 10 1.05 < 0.40 on the abnormal side. The converse is true of the Cold pain +0.320 10 0.10 < 0.90 Heat hypersensitive patients. In all patients except pain tolerance -0.750 5 0.58 < 0.60 case 5 the neutral zone is expanded on the *Ali values in °C. abnormal side. J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.42.5.422 on 1 May 1979. Downloaded from Sensory functions in chronic neuralgia 427 so°c PYPOSENSITIVE HP

43.

_40e C

<300

I20 C LEFT FOOT RIGHT FOOT (NORMAL) (ABNORMAL)

ST ST32.5 -ST DO.5 l2.5 NEVER UNPLEASANT CASE q 3 MIN. JUST COLD

CP 'o" lIo-c Fig. 1 Typical Marstock record from the normal and abnormal foot of a hyposensitive patient. Skin temperature (ST) and thresholds for warmth (W), Protected by copyright. cold (C), heat pain (HP), and cold pain (CP) are indicated as well as the size of the neutral zone (/A T). Diagonal slashes on the heat pain and cold pain traces indicate that the direction of the temperature change was reversed by the experimenter. Note the raised heat pain threshold and the depressed cold pain lhreshold on the abnormal side. The expanded neutral zone on the abnormal side is characteristic of neural pathology.

S50V *C HYPERSENSITIVP

HP

40 C

w http://jnnp.bmj.com/ _ 30 c

aT = 5.5° CP

LEFT RIGHT LATERAL THIGH LATERAL THIGH -20 c (NORMAL) (ABNORMAL) ST ST 30.5-

320 on October 2, 2021 by guest. CASE 4

3 MIN.

cP 10 5- _ 10* c Fig. 2 Typical Marstock record from the normal and abnormal lateral thigh of a hypersensitive patient. Symbols as in Fig. 1. Note that the heat pain threshold is depressed and the cold pain threshold raised. The expanded neutral zone is apparent on the thigh with neural pathology. J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.42.5.422 on 1 May 1979. Downloaded from 428 Ulf Lindblom and Ronald T. Verrillo HYPO HYPER rI- _- -- 50

40 I 40 7// 7/1 71//,.2j 30 X/, X/I A 1.// 7/1 X/,I 20 m E/ 20

10 10 cAM N. 1 2 3 9 11 8 4 5 6 7 10 Fig. 3 Individual results of Marstock measurements for the hypo- and hypersensitive groups (case 8 did not fall clearly into either group). In each case the left bar is the result from the normal side and the right bar from the abnormal side. The tops of the crossed-hatched areas indicate heat pain thresholds; the bottoms are warmth thresholds. The upper limits of the hatched areas are cold thresholds and the lower limits are thresholds for cold pain. The clear intermediate regions indicate the limits of the neutral zone.

The hypo- and hypersensitive groups are com- with an intrinsic characteristic of their thermal Protected by copyright. pared in Table 4 with respect to their raw score sensitivities. values for heat and cold pain. The mean difference The two groups are also clearly distinguishable scores between abnormal and normal sides from their mean difference scores (A A-N) for (A A-N) for the two groups are also shown in both heat and cold pain. Thus, the hypersensitive the Table. There were five patients in each group. group was significantly more sensitive to heat pain The patient, case 8, who clearly belonged in (A=-5.70; P<0.01) and to cold pain (A= neither group was omitted from this analysis. The + 10.70; P<0.001) on the abnormal side. The results show a highly significant difference be- hyposensitive group shows a significant loss on tween the abnormal sides of the two groups for the abnormal side to heat pain (A =+2.7; heat pain (A=+9.70; P<0.001) and cold pain P<0.02), but the results are equivocal for cold (A =-14.80; P<0.001). The nonsignificant dif- pain (A=-7.60; P<0.10). Examination of the ferences on the normal sides for heat pain ( A= individual cold pain data revealed two patients +1.30; P<0.30) and cold pain (A=+3.50; (cases 3 and 11 in Fig. 3) who did not experience P<0.40) indicate that the abnormal side dif- cold pain on either normal or abnormal side. It ferences were associated with the nature of the was our experience that a criterion for cold pain neural pathologies of the two groups rather than was more difficult for patients to establish than a http://jnnp.bmj.com/ Table 4 Comparison of hypo- and hypersensitive grops. Mean values* of heat and cold pain

Measure Side Hypo Hyper J hypo-hyper df t P Heat pain Abnormal 47.80 38.1° +9.70 8 10.37 < 0.001 Normal 45.1° 43.80 +1.30 8 1.24 < 0.30 41 (A-N) +2.70 -5.70 df 4 4 t 4.32 6.99 P <0.02 <0.01 on October 2, 2021 by guest. Cold pain Abnormal 10.1° 24.90 -14.80 8 9.06 < 0.001 Normal 17.70 14.2° +3.50 8 0.96 < 0.40 a (A-N) -7.60 + 10.70 df 4 4 t 2.40 10.89 P <0.10t <0.001 *AIl values in °C. tSee text. J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.42.5.422 on 1 May 1979. Downloaded from Sensory functions in chronic neuralgia 429 criterion for heat pain. It is possible that the lack is shown between the total group and the hypo- of any measurable thresholds for cold pain in sensitive and hypersensitive subgroups, respec- these two patients was the result of a difficulty in tively. The lack of clear differences in all establishing a clear criterion for their purpose. If measurements on the normal side is obvious. The the data are assessed omitting these patients, the deviations between groups as described above are mean difference increases to - 12.60 with P<0.01. conspicuous in the illustration of the abnormal None of the other values is affected by this pro- side. cedure. It is likely, therefore, that there is a A further comment should be made about the significant difference in the detection of cold pain heat pain tolerance measurements. The total between the normal and abnormal sides of the group showed very little difference in heat pain hyposensitive group. tolerance between the normal and abnormal sides Tests of significance were performed for all (-0.750; Table 3). However, when they were other thermal measurements comparing the hypo- divided according to heat pain thresholds, the and hypersensitive groups. In addition to the three patients of the hypersensitive group, whose thermal pain measurements, the groups were heat pain tolerance was tested, measured 2.50 different only with respect to the threshold for lower on the abnormal side with respect to the warmth (Ahypo-hyper=6.1; t=2.36; P<0.05; normal side. The corresponding figure for the df=8). Thus, there were no significant differ- hyposensitive group was +2.30. The tolerance ences between the groups with respect to cold levels for the hyper- and hyposensitive groups threshold, AT, or heat pain tolerance levels. were 43.80 and 48.80 respectively on the abnormal Figure 4 gives a summary of the grouped results side. On the normal side the thresholds were for the normal and abnormal sides. Comparison virtually the same (hyper=46.30; hypo=46.50). Although none of these differences reached statistical significance, they do indicate that fur- 'C NORMAL ABNORMAL ther tests should be made using a larger number Protected by copyright. TOTAL HYPO HYPER TOTAL HYPO HYPER of patients in both groups. Such tests might reveal 50 _ an important diagnostic indicator which could be overlooked on the basis of our small sample. Repeated testing, which was made at least twice on each patient over a period of six to 12 months, showed a remarkable similarity. There might be 40F quantitative variations, but the type of sensory abnormality-for example, hypo- or hyperaesthesia -was always the same. The resting pain was only a minor hindrance during the testing. With proper care of the patients, reassurance, pauses, and so 30_ on, they performed remarkably well and gave reproducible results. There was only one excep- tion, patient 10, whose threshold was almost normal on one occasion when her pain and hyperpathia were temporarily blocked by http://jnnp.bmj.com/ vibration. 20K MECHANICAL STIMULATION Table 5 shows the mean values of measurements made using displacement pulses delivered through the vibrator and those made using von Frey hairs. 10L_,.,,,,,, Thresholds are given in decibels referred to Fig. 4 Mean results of Marstock measurements from 1.0 ytm of peak displacement of the pulses and in on October 2, 2021 by guest. the normal and abnormal sides of the total, the grams for measurements made with von Frey hyposensitive, and the hypersensitive groups. The hairs. bars are explained in Fig. 3. Note the small It is apparent from examination of Table 5 differences between the groups on the normal side as that the patients were less sensitive to mechanical contrasted with the same measurements on the sides. The reaction abnormal side. An expanded neutral zone (clear stimulation on their abnormal areas) is evidenced on the abnormal side of all three time to touch also appeared to be longer on the groups. abnormal side. J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.42.5.422 on 1 May 1979. Downloaded from 430 Ulf Lindblom and Ronald T. Verrillo Table 5 Mean values of tactile measurements a similar separation could be made on the basis of their responses to mechanical stimulation. Al- Stimulus Measure Normal Abnormal though differences between the two groups on their Pulse Touch threshold 41.2 dB 50.9 dB abnormal sides were generally in the direction of Touch reaction time 0.29 s 0.37 s for the hypersensitive group, Pain threshold 60.6 dB greater sensitivity Pain reaction time 0.48 s the differences can be accepted only at very low levels of confidence. Thus, patients who are hypo- von Frey Touch threshold 0.43 g 1.06 g Pain threshold 3.7 g or hypersensitive with respect to thermal pain could not be identified on the basis of their Decibel values re 1.0 gm of peak displacement. responses to mechanical stimulation. We noted during both the clinical and experi- When the pulse amplitude was successively in- mental testing that, although the detection creased above the detection threshold, a new threshold for mechanical stimulation was raised. threshold was reached in six patients for whom the the patient often reported that suprathreshold pulse produced a painful instead of a tactile stimulation felt stronger on the abnormal side. This sensation. The average stimulus strength at which observation is consistent with clinical reports of this occurred was 60.6 dB as compared to 50.9 dB "over-reaction" as well as research evidence that for the touch threshold. As is also shown in steeper intensity functions, commonly referred to Table 5, the reaction time to the painful response as "recruitment," can accompany neural pathology was slightly longer. Pain could not be elicited on in various sense modalities (Barlow, 1976; Franz6n the normal side of any patient by the method of and Lindblom, 1976; Hallpike, 1976). A state of pulse stimulation. hypersensitivity or hyperaesthesia stands out as an The values for touch shown in Table 6 express essential feature of the sensory abnormalities which the mean differences of individual measurements are associated with many neuralgias. To obtain a on the normal side subtracted from those obtained measure of the suprathreshold hyperaesthesia, we Protected by copyright. on the abnormal side. The latter is shown to be decided to determine the intensity functions using significantly (P<0.01) less sensitive to displace- the mechanical pulses and the method of subjective ment pulses than the normal side. Although magnitude estimation. This was made on four measurements made with von Frey hairs yielded patients who had indicated hyperaesthesia (but not results in the same direction, the difference was pain) for mechanical pulse stimulation. After not significant (P<0.10). The individual data for determination of the detection threshold for single touch detection thresholds were plotted against pulses, a series of suprathreshold stimuli of dif- the pain ratings from visual analogue scaling. ferent intensities was presented in random order. There was no correlation between threshold eleva- After three presentations of each intensity, the tion and pain intensity. patients were asked to assign a number which The difference in reaction time to pulses be- they thought represented the subjective intensity tween normal and abnormal side was significant of the sensation. In order to eliminate bias in the (P<0.05) but not the difference (+0.17 s) be- slope values (Stevens, 1956; Hellman and tween the reaction times to touch and pain on the Zwislocki, 1961), no standard or modulus was abnormal side (df= 3; t=2.07; P<0.20). given, nor was a range of numbers suggested. Because the heat and cold pain measurements Each intensity was judged twice on both the http://jnnp.bmj.com/ revealed two distinct groups, one hypo- and the normal and abnormal sides. The numbers assigned other hypersensitive, we decided to examine were then averaged for the two trials and plotted the mechanical stimulation data according to the as a function of the physical intensity of the same division of patients in order to determine if stimulus in decibels referred to 1.0 ,tm of peak- displacement. Note that the slopes of the sub- Table 6 Mean difference values of tactile jective intensity curves have been computed in measurements terms of intensity rather than amplitude of dis- on October 2, 2021 by guest. Touch placement. This practice is recommended for several reasons. Research in several sense Stimulus Measure Abnormal- df t P modalities has shown that near the threshold of normal detectability there is a direct proportionality Pulse Threshold +9.7 dB 10 3.40 < 0.01 between the intensity of the stimulus and neural Reaction time +0.08 s 8 2.30 < 0.05 activity (Zwislocki, 1974). In addition, the use of von Frey Threshold +0.63 g 8 2.16 <0.10 intensity values permits direct comparisons be- Decibel value re 1.0 zm of peak displacement. tween sense modalities since intensity may be J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.42.5.422 on 1 May 1979. Downloaded from Sensory functions in chronic neuralgia 431 used across all systems, whereas amplitude of much more rapid growth of sensation on the displacement is limited to mechanoreceptive abnormal side (closed circles). systems. Direct comparison of our slopes with studies which report amplitude values may be Discussion made by halving the amplitude slope values. Graded intensity functions were obtained from HYPOAESTHESIA both sides of all patients, and the results from Hypoaesthesia as measured by means of con- two are illustrated in Fig. 5. The data in Fig. 5A ventional bedside tests like touch, pinprick, and are from a patient with a moderately raised warm and cold water has long been recognised as threshold. The curve from the abnormal side one of the sensory abnormalities in neuralgia (filled circles) is similar to that from the intact associated with lesions of peripheral nerves side (open circles) but is steeper and converges (Mitchell, 1872; Noordenbos, 1959; and others). at the level of maximum stimulus strength. The With recently developed quantitative methods, curves from the other three patients consistently sensory abnormalities can be assessed with higher showed a more rapid growth of sensation on the accuracy and graded more exactly (Dyck, 1975; abnormal side. In addition, although they showed Lindblom and Meyerson, 1975; Fruhstorfer et al., less threshold sensitivity on the abnormal side, 1 976b; Goldberg and Lindblom, unpublished). The they demonstrated hyperaesthesia in terms of methods used in the present study enable selective increased subjective magnitude at most stimulus measurement of passive touch, temperature, and strengths. The average slope of subjective magni- thermal sensations. Hypoaesthesia in terms of a tude for all patients was 0.51 on the normal side measurable increase in perception thresholds was as compared to 0.80 on the abnormal side. Figure found for both mechanical and thermal stimuli in SB illustrates an example of unimpaired threshold practically all cases. This is in contrast to, for response, which is the same on both sides, but a example, trigeminal where the sensory neuralgia Protected by copyright.

A B

LIn tD SLOPE - .91

z a z L In (U) z SLOPE =.56

z CD http://jnnp.bmj.com/ UI. I- C)

LATERAL THIGH O NORMAL (RIGHT) THRESHOLD 46 dB D * ABNORMAL (LEFT) >o THRESHOLD 46 dB l l 30 40 50 60 70 80 90 30 40 50 60 70 80 90 on October 2, 2021 by guest. DISPLACEMENT IN dB RE 1.0 MICRON PEAK Fig. 5 Subjective intensity functions for mechanical pulses obtained by the method of magnitude estimation from two patients, one hyposensitive (A) and the other hypersensitive (B). In both cases the growth of sensation as a function of stimulus intensity is more rapid on the abnormal side even when the threshold for detection is the same for both sides (B). This illustrates that a disturbance of suprathreshold functioning may result from neural pathology although threshold sensitivity is normal. J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.42.5.422 on 1 May 1979. Downloaded from 432 Ulf Lindblom and Ronald T. Verrillo functions are normal except for the trigger warm and cold than on the normal side. In the mechanism (Verrillo and Ecker, 1977). The present hyposensitive group the ranges for warm and cold results also demonstrate that a low degree hypo- sensation were comparable on both sides (Fig. 4). aesthesia can be assessed even in the presence of One possible explanation for the decreased spontaneous pain and hyperaesthesia. Using thermal pain threshold would be sensitisation of mechanical pulses it was confirmed that supra- the nociceptors for heat and cold pain. We would threshold hypoaesthesia can be measured by means then be concerned with increased sensitivity of a of magnitude estimation (Fig. 5A). normally nociceptive system, and the condition Hypoaesthesia is usually taken as a sign of would best be described as thermal hyperalgesia, denervation through the nerve lesion, and tactile or noxious thermal hyperaesthesia. Another possi- and thermal loss indicate injury of coarse and bility is that the painful responses which were fine nerve fibres, respectively (Dyck et al., 1971). evoked by non-noxious warm and cold stimuli are Histological studies in postherpetic neuralgia mediated by warm and cold fibres. Recent reaction (Noordenbos, 1959) have revealed a preferential time measurements indicate this possibility loss of large fibres which led to the assumption (Fruhstorfer and Lindblom, unpublished). Dis- that pain may result from loss of inhibitory large charges in such nerve fibres normally evoke fibre input. In the present study, as judged by the thermal sensations. If they instead produce pain, sensory tests, both large and fine fibre functions we would be concerned with an abnormal quality were impaired. There was no correlation between of sensation. Dysaesthesia would then, as discussed the degree of tactile hypoaesthesia and the in- below, be a more adequate description of these tensity of the neuralgia. Considerable pain, as responses, which could be specified as painful well as hyperaesthesia, occurred together with thermal dysaesthesia. Goldscheider (1926), citing only minute changes of the tactile threshold. Thus, Schilder's (1913) observations on cold hyper- lack of large fibre afferent inhibition did not seem aesthesia, has previously discussed the option of to be important for the development of the hypersensitivity of the thermal sense versus in- Protected by copyright. neuralgia in the cases studied. creased sensitivity of "pain points" to thermal Although hypoaesthesia most often can be stimulation. taken as a sign of neural pathology, the diagnosis Although three of the four patients we tested of a peripheral nerve lesion should preferably, as for sensation magnitude were hypoaesthetic at in most cases in this study, be based on other threshold on the abnormal side and one had equal evidence than the result of sensory testing. One thresholds on both sides, all of the magnitude has to consider that a functional block at spinal estimates could be fitted by a power function with or higher levels associated with the pain state may significantly higher slopes on the abnormal side produce hypoaesthesia. Such a mechanism was (Fig. 5). This is consistent with similar measure- seemingly operative in one of our patients (case ments for hearing (reviewed by Hallpike, 1976), 10) in whom evidence of a persistent peripheral vision (Barlow, 1976), and touch (Franzen and nerve lesion was lacking. Considerably improved Lindblom, 1976). The phenomenon of steepened sensory functions were recorded on one occasion sensation-magnitude functions associated with when she was temporarily relieved of her pain and elevated thresholds is generally called "recruit- typical hyperpathia by vibration. Otherwise the ment." The importance of testing at supra- threshold changes were unrelated to the pain threshold levels is underlined by the results http://jnnp.bmj.com/ level, and it was repeatedly confirmed that they illustrated in Fig. SB which show that hyper- were not caused by distraction due to pain and aesthesia at suprathreshold levels of stimulation paraesthesias. may exist in a patient with normal threshold. This phenomenon has been demonstrated in experi- HYPERAESTHESIA mental hyperalgesia (Hardy et al., 1952). Two measures of hyperaesthesia were obtained: No theory has been advanced that will ad- one was decreased thresholds for thermal pain equately explain the recruitment phenomenon in and the other augmented sensation on supra- any sense modality. However, for vibro-tactile on October 2, 2021 by guest. threshold mechanical stimulation. Five patients sensitivity it has been demonstrated that the slopes showed decreased thermal pain thresholds, in of functions in normal skin are inversely related most cases for both warm and cold stimuli (Fig. 3). to the sensitivity of the stimulated region (Bekesy, Since the thresholds for warm and cold were raised 1957, 1959; Stevens, 1959; Verrillo and Chamber- simultaneously, the ranges of thermal sensation lain, 1972). Verrillo and Chamberlain (1972) were compressed from both ends in this group. demonstrated that the steeper growth rate in areas This indicates steeper intensity functions for both of reduced sensitivity is probably related to the J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.42.5.422 on 1 May 1979. Downloaded from Sensory functions in chronic neuralgia 433 fewer number of neural units excited rather than We wanted to investigate the pathophysiological to a reduced receptor density as proposed by mechanism of the painful response to non- Bekesy (1957, 1959). This finding was later cor- noxious mechanical pulses. The first step was to roborated by Franzen and Lindblom (1976) on characterise the afferent pathway by reaction patients with peripheral nerve lesions. Thus, we time measurements. The reaction time to the may suggest that the increased slope of the sub- painful response was on average 0.48 s. This is jective intensity function in patients with elevated clearly too short to allow for conduction in C thresholds is governed by a central integrating fibres (Zotterman, 1933; Fruhstorfer, 1976). The mechanism in which the "gain" is affected by the times were longer than those to the tactile re- number of receptor inputs. An alternative ex- sponse evoked from contralateral normal skin. It is planation of the recruitment would be central possible that the afferent pathway consists of disinhibition allowing transmission and perception A-delta nociceptive fibres with an abnormal ex- of the mechanoreceptive discharges at a higher citability after regeneration, perhaps through "gain." A third hypothesis would invoke an heterotypic receptor connections. Such an arrange- enhanced responsiveness in the individual primary ment would allow them to be fired by the non- afferent fibres. This mechanism would imply that noxious mechanical pulses. With retained central the responsible mechanoreceptors have an ab- connections such fibres would then mediate painful normally high excitability as a result of the nerve sensations evoked by innocuous stimuli. However, lesion. It should be possible to test this hy- outgrowing fibres have a remarkable ability to pothesis by performing percutaneous micro- resume their normal function (Burgess and Horch, neurography on patients and studying the 1973), and the reaction times to the painful sensa- characteristics of single afferent units. tion were similar to the reaction times to the tactile responses evoked below the pain threshold. DYSAESTHESIA It is, therefore, most likely that the afferent Protected by copyright. Dysaesthesia literally means "bad sensation" and pathway is the tactile fibres, and that the abnormal the term would, therefore, denote various kinds painful character of the sensation is due to central of somatosensory disturbances including hyper- mechanisms. This is in agreement with the block- pathia. Operationally, however, dysaesthesia refers ing experiment of Wallin et al. (1976) in a patient more to qualitative than to quantitative changes with hyperalgesia to touch and cold stimulation. and indicates an abnormal sensation which is more The hyperalgesia disappeared simultaneously with or less unpleasant because it is painful or the touch and cold sensation while the C fibres unfamiliar. To the extent that the sensory abnor- were still conducting. It is appealing to speculate malities can be defined as hypo- and hyper- that the convergent dorsal horn cells which aesthesia, as they are in this study, it seems respond to both low threshold mechanical and appropriate to use these more descriptive terms noxious stimulation are involved. These cells are a and let dysaesthesia denote the array of primarily conspicuous and numerous population. They pro- qualitative changes for which more precise words ject to a large extent to higher levels but their are not yet available. One such change which will exact physiological role is unknown. Normally, be discussed here is the painful response to tactile the cells are suppressed by a descending tonic stimulation which is usually called hyperalgesia. inhibition (for references see Albe-Fessard and It was confirmed in this study that the same Fessard, 1975). If it is assumed that the cells are http://jnnp.bmj.com/ mechanical stimuli never evoke a painful sensa- disinhibited in the pathological state of neuralgia, tion in normal skin. We are thus concerned with and that their activity can produce a sensation, an abnormal quality of sensation, painful instead this would have the character of the painful of tactile, and it may be more appropriate to call tactile dysaesthesia. Other components of the the condition painful tactile dysaesthesia. This hyperpathic syndrome such as radiation of response was obtained in six patients, four of sensation and after-sensation may also be ex- whom belonged to the thermally hypersensitive plained by disintegrated central inhibition. This is group. In all six cases the detection threshold was still a hypothesis, however, and direct evidence on October 2, 2021 by guest. lower than that of the painful response. Thus, can probably only be obtained in experiments with there was always a range, although it might be chronic nerve lesions in animals. Clinical observa- small, in which the mechanical stimuli below the tions may give interesting information. For pain threshold evoked only tactile sensations. example, multiple sclerosis patients with demy- These were both hyper- and dysaesthetic but their elinating lesions involving the spinal grey matter existence shows that the tactual sense was in some may suffer from painful seizures (Shibasaki and way retained. Kuroiwa, 1974) which are evoked by tactile stimuli J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.42.5.422 on 1 May 1979. Downloaded from 434 Ulf Lindblom and Ronald T. Verrillo and have a similar pattern of radiation and after- and by skin vibrations. Journal of the A coustical sensation as is seen in the neuralgia patients. Society of America, 29, 1059-1069. Some general comments may be made on the Bekesy, G. von (1959). Neural funneling along the value of quantitative sensory testing in pain skin and between inner and outer hair cells of the patients. Such testing can be a valuable aid in the cochlea. Journal of the A coustical Society of diagnosis of a nerve lesion where America, 31, 1236-1249. conventional Burgess, P. R., and Horch, K. W. (1973). Specific methods are too crude. Furthermore, the course regeneration of cutaneous fibers in the cat. of a disease can be followed by repeated measure- Journal of Neurophysiology, 36, 101-114. ments in the same patient. Wider application in Denny-Brown, K., Kirk, E. J., and Yanagisawa, N. the clinic will probably help to classify various (1973). The tract of Lissauer in relation to sensory painful and other sensory disturbances which are transmission in the dorsal horn of spinal cord in the now grouped under various headings such as Macaque monkey. Journal of Comparative neuritis (Wartenberg, 1958). An important point Neurology, 151, 175-200. is whether spontaneous pain and the sensory abnor- Dickhaus, H., Zimmerman, M., and Zotterman, Y. malities, especially hyperalgesia, may have the (1976). The developments in regenerating cutaneous nerves of C-fiber receptors responding to noxious same pathophysiology. If so, a further close study heating of the skin. In Sensory Functions of the of the sensory dysfunction may provide evidence Skin in Primates, pp. 415-423. Edited by Y. about pain mechanisms and perhaps contribute Zotterman. Pergamon Press: Oxford. to the search for new and more affective remedies. Dyck, P. J., Lambert, E. H., and Nicholas, P. C. On the other hand hyperpathia is often seen (1971). Quantitative measurement of sensation without spontaneous pain during nerve regenera- related to compound potential and number and tion (Head et al., 1905) and in patients with vari- sizes of myelinated and unmyelinated fibers of ous neuropathies. The converse is also true, sural nerve in health, Friedreich's ataxia, hereditary sensory neuropathy, and tabes dorsalis. In Hand-

namely that pain may occur disturbed Protected by copyright. without book of Electroencephalography and Clinical sensation as in trigeminal neuralgia. Deductions Neurophysiology, volume 9, pp. 83-118. Edited by about pain mechanisms from the characteristics W. A. Cobb. Elsevier: Amsterdam. of the sensory abnormalities should, therefore, be Dyck, P. J. (1975). Quantitation of cutaneous sensa- made with caution. tion in man. In Peripheral Neuropathy, pp. 465- 479. Edited by P. J. Dyck, P. K. Thomas, and E. H. We are indebted to Dr Bjorn Meyerson and the Lambert. W. B. Saunders: Philadelphia. Department of Neurosurgery, Karolinska Foerster, 0. (1927). Die Leitungsbahnen des Schmer- Sjukhuset, for offering patients for study, and to zgefuhle. Urban and Schwartzenberg: Wien. Mrs Berit Lindblom for excellent technical assist- Franzen, O., and Lindblom, U. (1976). Tactile in- ance and patient care. The was tensity functions in patients with sutured peripheral study supported nerve. 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