Medical modification of sensation CHARLES J. HODGI~ JR., M.D., AND ROBERT B. KING, M.D.
Department of Neurosurgery, Upstate Medical Center, Syracuse, New York ~" The authors describe the sensory examinations of three patients who bad undergone cervical rhizotomy alone and in combination with trigeminal tractotomy and section of the nervus intermedius, the glossopharyngeal nerve, and the upper portion of the vagus nerve. Following administration of L-dopa there was an increase in their pain and a decrease in the area of clinically anesthetic or analgesic skin. When methyldopa was given, the subjective and objective changes were the opposite of those elicited by L-dopa. These observations support the existence of a wider dorsal root cutaneous distribution than is usually accepted as well as significant control of cutaneous sensation by suprasegmental areas of the central nervous system. Part of the suprasegmental bias supplied to the area in the spinal cord that processes sensory information apparently occurs by way of an aminergic descending reticulospinal tract. These findings are discussed in terms of attempts totally to denervate restricted cutaneous areas of the body for treatment of pain-producing states. KEvWORDS pain s p i n a l nerve r o o t s 9
9 L-dopa 9 methyldopa cutaneous sensation
y the method of remaining sensibilities and a construction technique, Foerster 1~ demonstrated a moderate overlap of the cutaneous distribution of neighboring dorsal roots. Each area of skin was thought to be supplied by three nerve roots. His observations confirmed the earlier work of Sherrington 27 in monkeys, and Head and CampbelP 6 in humans. Because anterolateral cordotomy may not provide sustained relief of chronic pain, rhizotomy has been suggested for the relief of pain in limited regions of the abdominal or thoracic wall? 4 When the craniocervical junction is involved, denervation is more complex. This has been attempted through sectioning multiple sensory cranial nerves and the upper cervical dorsal roots, at times in combination with a trigeminal t r a c t o t o m y ? 4 The results of
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J. Neurosurg. / Volume 44 /January, 1976
9
trigeminalnerve
9
rhizotomies are frequently poor even though several roots are sectioned rostral and caudal to the area primarily involved in the painful process. 23,2~ The reason for these failures to achieve adequate denervation is unclear, although variations in dermatome, scleratome, and m y o t o m e distributions have been suggested? 3 Denny-Brown and his associates have suggested that the overlap of cutaneous sensory dermatomes, including that of the fifth cranial nerve, exceeds the usual limits described in the literature and that transmission through a single root is variable. 1~176 The present study was undertaken to determine if the variability of sensory perception described by Denny-Brown 1~176 in monkeys is also present in man, and if this variability has any significance in relation to the recurrence of pain after what was presumed
21
C. J. H o d g e , Jr. a n d R. B. K i n g
FIG. 1. Case 1. Upper." Results of sensory examination before operation (left), 1 month after (center) and 17 months after operation (right). Seventeen months postoperatively, using electrical stimuli, sensory cutaneous responses could be elicited from all areas of the skin that were apparently anesthetic to standard clinical stimuli. Lower: Diagram showing the extent of the constriction of the area of anesthesia 60 minutes after a single oral dose of L-dopa (250 mg). There was no significant change in the area of analgesia.
to be adequate unilateral denervation of the head and neck.
Methods The three patients we are describing had severe pain that was not controlled with narcotics; we felt that denervation procedures for pain relief were justified in each case. Postoperatively, a variety of medications were given including L-dopa, methyldopa, and 20% nitrous oxide. The patients understood that these drugs were being used experimentally, that the option to withdraw from the study was open at all times, and that withdrawal would have no bearing on their future or present care. The patients were all examined during the day usually by both authors in a 68 ~ to 70~ treatment room. The examinations were not completed or recorded if the patients were fatigued, uncomfortable, or anxious. There was at least a 4-hour lapse between the patients' most recent pain medication and the time of the examination. Sensory testing was carried out in a standard fashion. Wisps of cotton were used for tactile stimuli and pinpricks for superficial noxious
22
stimuli. In one patient electrical cutaneous stimulation was also used. The patterns of sensory changes were mapped on the skin and then transposed to standard sensory charts. In some instances photographic records were made.
Case Reports Case 1 This 46-year-old woman underwent section of the dorsal roots of C1-4 because of intractable postauricular and occipital pain secondary to massive bone degenerative proliferation at the C2-3 facet. Figure 1 upper depicts her sensory status pre- and postoperatively. Preoperatively there was mild hypesthesia over the second and third cervical dermatomes on the right which was most dense in the distribution of the postauricular nerve. In the stable early postoperative period there was the expected anesthesia surrounded by a band of analgesia involving the C-2, C-3, and C-4 dermatomes. The patient was free from pain at that time.
J. Neurosurg. / Volume 44 / January, 1976
Medical modification of sensation
FIG. 2. Case 2. Results of sensory examination before (left) and 1 week after (right) trigeminal tractotomy and section of the nervus intermedius, the glossopharyngeal nerve, the upper rootlets of the vagus nerve and C 1-4 dorsal roots. Postoperatively there was a thin band of hypesthesia, marked by the solid black line, surrounding the anesthetic area.
Seventeen months later she complained of recurrent pain over the right side of her neck and occasionally in her right shoulder. Examination revealed constriction of the area of anesthesia. In the suboccipital region light touch was intermittently perceived but was poorly localized. In the supraclavicular area repetitive pinprick was interpreted as scratch or itch. With electrical stimulation of the clinically anesthetic skin (repetitive monopolar isolated square-wave stimuli) there was no area from which a cutaneous sensory response could not be elicited, although the threshold throughout was higher than that of normal skin. Following a single oral dose of L-dopa (250 mg) there was subsequent further constriction of the area of anesthesia. Figure 1 lower left shows the area of skin, previously anesthetic, in which touch could be perceived after L-dopa. The examination during the administration of 20% nitrous oxide in oxygen was similar to that of the immediate postoperative period.
Case 2 This 59-year-old man suffered intractable right jaw, ear, and neck pain secondary to a pharyngeal mucoepidermoid carcinoma metastatic to the lymph nodes of the right side of his neck. Figure 2 shows the results of his pre- and postoperative sensory examination. There was hypalgesia over the third division of the trigeminal nerve and hypesthesia over the anterior neck on the right. A trigeminal tractotomy was done 4 mm below the obex; the nervus intermedius, the
J. Neurosurg. / Volume 44 /January, 1976
glossopharyngeal nerve, the upper two rootlets of the vagus nerve, and the C1-4 dorsal roots on the right were severed. The postoperative extent of analgesia and anesthesia was consistent with the tractotomy and rhizotomies. There was an area of intact sensation around the external auditory canal even though the gag reflex and general sensation on the right side of the pharynx were absent. The analgesia of the right side of the patient's face spared the paranasal area, a finding most likely related to the level of the tractotomy. 21 An unusual finding, when compared to the normal dissociative sensory loss following rhizotomy, 8'12,2~was that the area of loss of light touch was greater than the area of analgesia. At this time the patient was free of pain. Two months postoperatively he was given a 6-day course of L-dopa (500 mg/6 hr for 3 days and 1 gm/6 hr for 3 days). He complained of burning pain about his right eye and a deep ache in his jaw and right shoulder while taking L-dopa. The sensory examination performed at that time is shown in Fig. 3. There was a decrease of both the area of anesthesia from the rhizotomies and the area of analgesia from the tractotomy. The small area about the tragus where sensation was intact had increased in size. When larger doses of L-dopa were given, light touch in the supraclavicular region was spottily identified and in places repetitive pinprick was recognized as painful, this sensation frequently being referred to the suboccipital area. When administration of L-dopa was stopped, the area of sensory deficit reverted to 23
C. J. Hodge, Jr. and R. B. King
FI~. 3. Case 2. Results of sensory examination 2 months postoperativelywhile patient was receiving L-dopa, 500 mg/6 hr (left) and 1 gm/6 hr (right). The border of normal sensation while he was on no medication is shown by the crossed line. the premedication boundaries and the patient no longer complained of pain. His sensory examination stabilized, but as his tumor grew he again became uncomfortable with rightsided neck and face pain. He was then given a placebo with little change in his sensory examination (Fig. 4 left) and no change in the pain he was reporting. At this time he was given methyldopa (250 mg/6 hr) for 3 days. While taking his medication, he was again free of pain and felt as well as he had at any time since his surgery, despite his deteriorating clinical condition. On examination (Fig. 4 right) there was some increase in the areas of anesthesia and analgesia compared to when he was taking the placebo.
Three weeks postoperatively she complained of minimal left ear and jaw pain but had little change in her examination except for some paranasal loss of analgesia. She was then given a 3-day course of L-dopa (250 mg/6 hr). During this period her pain became much more severe, particularly about the left ear and eye. Results of a sensory examination at this time are shown in Fig. 6. The lower border of anesthesia and hypesthesia had shifted upwards from her trunk so that only her neck and upper sternum were included. The face remained analgesic only over the third division of the fifth nerve and there was a patch of normal sensation about the tragus and external canal. After receiving placebos for several days, she returned to her control state. She was then started on methyldopa (750 mg/24 hrs) with prompt relief of the pain which she had been reporting while taking the placebo. There was expansion of her anesthetic areas as shown in Fig. 7. The area of anesthesia extended well down to her trunk and over her shoulder. She was then given a trial of nitrous oxide (20%) in oxygen with further expansion in the apparent areas of denervation. Figure 8 is a composite of the extremes of her sensory loss under the influence of the medication mentioned. Because of the striking pain relief obtained while she was receiving methyldopa, the patient remained on low doses of this drug until her death 2 months later.
Case 3 This 54-year-old woman suffered severe left face, ear, and neck pain from carcinoma of her left middle ear with left-sided neck metastases. She underwent trigeminal tractotomy 5 mm below the obex, section of the nervus intermedius, glossopharyngeal nerve, upper rootlets of the vagus nerve, and the C1-4 dorsal roots. Preoperatively (Fig. 5 left) there was anesthesia over the distribution of the third division of the trigeminal nerve on the left and mild hypesthesia over the area served by the first two branches of the fifth nerve as well as the anterior neck. Her postoperative status was what would be expected from the rhizotomies and trigeminal tractotomy (Fig. 5 right). However, she too Discussion showed a reversal of the normal dissociative The observations made in the study of these anesthetic pattern generally seen after dorsal rhizotomy. She was free of pain at that time. patients emphasize the variability of sensory 24
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Medical modification of sensation
F~. 4. Case 2. Results of sensory examination l0 weeks postoperatively while patient was taking placebos (left) and metbyldopa, 250 rag/6 hr (right). The solid line represents the border of normal touch perception.
FIG. 5. Case 3. Results of sensory examination before (left) and 2 weeks after (right) trigeminal tractotomy, and section of the nervus intermedius, the glossopharyngeal nerve, the upper rootlets of the vagus nerve, and the C1-4 dorsal roots. loss following rhizotomy and tractotomy within an individual over short periods of time incident to drug administration. It has been implied that the sensory loss following rhizotomy is relatively stable 34 and that failure of rhizotomy as a pain-relieving procedure may be related to unknown patterns of more extensive segmental overlap of deep structures. TM Variation in dermatomes between individuals has been described by Sicard, et al., 28 and by White and Sweet 3a and has been attributed, at least in part, to anastamoses between the dorsal roots. '~,z6 The fact that two of our patients, one after L-dopa and one spontaneously, developed cutaneous sensation and spontaneous pain in the center of the denervated field suggests that the cutaneous overlap in distribution of the dorsal roots is more extensive than is generally accepted. It seems reasonable to J. Neurosurg. / Volume 44 / January, 1976
assume that larger areas of preserved sensation could have been unmasked if we had higher doses of L-dopa in these studies. The anatomical basis for suggesting wider central distribution of dorsal roots is firm in that Szenthgothai, 29 using degeneration techniques, had demonstrated a cord distribution of up to six segments for the terminals of a single root in the substantia gelatinosa. Illis 18 has shown a similar distribution of dorsal root terminals in the central and ventral portions of the spinal gray matter. Although it is certainly not definite, the return of sensation in the central denervated area seen in Case 1, 17 months postoperatively, does not seem to be due to the phenomenon of dorsal root sprouting as described by Liu and Chambers, 22 but rather to increased transmission and functional reorganization through already existing pathways. If such were not 25
C. J. Hodge, Jr. and R. B. King
Fic. 6. Case 3. Results of sensory examination while the patient was receiving L-dopa, 250 mg/6 hr. The border of normal sensation while on no medications is shown by the crossed line.
FIG. 7. Case 3. Areas of anesthesia added by administering methyldopa (left) and then 20% N20 (right) are indicated by the solid black areas.
F~. 8. Case 3. Drawing illustrating the borders of anesthesia while the patient was taking L-dopa (solid black), methyldopa (parallel lines), and nitrous oxide (dots) have been transposed to one drawing for purposes of comparison. When the anesthetic area was constricted (L-dopa) she reported increasingly severe pain in the ear, neck, and head but was quite comfortable while taking methyldopa and during 20% N20 inhalation. 26
the case, it would be most difficult to explain the nearly identical change in Case 2, 2 months postoperatively, only while receiving L-dopa. The more extensive distribution of dorsal root innervation is further supported by the observation in Case 1 that there was no area that was totally insensitive to monopolar electrical stimulation. In two other patients not reported here, both with four-level thoracic intradural rbizotomies, we did not find any area of total anesthesia by testing with electrical stimuli. These observations strongly support the conclusions that Kirk and Denny-Brown 2~ made in a study of macaque monkeys, namely, that each area of skin was apparently supplied with representation from at least five separate roots. As noted in monkeys 11 there was some effect of section of the descending tract of the fifth nerve on areas other than those innervated by that nerve. The normal pattern of sensory loss following rhizotomy is that the area of analgesia is more extensive than the area of anesthesia. "'16'27 In both Cases 2 and 3 this pattern was reversed and may represent a lack of the facilitory background convergence onto cells transmitting from the small-fiber system. Denny-Brown, et al., H have described the importance of an intact central system of convergence, by way of Lissauer's tract and the descending tract of the fifth nerve, for adequate summation of noxious stimuli from the periphery? T M The mechanism whereby L-dopa has enhanced transmission from the partially denervated areas in these patients is uncertain. Aminergic pathways are manifold in the brain and spinal cord. 6'9 They include a descending reticulospinal pathway originating from the lower pons and upper medulla which terminates in the ipsilateral spinal cord. The terminations are several and include the ventral horn, the lateral gray column, and the posterior aspect of the substantia gelatinosa. That sensory input may be affected by descending suprasegmental influences is clear. ~,1~,~7,2''3~ The aminergic pathway described may contribute to the suprasegmental modulation of sensory events in the dorsal horn. This pathway, studied by And6n, et al., ~,z and Baker and Anderson, 3 has an effect somewhat similar to that seen in the decerebrate preparation; 7 that is, its activation by L-dopa causes inhibition of the J. Neurosurg. / Volume 44 /January, 1976
Medical modification of sensation transmission from the flexor reflex afferents (FRA) to motor neurons, ascending systems, and segmental interneurons. The response to prolonged noxious cutaneous stimulation is, however, enhanced presumably reflecting a late effect on the pathways from the FRA. 24 Presumably methyldopa acts by blocking decarboxylation of dopa and thereby decreasing tissue levels of norepinephrine. TM The effect noted in the sensory examination did not seem related to the general depressant effect of this medication as the sedative effect was transient, but the sensory changes persisted as long as the medication was given. That the changes in sensation reported here and the effects of L-dopa in experimental studies are due to modification of substantia gelatinosa activity is hypothetical. The role of the substantia gelatinosa is not certain since some cells in the midportion of the spinal gray matter also respond to polymodal and polysensory stimulation, where time courses and spatial characteristics suggest a functionmodulating sensory transmission by presynaptic potential alterations. 4 This process has been relegated by others to the substantia gelatinosa? ~ Nonetheless, it is clear that the patients described in this study reported an increase or recurrence of pain and a concurrent increase in perception of cutaneous stimuli applied to the presumably denervated area while receiving L-dopa. There was also a decrease in pain and expanded areas of anesthesia when methyldopa or 20% nitrous oxide were administered. The surgical implications of these observations are several. First, the areas of anesthesia following rhizotomy are variable in a given patient and apparently depend on both the suprasegmental control of afferent transmission, and a wider distribution of individual dorsal roots than is usually accepted. Thus, cutaneous denervation by rhizotomy may require a procedure that is so extensive as to be impractical for many patients. To effect lasting regional total cutaneous denervation it may be necessary to extirpate regions of the central nervous system where the peripheral segmental input and suprasegmental input converge. Whether such a procedure must include only the substantia gelatinosa, or more extensive areas of the spinal cord or medulla, remains to be more thoroughly evaluated. J. Neurosurg. / Volume 44 / January, 1976
References
1. And6n NE, Jukes MGM, Lundberg A: The effect of DOPA on the spinal cord. 2. A pharmacological analysis. Aeta Physiol Sc~d 67:387-397, 1966 2. And6n NE, Jukes MGM, Lundberg A, et al: The effect of DOPA on the spinal cord. 1. Influence on transmission from primary afferents. Acta Physiol Scand 67:373-386, 1966 3. Baker RG, Anderson EG: The effect of L-3-4 dihydroxyphenylalanine on spinal reflex activity. J Pharmacol Exp Ther 173:212-231, 1970 4. Besson JM, Rivot JP: Spinal intraneurones involved in presynaptic control of supraspinal origin. J Physiol (Lond) 230:235-254, 1973 5. Brown AG, Kirk EJ, Martin HF 3rd: Descending and segmental inhibition of transmission through the spinocervical tract. J Physiol (Lond) 230:689-705, 1973 6. Carlsson A, Falck B, Fuxe K, et al: Cellular localization of monamines in the spinal cord. Aeta Physiol Scand 60:112-119, 1964 7. Carpenter D, Engberg I, Funkenstein H, et al: Decerebrate control of reflexes to primary afferents. Acta Physiol Seand 59:424-437, 1963 8. Cushing H: The sensory distribution of the fifth cranial nerve. Bull Johns Hopkins Hosp 15:213-231, 1904 9. Dahlstr6m A, Fuxe K: Evidence for the existence of monamine neurons in the central nervous system. 2. Experimentally induced changes in the intraneuronal amine levels of bulbospinal neuron systems. Acta Physiol Scand Suppl 247:1-36, 1965 10. Denny-Brown D, Kirk EJ, Yanagisawa N: The tract of Lissauer in relation to sensory transmission in the dorsal horn of spinal cord in the Macaque monkey. J Comp Neurol 151:175-200, 1973 11. Denny-Brown D, Kirk EJ, Yanagisawa N: The function of the descending root of the fifth nerve. Brain 96:783-814, 1973 12. Foerster O: The dermatomes in man. Brain 56:1-39, 1933 13. Freeman W: Motor and sensory overlap in the spinal roots. Ann Surg 101:133-137, 1935 14. Goodman LS, Gilman A (eds): The Pharmacological Basis of Therapeutics. New York, Macmillan & Co, 1966 15. Hagbarth K-E, Kerr DIB: Central influences on spinal afferent conduction. J Neurophysiol 17:295-307, 1954 16. Head H, Campbell AW: The pathology of herpes zoster and its bearing on sensory localization. Brain 23:353-523, 1900 17. Hillman P, Wall PD: Inhibitory and excitatory factors influencing the receptive fields 27
C. J. Hodge, Jr. and R. B. King
18. 19.
20.
21.
22. 23. 24.
25. 26.
28
of lamina 5 spinal cord cells. Exp Brain Res 27. Sherrington CS: The spinal roots and dissociative anesthesia in the monkey. J Physiol 9:284-306, 1969 Illis LS: Experimental model of regeneration (Lond) 27:360-371, 1901 in the central nervous system. Brain 96:47-60, 28. Sicard JA, Haguenau J, Lichtwitz L: l~tude 1973 des sensibilit6s aprbs radiocotomie post6rieure Kellgren JH: On the distribution of pain arispour causalgie. Rev Neurol 42:242-244, 1926 ing from deep somatic structures with charts 29. Szentfigothai J: Neuronal and synaptic of segmental pain areas. Clin Sci 4:35-46, arrangement in the substantia gelatinosa rolandi. J Comp Neurol 122:2!9-239, 1964 1939 Kirk E J, Denny-Brown D: Functional 30. Wall PD: Excitability changes in afferent fibre terminations and their relation to slow potenvariations in dermatomes in the Macaque tials. J Physiol (Lond) 142:1-21, 1958 monkey following dorsal root lesions. J Comp Neurol 139:304-320, 1970 31. Wall PD: The laminar organization of dorsal Kunc Z: Significance of fresh anatomic data horn and effects of descending impulses. J on spinal trigeminal tract for possibility of Physiol (Lond) 188:403-423, 1967 selective tractotomies, in Knighton RS, 32. Wall PD: The origin of a spinal cord slow Dumke PE (eds): Pain. Boston, Little-Brown, potential. J Physiol (Lond) 164:508-526, 1962 1966, pp 351-364 33. White JC, Sweet WH: Pain and the Liu C-N, Chambers WW: Intraspinal Neurosurgeon: A Forty Year Experience. sprouting of dorsal root axons. Arch Neurol Springfield, Ill, Charles C Thomas, 1969 Psychiatry 79:46-61, 1958 Loeser JD: Dorsal rhizotomy for the relief of chronic pain. J Neurosurg 36:745-750, 1972 Lundberg A: Integration in the reflex pathway, in Granit R (ed): Nobel Symposium This study was supported in part by Training No. 1: Muscular Afferents and Motor Control. New York, John Wiley & Sons, 1966, pp Grant N05-T01-NS-05605 from the National Institute of Neurological and Communicative 275-306 Onofrio BM, Campa HK: Evaluation of Diseases and Stroke. Address reprint requests to: Charles J. Hodge, rhizotomy. Review of 12 years' experience. J M.D., Department of Neurosurgery, Upstate Neurosurg 36:751-755, 1972 Schwartz HG: Anastomoses between cervical Medical Center, 750 East Adams Street, Syracuse, New York 13210. nerve roots. J Neurosurg 13:190-194, 1956
J. Neurosurg. / Volume 44 /January, 1976
Department of Neurosurgery, Upstate Medical Center, Syracuse, New York ~" The authors describe the sensory examinations of three patients who bad undergone cervical rhizotomy alone and in combination with trigeminal tractotomy and section of the nervus intermedius, the glossopharyngeal nerve, and the upper portion of the vagus nerve. Following administration of L-dopa there was an increase in their pain and a decrease in the area of clinically anesthetic or analgesic skin. When methyldopa was given, the subjective and objective changes were the opposite of those elicited by L-dopa. These observations support the existence of a wider dorsal root cutaneous distribution than is usually accepted as well as significant control of cutaneous sensation by suprasegmental areas of the central nervous system. Part of the suprasegmental bias supplied to the area in the spinal cord that processes sensory information apparently occurs by way of an aminergic descending reticulospinal tract. These findings are discussed in terms of attempts totally to denervate restricted cutaneous areas of the body for treatment of pain-producing states. KEvWORDS pain s p i n a l nerve r o o t s 9
9 L-dopa 9 methyldopa cutaneous sensation
y the method of remaining sensibilities and a construction technique, Foerster 1~ demonstrated a moderate overlap of the cutaneous distribution of neighboring dorsal roots. Each area of skin was thought to be supplied by three nerve roots. His observations confirmed the earlier work of Sherrington 27 in monkeys, and Head and CampbelP 6 in humans. Because anterolateral cordotomy may not provide sustained relief of chronic pain, rhizotomy has been suggested for the relief of pain in limited regions of the abdominal or thoracic wall? 4 When the craniocervical junction is involved, denervation is more complex. This has been attempted through sectioning multiple sensory cranial nerves and the upper cervical dorsal roots, at times in combination with a trigeminal t r a c t o t o m y ? 4 The results of
B
J. Neurosurg. / Volume 44 /January, 1976
9
trigeminalnerve
9
rhizotomies are frequently poor even though several roots are sectioned rostral and caudal to the area primarily involved in the painful process. 23,2~ The reason for these failures to achieve adequate denervation is unclear, although variations in dermatome, scleratome, and m y o t o m e distributions have been suggested? 3 Denny-Brown and his associates have suggested that the overlap of cutaneous sensory dermatomes, including that of the fifth cranial nerve, exceeds the usual limits described in the literature and that transmission through a single root is variable. 1~176 The present study was undertaken to determine if the variability of sensory perception described by Denny-Brown 1~176 in monkeys is also present in man, and if this variability has any significance in relation to the recurrence of pain after what was presumed
21
C. J. H o d g e , Jr. a n d R. B. K i n g
FIG. 1. Case 1. Upper." Results of sensory examination before operation (left), 1 month after (center) and 17 months after operation (right). Seventeen months postoperatively, using electrical stimuli, sensory cutaneous responses could be elicited from all areas of the skin that were apparently anesthetic to standard clinical stimuli. Lower: Diagram showing the extent of the constriction of the area of anesthesia 60 minutes after a single oral dose of L-dopa (250 mg). There was no significant change in the area of analgesia.
to be adequate unilateral denervation of the head and neck.
Methods The three patients we are describing had severe pain that was not controlled with narcotics; we felt that denervation procedures for pain relief were justified in each case. Postoperatively, a variety of medications were given including L-dopa, methyldopa, and 20% nitrous oxide. The patients understood that these drugs were being used experimentally, that the option to withdraw from the study was open at all times, and that withdrawal would have no bearing on their future or present care. The patients were all examined during the day usually by both authors in a 68 ~ to 70~ treatment room. The examinations were not completed or recorded if the patients were fatigued, uncomfortable, or anxious. There was at least a 4-hour lapse between the patients' most recent pain medication and the time of the examination. Sensory testing was carried out in a standard fashion. Wisps of cotton were used for tactile stimuli and pinpricks for superficial noxious
22
stimuli. In one patient electrical cutaneous stimulation was also used. The patterns of sensory changes were mapped on the skin and then transposed to standard sensory charts. In some instances photographic records were made.
Case Reports Case 1 This 46-year-old woman underwent section of the dorsal roots of C1-4 because of intractable postauricular and occipital pain secondary to massive bone degenerative proliferation at the C2-3 facet. Figure 1 upper depicts her sensory status pre- and postoperatively. Preoperatively there was mild hypesthesia over the second and third cervical dermatomes on the right which was most dense in the distribution of the postauricular nerve. In the stable early postoperative period there was the expected anesthesia surrounded by a band of analgesia involving the C-2, C-3, and C-4 dermatomes. The patient was free from pain at that time.
J. Neurosurg. / Volume 44 / January, 1976
Medical modification of sensation
FIG. 2. Case 2. Results of sensory examination before (left) and 1 week after (right) trigeminal tractotomy and section of the nervus intermedius, the glossopharyngeal nerve, the upper rootlets of the vagus nerve and C 1-4 dorsal roots. Postoperatively there was a thin band of hypesthesia, marked by the solid black line, surrounding the anesthetic area.
Seventeen months later she complained of recurrent pain over the right side of her neck and occasionally in her right shoulder. Examination revealed constriction of the area of anesthesia. In the suboccipital region light touch was intermittently perceived but was poorly localized. In the supraclavicular area repetitive pinprick was interpreted as scratch or itch. With electrical stimulation of the clinically anesthetic skin (repetitive monopolar isolated square-wave stimuli) there was no area from which a cutaneous sensory response could not be elicited, although the threshold throughout was higher than that of normal skin. Following a single oral dose of L-dopa (250 mg) there was subsequent further constriction of the area of anesthesia. Figure 1 lower left shows the area of skin, previously anesthetic, in which touch could be perceived after L-dopa. The examination during the administration of 20% nitrous oxide in oxygen was similar to that of the immediate postoperative period.
Case 2 This 59-year-old man suffered intractable right jaw, ear, and neck pain secondary to a pharyngeal mucoepidermoid carcinoma metastatic to the lymph nodes of the right side of his neck. Figure 2 shows the results of his pre- and postoperative sensory examination. There was hypalgesia over the third division of the trigeminal nerve and hypesthesia over the anterior neck on the right. A trigeminal tractotomy was done 4 mm below the obex; the nervus intermedius, the
J. Neurosurg. / Volume 44 /January, 1976
glossopharyngeal nerve, the upper two rootlets of the vagus nerve, and the C1-4 dorsal roots on the right were severed. The postoperative extent of analgesia and anesthesia was consistent with the tractotomy and rhizotomies. There was an area of intact sensation around the external auditory canal even though the gag reflex and general sensation on the right side of the pharynx were absent. The analgesia of the right side of the patient's face spared the paranasal area, a finding most likely related to the level of the tractotomy. 21 An unusual finding, when compared to the normal dissociative sensory loss following rhizotomy, 8'12,2~was that the area of loss of light touch was greater than the area of analgesia. At this time the patient was free of pain. Two months postoperatively he was given a 6-day course of L-dopa (500 mg/6 hr for 3 days and 1 gm/6 hr for 3 days). He complained of burning pain about his right eye and a deep ache in his jaw and right shoulder while taking L-dopa. The sensory examination performed at that time is shown in Fig. 3. There was a decrease of both the area of anesthesia from the rhizotomies and the area of analgesia from the tractotomy. The small area about the tragus where sensation was intact had increased in size. When larger doses of L-dopa were given, light touch in the supraclavicular region was spottily identified and in places repetitive pinprick was recognized as painful, this sensation frequently being referred to the suboccipital area. When administration of L-dopa was stopped, the area of sensory deficit reverted to 23
C. J. Hodge, Jr. and R. B. King
FI~. 3. Case 2. Results of sensory examination 2 months postoperativelywhile patient was receiving L-dopa, 500 mg/6 hr (left) and 1 gm/6 hr (right). The border of normal sensation while he was on no medication is shown by the crossed line. the premedication boundaries and the patient no longer complained of pain. His sensory examination stabilized, but as his tumor grew he again became uncomfortable with rightsided neck and face pain. He was then given a placebo with little change in his sensory examination (Fig. 4 left) and no change in the pain he was reporting. At this time he was given methyldopa (250 mg/6 hr) for 3 days. While taking his medication, he was again free of pain and felt as well as he had at any time since his surgery, despite his deteriorating clinical condition. On examination (Fig. 4 right) there was some increase in the areas of anesthesia and analgesia compared to when he was taking the placebo.
Three weeks postoperatively she complained of minimal left ear and jaw pain but had little change in her examination except for some paranasal loss of analgesia. She was then given a 3-day course of L-dopa (250 mg/6 hr). During this period her pain became much more severe, particularly about the left ear and eye. Results of a sensory examination at this time are shown in Fig. 6. The lower border of anesthesia and hypesthesia had shifted upwards from her trunk so that only her neck and upper sternum were included. The face remained analgesic only over the third division of the fifth nerve and there was a patch of normal sensation about the tragus and external canal. After receiving placebos for several days, she returned to her control state. She was then started on methyldopa (750 mg/24 hrs) with prompt relief of the pain which she had been reporting while taking the placebo. There was expansion of her anesthetic areas as shown in Fig. 7. The area of anesthesia extended well down to her trunk and over her shoulder. She was then given a trial of nitrous oxide (20%) in oxygen with further expansion in the apparent areas of denervation. Figure 8 is a composite of the extremes of her sensory loss under the influence of the medication mentioned. Because of the striking pain relief obtained while she was receiving methyldopa, the patient remained on low doses of this drug until her death 2 months later.
Case 3 This 54-year-old woman suffered severe left face, ear, and neck pain from carcinoma of her left middle ear with left-sided neck metastases. She underwent trigeminal tractotomy 5 mm below the obex, section of the nervus intermedius, glossopharyngeal nerve, upper rootlets of the vagus nerve, and the C1-4 dorsal roots. Preoperatively (Fig. 5 left) there was anesthesia over the distribution of the third division of the trigeminal nerve on the left and mild hypesthesia over the area served by the first two branches of the fifth nerve as well as the anterior neck. Her postoperative status was what would be expected from the rhizotomies and trigeminal tractotomy (Fig. 5 right). However, she too Discussion showed a reversal of the normal dissociative The observations made in the study of these anesthetic pattern generally seen after dorsal rhizotomy. She was free of pain at that time. patients emphasize the variability of sensory 24
J. Neurosurg. / Volume 44 /January, 1976
Medical modification of sensation
F~. 4. Case 2. Results of sensory examination l0 weeks postoperatively while patient was taking placebos (left) and metbyldopa, 250 rag/6 hr (right). The solid line represents the border of normal touch perception.
FIG. 5. Case 3. Results of sensory examination before (left) and 2 weeks after (right) trigeminal tractotomy, and section of the nervus intermedius, the glossopharyngeal nerve, the upper rootlets of the vagus nerve, and the C1-4 dorsal roots. loss following rhizotomy and tractotomy within an individual over short periods of time incident to drug administration. It has been implied that the sensory loss following rhizotomy is relatively stable 34 and that failure of rhizotomy as a pain-relieving procedure may be related to unknown patterns of more extensive segmental overlap of deep structures. TM Variation in dermatomes between individuals has been described by Sicard, et al., 28 and by White and Sweet 3a and has been attributed, at least in part, to anastamoses between the dorsal roots. '~,z6 The fact that two of our patients, one after L-dopa and one spontaneously, developed cutaneous sensation and spontaneous pain in the center of the denervated field suggests that the cutaneous overlap in distribution of the dorsal roots is more extensive than is generally accepted. It seems reasonable to J. Neurosurg. / Volume 44 / January, 1976
assume that larger areas of preserved sensation could have been unmasked if we had higher doses of L-dopa in these studies. The anatomical basis for suggesting wider central distribution of dorsal roots is firm in that Szenthgothai, 29 using degeneration techniques, had demonstrated a cord distribution of up to six segments for the terminals of a single root in the substantia gelatinosa. Illis 18 has shown a similar distribution of dorsal root terminals in the central and ventral portions of the spinal gray matter. Although it is certainly not definite, the return of sensation in the central denervated area seen in Case 1, 17 months postoperatively, does not seem to be due to the phenomenon of dorsal root sprouting as described by Liu and Chambers, 22 but rather to increased transmission and functional reorganization through already existing pathways. If such were not 25
C. J. Hodge, Jr. and R. B. King
Fic. 6. Case 3. Results of sensory examination while the patient was receiving L-dopa, 250 mg/6 hr. The border of normal sensation while on no medications is shown by the crossed line.
FIG. 7. Case 3. Areas of anesthesia added by administering methyldopa (left) and then 20% N20 (right) are indicated by the solid black areas.
F~. 8. Case 3. Drawing illustrating the borders of anesthesia while the patient was taking L-dopa (solid black), methyldopa (parallel lines), and nitrous oxide (dots) have been transposed to one drawing for purposes of comparison. When the anesthetic area was constricted (L-dopa) she reported increasingly severe pain in the ear, neck, and head but was quite comfortable while taking methyldopa and during 20% N20 inhalation. 26
the case, it would be most difficult to explain the nearly identical change in Case 2, 2 months postoperatively, only while receiving L-dopa. The more extensive distribution of dorsal root innervation is further supported by the observation in Case 1 that there was no area that was totally insensitive to monopolar electrical stimulation. In two other patients not reported here, both with four-level thoracic intradural rbizotomies, we did not find any area of total anesthesia by testing with electrical stimuli. These observations strongly support the conclusions that Kirk and Denny-Brown 2~ made in a study of macaque monkeys, namely, that each area of skin was apparently supplied with representation from at least five separate roots. As noted in monkeys 11 there was some effect of section of the descending tract of the fifth nerve on areas other than those innervated by that nerve. The normal pattern of sensory loss following rhizotomy is that the area of analgesia is more extensive than the area of anesthesia. "'16'27 In both Cases 2 and 3 this pattern was reversed and may represent a lack of the facilitory background convergence onto cells transmitting from the small-fiber system. Denny-Brown, et al., H have described the importance of an intact central system of convergence, by way of Lissauer's tract and the descending tract of the fifth nerve, for adequate summation of noxious stimuli from the periphery? T M The mechanism whereby L-dopa has enhanced transmission from the partially denervated areas in these patients is uncertain. Aminergic pathways are manifold in the brain and spinal cord. 6'9 They include a descending reticulospinal pathway originating from the lower pons and upper medulla which terminates in the ipsilateral spinal cord. The terminations are several and include the ventral horn, the lateral gray column, and the posterior aspect of the substantia gelatinosa. That sensory input may be affected by descending suprasegmental influences is clear. ~,1~,~7,2''3~ The aminergic pathway described may contribute to the suprasegmental modulation of sensory events in the dorsal horn. This pathway, studied by And6n, et al., ~,z and Baker and Anderson, 3 has an effect somewhat similar to that seen in the decerebrate preparation; 7 that is, its activation by L-dopa causes inhibition of the J. Neurosurg. / Volume 44 /January, 1976
Medical modification of sensation transmission from the flexor reflex afferents (FRA) to motor neurons, ascending systems, and segmental interneurons. The response to prolonged noxious cutaneous stimulation is, however, enhanced presumably reflecting a late effect on the pathways from the FRA. 24 Presumably methyldopa acts by blocking decarboxylation of dopa and thereby decreasing tissue levels of norepinephrine. TM The effect noted in the sensory examination did not seem related to the general depressant effect of this medication as the sedative effect was transient, but the sensory changes persisted as long as the medication was given. That the changes in sensation reported here and the effects of L-dopa in experimental studies are due to modification of substantia gelatinosa activity is hypothetical. The role of the substantia gelatinosa is not certain since some cells in the midportion of the spinal gray matter also respond to polymodal and polysensory stimulation, where time courses and spatial characteristics suggest a functionmodulating sensory transmission by presynaptic potential alterations. 4 This process has been relegated by others to the substantia gelatinosa? ~ Nonetheless, it is clear that the patients described in this study reported an increase or recurrence of pain and a concurrent increase in perception of cutaneous stimuli applied to the presumably denervated area while receiving L-dopa. There was also a decrease in pain and expanded areas of anesthesia when methyldopa or 20% nitrous oxide were administered. The surgical implications of these observations are several. First, the areas of anesthesia following rhizotomy are variable in a given patient and apparently depend on both the suprasegmental control of afferent transmission, and a wider distribution of individual dorsal roots than is usually accepted. Thus, cutaneous denervation by rhizotomy may require a procedure that is so extensive as to be impractical for many patients. To effect lasting regional total cutaneous denervation it may be necessary to extirpate regions of the central nervous system where the peripheral segmental input and suprasegmental input converge. Whether such a procedure must include only the substantia gelatinosa, or more extensive areas of the spinal cord or medulla, remains to be more thoroughly evaluated. J. Neurosurg. / Volume 44 / January, 1976
References
1. And6n NE, Jukes MGM, Lundberg A: The effect of DOPA on the spinal cord. 2. A pharmacological analysis. Aeta Physiol Sc~d 67:387-397, 1966 2. And6n NE, Jukes MGM, Lundberg A, et al: The effect of DOPA on the spinal cord. 1. Influence on transmission from primary afferents. Acta Physiol Scand 67:373-386, 1966 3. Baker RG, Anderson EG: The effect of L-3-4 dihydroxyphenylalanine on spinal reflex activity. J Pharmacol Exp Ther 173:212-231, 1970 4. Besson JM, Rivot JP: Spinal intraneurones involved in presynaptic control of supraspinal origin. J Physiol (Lond) 230:235-254, 1973 5. Brown AG, Kirk EJ, Martin HF 3rd: Descending and segmental inhibition of transmission through the spinocervical tract. J Physiol (Lond) 230:689-705, 1973 6. Carlsson A, Falck B, Fuxe K, et al: Cellular localization of monamines in the spinal cord. Aeta Physiol Scand 60:112-119, 1964 7. Carpenter D, Engberg I, Funkenstein H, et al: Decerebrate control of reflexes to primary afferents. Acta Physiol Seand 59:424-437, 1963 8. Cushing H: The sensory distribution of the fifth cranial nerve. Bull Johns Hopkins Hosp 15:213-231, 1904 9. Dahlstr6m A, Fuxe K: Evidence for the existence of monamine neurons in the central nervous system. 2. Experimentally induced changes in the intraneuronal amine levels of bulbospinal neuron systems. Acta Physiol Scand Suppl 247:1-36, 1965 10. Denny-Brown D, Kirk EJ, Yanagisawa N: The tract of Lissauer in relation to sensory transmission in the dorsal horn of spinal cord in the Macaque monkey. J Comp Neurol 151:175-200, 1973 11. Denny-Brown D, Kirk EJ, Yanagisawa N: The function of the descending root of the fifth nerve. Brain 96:783-814, 1973 12. Foerster O: The dermatomes in man. Brain 56:1-39, 1933 13. Freeman W: Motor and sensory overlap in the spinal roots. Ann Surg 101:133-137, 1935 14. Goodman LS, Gilman A (eds): The Pharmacological Basis of Therapeutics. New York, Macmillan & Co, 1966 15. Hagbarth K-E, Kerr DIB: Central influences on spinal afferent conduction. J Neurophysiol 17:295-307, 1954 16. Head H, Campbell AW: The pathology of herpes zoster and its bearing on sensory localization. Brain 23:353-523, 1900 17. Hillman P, Wall PD: Inhibitory and excitatory factors influencing the receptive fields 27
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