Cell Stations in the Upper Sympathetic Chain

Evidence that Functional Regeneration of Sympathetic Nerves in Man Occurs only in Postganglionic Neurones

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The inferences and conclusions that are presented in this paper are derived from studies on patients after various types of sympathectomy and apply only to the sympathetic neurones that innervate sweat glands. In a previous communication,4 we presented evidence to show that the pilocarpine (or mecholyl) sweating test might serve as a method of differentiating pre- and postganglionic sympathectomy. We feel that if sufficient time is allowed for degeneration of postganglionic neurones, the sweat glands that they had innervated will not respond to pilocarpine (gr. ⅕) or mecholyl (gm. 0.025) when injected hypodermically. Two to 3

The inferences and conclusions that are presented in this paper are derived from studies on patients after various types of sympathectomy and apply only to the sympathetic neurones that innervate sweat glands. In a previous communication,4 we presented evidence to show that the pilocarpine (or mecholyl) sweating test might serve as a method of differentiating pre- and postganglionic sympathectomy. We feel that if sufficient time is allowed for degeneration of postganglionic neurones, the sweat glands that they had innervated will not respond to pilocarpine (gr. ⅕) or mecholyl (gm. 0.025) when injected hypodermically. Two to 3 weeks may be sufficient time for degeneration in some patients, but unless the sympathectomized zone is completely anhidrotic to mecholyl, one should not draw final conclusions until 2 months have elapsed. It appears that the cholinergic drug does not act directly on the gland in the doses used but acts at the neuroglandular junction (end plate), and in some cases evidently more than 2 weeks are required for the end plate to become pharmacologically inactive. If the post-ganglionic neurone remains intact as after preganglionic sympathectomy, the sweat glands will respond to the cholinergic drugs indefinitely. Such glands do not atrophy from disuse at least up to 2 years (proven by biopsy in 2 cases). After preganglionic sympathectomy sweat glands will often respond more copiously to the cholinergic drugs than they did before sympathectomy. This also holds true for a short time after postganglionic sympathectomy. We feel that this so-called increased sensitivity of the gland is due to the fact that central connections have been severed and hence, the gland is uninhibited and completely free to respond to the drug. Drug sweating after postganglionic sympathectomy ultimately decreases so that from 2 weeks to 2 months postoperatively it ceases to occur.

Patients vary greatly in their response to pilocarpine and mecholyl, and if studies are to be made, a normal sweating test should be done before sympathectomy and a photograph taken so that accurate comparisons may be made with the results after sympathectomy. Many patients react so weakly to the drugs normally that they are not suitable for study. The lower extremities, unless normally hyperhidrotic, usually respond too weakly to pilocarpine to provide conclusive information.

A heat sweating test should be done within a few days of the corresponding drug test so that the two may be accurately compared. In making our studies concerning cell stations we have conformed to the above principles.

METHOD

The sweating tests were carried out by using the Minor8 starch-iodine preparation as an indicator.

The thermoregulatory or heat test was carried out by placing the subject in a Burdick heat cabinet where he was exposed for 20–30 minutes to a dry heat of 110 to 120°F. The response which occurred only in skin that was not in contact with anything was considered valid.3

The drug test was performed at room temperature. Either ⅕ gr. of pilocarpine hydrochloride or 0.025 gm. of mecholyl (acetyl-beta methylcholine chloride) was injected intramuscularly. Although the subjective response to mecholyl is more severe, the drug acts more quickly and apparently causes a greater sweating response than pilocarpine. Either drug should otherwise give the same result.

CELL STATIONS OF POSTGANGLIONIC NEURONES TO SWEAT GLANDS OF THE FACE

In a previous report,4 we presented 5 patients who were studied after cervicodorsal ganglionectomy (removal of inferior cervical and 1st and 2nd dorsal ganglia). The anhidrotic zone after pilocarpine was identical with the anhidrotic zone after a heat sweating test. Since the face was anhidrotic after pilocarpine, we concluded that in these patients a removal of the inferior cervical ganglion constituted a postganglionic sympathectomy to the face. Hence, it was also concluded that the postganglionic cells governing sweat glands of the face were in the inferior cervical ganglion or below and that none resided in the superior cervical ganglion. We repeated the heat, pilocarpine and mecholyl test on M. B., reported previously.4 The patient had had a bilateral cervicodorsal ganglionectomy. The repeat tests were made 2 years after those shown in Fig. 3 of the previous report. The sweat patterns in the repeat tests were identical in every respect to those shown in the photographs of 2 years before, indicating no regeneration. Both the heat and drug tests showed complete anhidrosis of the face and upper extremities.

Fig. 3.
Fig. 3.

Case 5 (G.M.). Pilocarpine sweating test 79 days after removal of the right superior cervical ganglion. The upper pole of the ganglion was left intact. There is anhidrosis on the right side of the face except for a few small spots on the right forehead, which could be accounted for by cell bodies in the intact upper pole of the ganglion.

Since that paper was published we have encountered the following 3 patients who maintained drug sweating on the face after removal of the inferior cervical ganglion.

Case 1. Wm. K. (88-22270). White male, aged 66.

Mar. 20, 1939. The inferior cervical and 1st dorsal ganglia (stellate ganglion) were removed on the left.

Jan. 11, 1941. A heat sweating test (22 months following operation) revealed an anhidrosis of the left face and shoulder. A pilocarpine test showed free sweating that seemed equal on both sides of the face. The heat test proved that there had been no regeneration.

Case 2. E. V. (40-6956). White female, aged 45.

Aug. 19, 1940. On the right the sympathetic chain was cut below D3. All rami to and from D2 and D3 were cut, but no others. The free end of the chain was sutured to the nearest muscle.

On the left the inferior cervical and upper 2 dorsal ganglia were removed.

Oct. 15, 1940. A heat test 2 months later revealed complete anhidrosis down to the skin level of D4 on the right and to D3 on the left.

After pilocarpine there was sweating on both sides of the face, but that on the left, the side of cervicodorsal ganglionectomy, was 50 per cent of that on the right and the line of demarcation on the forehead was sharp. (Since the preoperative response on the upper extremities was poor to both heat and drug, the patient did not provide any information concerning the upper extremities.)

The difference in degree of sweating on the two sides of the face was definite. Drug sweating was at least twice as prominent on the side where the inferior cervical and upper 2 dorsal ganglia had not been removed. This would indicate that some postganglionic cells in question resided in these ganglia, keeping in mind that the heat test showed that all central connections to the face were interrupted. The 50 per cent sweating on the left side of the face would indicate that all postganglionic cells to the face in this patient did not reside in the inferior cervical ganglion or below. Some were situated in the superior (or middle) cervical ganglia.

The third case in this category is R. McC. (Case 8), and is reported in detail under the caption The Problem of Regeneration.

Conclusion. The results in the 3 cases just cited would indicate that post-ganglionic cell stations to the face were located above the inferior cervical ganglion. Although this has been true for only a few patients, it undoubtedly constitutes a variation.

CASES IN WHICH THE INFERIOR CERVICAL GANGLION WAS NOT MOLESTED AND THE UPPER TWO OR THREE DORSAL GANGLIA WERE LEFT ATTACHED TO THE CHAIN AFTER CUTTING THEIR RAMI

There were 5 cases, and they are referred to here because in all of the cases of this type drug sweating persisted in the face (while heat sweating was absent.) Three of the cases are N. B. (Case 7), right side; R. McC. (Case 8), right side; and E. V. (Case 2), right side, qui vide. The other two are Cases 3 and 4 as follows:

Case 3. M. G. (40-9415). White female, aged 23.

Oct. 2, 1940. On the right the sympathetic chain was cut below D3 and the rami of D2 and D3 were severed. The free end of the chain was sutured to the nearest muscle.

On the left, the chain was cut below D2 and all rami of D2 were severed.

Dec. 28. 1940. A heat test approximately 3 months later showed complete anhidrosis down to D4 on the right and to D3 on the left.

Mecholyl caused sweating on the neck and face. There was a band of anhidrosis in the distribution of D2 and D3 on the right, and of D2 on the left. These were zones of postganglionic sympathectomy because the rami were cut (Fig. 1). (The upper extremities responded very poorly to the drug preoperativeiy, and hence the results in respect to them are discounted.)

Fig. 1.
Fig. 1.

Case 3 (M.G.). Mecholyl sweating test. On the right side the sympathetic chain was cut below the D3 ganglion and all rami of D2 and D3 were. Severed. On the left side the chain was cut below D2 and all rami of D2 were severed. See text for description of sweat pattern. Note band of anhidrosis in D2 and 3 distribution on the right and in D2 on the left in relation to the inferences at the end of the paper.

Case 4. M.S. (41-1217). White female, aged 26.

Feb. 4, 1941. On the right the sympathetic chain was cut below D3 and all rami of D2 and D3 were severed. The free end of the chain was sutured to the nearest muscle.

On the left the 2nd dorsal ganglion only was removed.

Feb. 22, 1941. A heat sweating test 18 days later showed complete anhidrosis down to D4 on the right and to D3 on the left.

Pilocarpine caused sweating on the face and sufficient sweating on the chest and back to bring out a band of anhidrosis in the distribution of D2 and D3 on the right and of D2 on the left (Fig. 2).

Fig. 2.
Fig. 2.

Case 4 (M.S.). Pilocarpine sweating test. See text for significance of sweat pattern. On the right the sympathetic chain was cut below D3 and all rami of D2 and 3 were severed. On the left the chain was cut below D2 and all rami of D2 were severed.

The patient responded very poorly in general to mecholyl before operation and practically not at all on the upper extremities. No information was provided, therefore, in respect to the upper extremities.

Comment. In Cases 3 and 4, in which rami to a thoracic nerve were severed, the drug test showed a band of anhidrosis in the distribution of that nerve or segment. This has held true in all of our patients whether the ganglionectomy was of the upper or lower thoracic chain. When one upper dorsal ganglion has been removed, the anhidrosis is obvious on the back but may not be obvious on the anterior chest. It was not present on the anterior chest in N. B. (Case 7) and R. McC. (Case 8). It may be quite possible that the supraclavicular nerves carry some sweat fibers to this distribution on the upper anterior chest. The drug anhidrosis has been obvious on both front and back after low dorsal ganglionectomies. We make a point of this because elimination of rami to a thoracic nerve unquestionably constitutes a post-ganglionic sympathectomy to that nerve. The consistency and persistency of drug anhidrosis in such cases supports the validity of our thesis concerning drug sweating.

RESULTS FROM REMOVAL OF SUPERIOR CERVICAL GANGLION

If our proposition is correct concerning drug sweating, then a complete removal of a superior cervical ganglion should always be followed by anhidrosis on the same side after adequate time has elapsed. The superior cervical ganglion should be the last outpost of cell bodies to sweat glands of the face, especially the forehead. It is conceivable that some cells may lie scattered beyond this ganglion, but, if any, they would constitute a small percentage. Eccles,1 quoted by Gibson,2 concluded that all preganglionic fibers to the face end in synapses on the cells of the superior cervical ganglion.

The following 2 patients are the only ones whom we have studied after removal of a superior cervical ganglion.

Case 5. G.M. (42-7131). White male, aged 61.

July 6, 1942. Superior cervical ganglion partially removed on the right. The upper pole, about ¼ of the ganglion, was left intact.

Sept. 23, 1942 (79 days after operation). A heat sweating test showed a complete anhidrosis on the right side of the face.

A pilocarpine test showed an identical anhidrosis except for a few small spots on the right forehead (Fig. 3). It is not unlikely that the superior pole of the ganglion which was left intact contained a few postganglionic cell bodies.

Case 6. D.C. (42-10887). White female, aged 38.

Oct. 23, 1942. The superior cervical ganglion on the left was completely removed.

Oct. 29, 1942. Six days after operation a heat sweating test showed complete anhidrosis on the left half of the face.

A mecholyl test showed some delay in sweating on the left but in 5 minutes sweating was equal on the two sides of the face (Fig. 4).

Fig. 4.
Fig. 4.

Case 6 (D.C.). A mecholyl sweating test 6 days after complete removal of the left superior cervical ganglion. The appearance of sweat was delayed on the left but ultimately was equal on the two sides. See Fig. 5, a later test.

Nov. 17, 1942 (25 days after operation). A mecholyl test showed a complete anhidrosis on the left side of the face (Fig. 5).

Fig. 5.
Fig. 5.

Case 6 (D.C.). A mecholyl sweating test repeated 25 days after removal of the left superior cervical ganglion. There is complete anhidrosis on the left side of the face identical with the anhidrosis from a heat sweating test. Compare with the mecholyl test done 6 days after operation as shown in Fig. 4.

Comment. Although only 2 cases of this type are presented, they satisfactorily bear out the proposition that after degeneration of postganglionic fibers, sweat glands do not respond to pilocarpine or mecholyl.

EVIDENCE THAT REMOVAL OF THE SECOND DORSAL GANGLION CONSTITUTES A POSTGANGLIONIC SYMPATHECTOMY TO THE UPPER EXTREMITY

Case 7. N.B. (40-8529). White female, aged 43.

July 6, 1940. The 2nd dorsal sympathetic ganglion only on the right was removed.

Sept. 16, 1940 (72 days after operation). A heat sweating test showed a complete anhidrosis of the face, arm and shoulder on the right down to the level of D3—the same extent of anhidrosis that follows removal of the inferior cervical and upper 2 dorsal ganglia. A photograph showing the result of this heat sweating test may be seen as Fig. 1 in a previous communication.5

A pilocarpine test resulted in marked sweating of the chest, face and left upper extremity. The right upper extremity was anhidrotic. Sweat appeared on the right side of the face and right shoulder first and was more abundant than in corresponding parts on the left (Fig. 6). This test was repeated on two other occasions with the same result.

Fig. 6.
Fig. 6.

Case 7 (N.B.). A pilocarpine sweating test 72 days after removal of only the 2nd dorsal ganglion on the right. There is anhidrosis of the right arm to the level of the axilla, See text for description of a heat sweating test.

This result (in respect to the heat test) indicates that removal of the 2nd dorsal ganglion in man interrupts all central connections to the sweat glands of the face, shoulder and upper extremity down to the level of D3, thus being as complete a sympathectomy in this respect as removal of the inferior cervical and upper 2 dorsal ganglia—the formerly accepted procedure for upper dorsal sympathectomy. The result in respect to the drug test indicates that postganglionic cells governing sweat glands of the upper extremity reside in the 2nd dorsal ganglion and/or below and that postganglionic cells controlling the sweat glands of the shoulder, neck and face reside above the 2nd dorsal ganglion.

Note that the segmental distribution of D2 on the right chest anteriorly is not anhidrotic. This segment was anhidrotic on the back. This discrepancy may be due to sympathetic fibers that accompany the supraclavicular nerves and whose postganglionic cells reside above D2. In some cases this band of anhidrosis is exhibited on the anterior chest, i.e. in Cases 3 and 4, represented by Figs. 1 and 2 respectively.

Compare this case with Case 8. In Case 8, the 2nd dorsal ganglion on the right was removed and regeneration occurred exclusively and precisely to the zone in the upper extremity that is shown to be anhidrotic to pilocarpine in this case. Moreover, in Case 8, after subsequently removing the D3 and D4 ganglia, which means that the D2, 3 and 4 ganglia were gone on the right, the drug sweating pattern on the right side was identical with that of the pilocarpine test shown in this case. These 2 cases then present an identical picture and provide a check on the proposition that postganglionic cells for the upper extremity reside for the most part below the 2nd dorsal ganglion.

THE PROBLEM OF REGENERATION

We have seen evidence of regeneration of the sympathetic nerves in only 1 patient, R. McC. (Case 8), discussed later. The following cases are presented in which no regeneration was evident by the heat sweating test at varying intervals following sympathectomy. (These cases are not numbered unless they have been presented elsewhere in the paper.)

After Superior Cervical Ganglionectomy.

G.M. (Case 5). There was no evidence of regeneration 79 days after operation.

After Stellate Ganglionectomy.

Wm. K. (Case 1). There was no evidence of regeneration 22 months after operation.

L.C. (39-3056). White female, aged 38. Stellate ganglionectomy on the right, Jan. 19, 1940. There was no evidence of regeneration in 9 months.

After Cervicodorsal Ganglionectomy (removal of inferior cervical and two or more dorsal ganglia).

M.B. (38-19707). White female, aged 31. Removal of inferior cervical and upper 3 dorsal ganglia on the left Dec. 15, 1938. Removal of inferior cervical and upper 2 dorsal ganglia on the right Jan. 18, 1940. There was no evidence of regeneration on the left 2 years and 9 months after operation and no evidence of regeneration on the right 1 year and 8 months after operation on that side.

F.C. (38-17763). White male, aged 57. Removal of inferior cervical and upper 2 dorsal ganglia on the left Aug. 6, 1938. There was no evidence of regeneration 2 years after operation.

After Other Types of Upper Dorsal Sympathectomy.

E.V. (Case 2). Removal of inferior cervical and upper 2 dorsal ganglia on the left. On the right the sympathetic chain was cut below D3 and all rami of the 2nd and 3rd ganglia were cut. The free end of the chain was sutured to the nearest muscle. There was no evidence of regeneration on either side 132 days after operation.

M.G. (Case 3). On the right the chain was cut below D3 and all rami to the 2nd and 3rd ganglia were severed. On the left the chain was cut below D2 and all rami of the 2nd ganglion were severed. The free ends of the chain on both sides were sutured to the nearest muscle. There was no evidence of regeneration 2 years after operation.

After Lumbar Ganglionectomy.

E.R. (38-24697). White female, aged 38. On Sept. 19, 1938 the splanchnic nerves were cut below the diaphragm and the 1st and 2nd lumbar ganglia with their intervening cord were removed on the right. This was followed by the usual anhidrosis below the knee on the right. There was no evidence of regeneration 26 months after operation.

A.B. (41-5342). White female, aged 29. On Jan. 20, 1942 a left subdiaphragmatic splanchnicotomy was done with removal of the 1st, 2nd and 3rd lumbar ganglia and intervening cords. A heat sweating test was performed and a photograph was taken. There was the usual anhidrosis below the knee on the left. There was no evidence of regeneration 10 months after operation.

REGENERATION AFTER REMOVAL OF SECOND DORSAL GANGLION

Case 8. R.McC. (42-2457). White girl aged 15 years. Raynaud's disease.

April 1, 1942. On the left the inferior cervical and upper 2 dorsal ganglia were removed. On the right the 2nd dorsal ganglion only was removed and no precaution was taken to prevent regeneration.

A heat sweating test before the patient was discharged showed a complete anhidrosis of the face, arms and chest down to the level of D3 on both sides.

The patient returned to the hospital Aug. 8, 1942 and a heat sweating test was repeated 4 months after operation. The pattern of heat anhidrosis was now changed in that there was heat sweating on the entire right upper extremity up to the shoulder (Fig. 7). Otherwise the zone of anhidrosis was not changed from that demonstrated 4 months previously. Photographs had been taken for reference.

Fig. 7.
Fig. 7.

Case 8 (R.McC). A heat sweating test 4 months after removal of the inferior cervical and upper 2 dorsal ganglia on the left and removal of only the 2nd dorsal ganglion on the right. A heat test made 10 days after the operation showed an anhidrosis of the right upper extremity also. The recurrent sweating is evidence of regeneration to the right upper extremity only. The black strip in the midline of the chest is an artefact.

The drug sweating test showed abundant sweating on the right upper extremity, shoulder and neck and on the entire forehead. The neck, shoulder and upper extremity on the left (the side of the cervicodorsal ganglionectomy) remained anhidrotic (Fig. 8, A and B). On the right side of the back there was a well defined band of anhidrosis corresponding to the distribution of D2.

Fig. 8.
Fig. 8.

Case 8 (R.McC). Mecholyl sweating test done before the 2nd operation and on the same day that the heat test shown in Fig. 7 was done. A) Front view. There is abundant sweating on both sides of the forehead, right upper extremity and right side of neck and chest. B) Back view. Note the strip of anhidrosis on the right corresponding to the distribution of D2 and which is bounded above and below by sweating. The margin of sweating below is faint but definite.

On Aug. 19, 1942, approximately 4½ months following the 1st operation, the 10th and 11th dorsal ganglia and the 1st, 2nd and 3rd lumbar ganglia on the left were removed. The 12th dorsal ganglion was left intact.

On Sept. 25, 1942, about a month later, the 1st, 2nd and 3rd lumbar ganglia on the right were removed. At the same time the upper dorsal wound on the right was reopened and 3rd and 4th dorsal ganglia were removed. This time, as before, the inferior cervical and 1st dorsal ganglia with their rami were not molested. Because of scar tissue it was impossible to isolate fibers that might have been identified as regenerated fibers macroscopically. (This operation will be referred to as the 2nd operation for convenience in the discussion to follow.)

On Oct. 5, 1942, 10 days after the last operation, a heat sweating test showed a complete anhidrosis down to the level of D5 on the right and to D3 on the left (Fig. 9).

Fig. 9.
Fig. 9.

Case 8 (R.McC). A heat sweating test following reoperation on the right at which time only the 3rd and 4th dorsal ganglia were removed. The right upper extremity is again anhidrotic. The right chest is now anhidrotic down to the level of D5. We feel that the result from this operation is incontrovertible evidence that the recurrent sweating shown in Fig. 7 was due to regeneration of sympathetic fibers to the upper extremity.

Comment. We feel this result to be incontrovertible evidence that the recurrent sweating in the right upper extremity was due to regeneration of the sympathetic fibers after the 1st operation.

Mecholyl test following 2nd operation (removal of the 3rd and 4th ganglia on the right). This test was done on Oct. 10, 1942, 15 days following the 2nd operation (Fig. 10, A and B). The right upper extremity was now anhidrotic to the axilla, corresponding to the result in N. B. (Fig. 6). The heat test (Fig. 9) showed the sympathectomy to be complete down to the level of D5 and the mecholyl test showed it to be postganglionic for the upper extremity.

Fig. 10.
Fig. 10.

Case 8 (R.McC). A mecholyl test 15 days after removal of the 3rd and 4th dorsal ganglia (and the 1st, 2nd and 3rd lumbar ganglia) on the right and 52 days after removal of the 10th and 11th dorsal and 1st, 2nd and 3rd lumbar ganglia on the left. A) Front view. The only change from the pattern shown in Fig. 8-A is that now the right upper extremity is anhidrotic to the level of the axilla. Compare with Fig. 6. B) Back view. The band of anhidrosis on the right back has widened to include the distribution of D2, 3 and 4. Note the band of anhidrosis on the left in the distribution of D10 and 11.

Note that the anhidrotic band on the right in the back view has been widened to include D3 and 4. Also note the band of anhidrosis corresponding to D10 and 11 on the left. A heat test 116 days later showed no regeneration to these zones.

EVIDENCE INDICATING THE PROBABILITY THAT ONLY THE AXONS OF POST-GANGLIONIC NEURONES ARE CAPABLE OF FUNCTIONAL REGENERATION

The possibility or probability that preganglionic fibers do not regenerate in man was suggested in only 1 case (Case 8, R. McC). The patient made an excellent case for study because she responded so well to both heat and drug.

Four months following removal of the 2nd dorsal ganglion on the right, regeneration of sympathetic fibers was indicated by the recurrent heat sweating on the right upper extremity only (Fig. 7). We feel that there is no question but that the sweating in this zone was governed by regenerated fibers exclusively because (1) a heat sweating test 10 days after the 1st operation showed the right upper extremity to be anhidrotic and (2) we were very careful at the 2nd operation to remove only the 3rd and 4th dorsal ganglia on the right, and after this operation the right upper extremity was again anhidrotic to heat. This heat test was made 10 days after the 2nd operation (Fig. 9).

The recurrent sweating shown in Fig. 7, and hence the regeneration of the fibers in question, extended down to the finger tips, which is longer than the distance to the chest, shoulder and face. Yet there was no evidence whatever of regeneration to the chest, shoulder and face. Hence, it is fair to deduce that the regeneration was selective. That the regenerating fibers were exclusively postganglionic is indicated by two observations. (1) The zone of recurrent heat sweating in Fig. 7 corresponds exactly to the anhidrotic zone in the right upper extremity in Case 7, Fig. 6, and it was concluded that the sympathectomy to the right upper extremity in the latter case was post-ganglionic. (2) After the sympathetic chain was again interrupted below D2 (2nd operation) in Case 8, the right upper extremity became anhidrotic to the drug test (Fig. 10 A) and the zone of anhidrosis was identical to that shown in Fig. 6. Moreover, the drug sweat pattern on the chest, shoulder and face after the 2nd operation was unchanged and was the same as that in Case 7, Fig. 6. It was concluded that the sympathectomy to these latter zones was preganglionic. The deduction, therefore, insofar as this one study is concerned, is that only axons of postganglionic neurones took part in regeneration and that preganglionic fibers did not regenerate, at any rate functionally.

To recapitulate briefly the findings and reasoning in this important case, the following statements may be made:

  1. The 2nd dorsal ganglion only was removed on the right and no provision made to prevent regeneration. A heat sweating test before the patient was discharged showed a complete anhidrosis of the face, upper extremity, and shoulder to D3 on that side.

  2. Four months later a heat sweating test showed sweating of the entire upper extremity to the shoulder but nowhere else in the distribution under consideration. The upper extremity to the shoulder had been assumed from previous studies to be a postganglionectomized zone after removal of the D2 ganglion. Moreover, drug sweating at this time was abundant on the right upper extremity, as would be expected, and was abundant as well in the remainder of the cervicodorsal distribution, except over the D2 segment on the back. From previous studies it had been assumed that this face and shoulder distribution is preganglionectomized after removal of the D2 ganglion, thus accounting for the drug sweating.

  3. At a 2nd operation only the 3rd and 4th dorsal ganglia on the right were removed. The heat sweating test now again showed complete anhidrosis of the upper extremity as well as in the rest of the cervicodorsal distribution in question. This pattern was unchanged 116 days after the 2nd operation and we feel the result clearly indicates that the recurrent sweating 4 months after the 1st operation can be attributed to regeneration of sympathetics to the upper extremity.

  4. Drug sweating after the 2nd operation failed to occur on the upper extremity in exactly that distribution which had shown recurrent sweating to heat. Drug sweating in the rest of the cervicodorsal distribution in question was unchanged from the previous status. We feel that this result indicates that the neurones that had regenerated were strictly postganglionic and that their cell bodies resided below the D2 ganglion.

If it be a biological law that only postganglionic neurones are capable of regeneration, it would not be out of order with the laws governing regeneration of somatic nerves in man.

Some work has been done in animals, mostly cats, on regeneration of sympathetic fibers. Gibson2 studied regeneration in the cat after cutting the cervical chain 2.5 cm. proximal to the superior cervical ganglion. He followed the histological evidence of regeneration as well as the physiological evidence. He concluded that preganglionic fibers regenerated and resumed their synaptic connections with the postganglionic cell bodies in the superior cervical ganglion. Concomitant with this the cells of the superior cervical ganglion and their fibers appeared to resume function. Function was determined by demonstrating action potentials with the cathode-ray oscillograph. Gibson2 quoted others who had done essentially the same work but who had utilized the pupil and nictitating membrane as indicators of functional regeneration. They, too, concluded that functional regeneration occurred. The histological evidence presented by Gibson is good but these studies do not prove that the resumption of function was not due exclusively to the regeneration of postganglionic axons which merely passed through the superior cervical ganglion to their destination. We have given evidence to show that the cell bodies of postganglionic neurones to the sweat glands of the face do not reside exclusively in the superior cervical ganglion. Some reside in the stellate ganglion and this could be equally true of sympathetics to other structures about the head and face.

Other Cases Providing Inferential Evidence of a Negative Nature Related to the Problem of Regeneration

Case 9. S.B. (40-12992). White male, aged 53.

On May 8, 1942 the 2nd dorsal ganglion on the right was removed and the rami of the stellate ganglion were severed. No provision was made to prevent regeneration.

On Nov. 17, 1942, 193 days after the operation, a heat sweating test showed complete anhidrosis of the right face, upper extremity and chest down to the level of D3. There was no evidence of regeneration. A mecholyl test showed an identical zone of anhidrosis except for sweating on the right face. That on the right forehead was less in amount, however, than that on the left forehead.

This result indicated that the sympathectomy to the shoulder, chest and upper extremity was postganglionic as was expected. Regeneration, however, did not occur in 193 days. The difference in this case and Case 8 is that all rami to the stellate ganglion were severed in addition to removal of the 2nd dorsal ganglion, whereas in Case 8 the rami to and from the stellate ganglion were left intact. (Mecholyl caused sweating on the chest, shoulder and upper extremity on the left (normal) side serving as a control to the findings on the side of the operation. The result again bears out the postulate that cholinergic drugs under the conditions of the test do not cause sweating in a postganglionic sympathectomized zone.) That regeneration did not occur in this case might be because the rami of the stellate ganglion were severed. This raises the conjecture that intact rami may be necessary to the growth of axons down the peripheral nerve trunks.

Case 1, Win. K., is similar to the case just described. By referring to it, it will be noted that 22 months after removal of only the stellate ganglion on the left, there was no evidence of regeneration as indicated by the heat sweating test. A pilocarpine test showed sweating on the face. Hence, the deduction that in this subject removal of the stellate ganglion constituted a preganglionic sympathectomy to the face and no regeneration to the face occurred. Moreover, no regeneration of even postganglionic neurones to the upper extremity occurred.

This result would again raise the conjecture that when a ganglion is removed, axons, even postganglionic, cannot regenerate down the nerve trunks to which the removed ganglion had provided rami. The same situation obtains as when all the rami to the nerve trunk are severed.

In all of our cases where a ganglion was removed or all rami to a nerve trunk were severed, two phenomena were exhibited unfailingly: (1) After the lapse of 2 weeks or more the skin distribution of the segment involved was strictly anhidrotic after cholinergic drugs. There is no doubt about this type of sympathectomy being postganglionic in its segmental distribution—that distribution allotted to the severed gray rami. (2) Although the sympathectomy is postganglionic, there has never been the slightest indication of regeneration to the segmental zone in question.

It is true that of the many sweating tests we have made we have never observed evidence of regeneration except in the 1 case (Case 8). This is the only positive evidence we have seen, and it would indicate the rarity of regeneration in man. Criticism of the foregoing conjectures concerning the improbability or impossibility of regeneration from sympathetic trunk to peripheral nerve trunk after their intervening ganglia or rami have been removed might be proffered because of the negative character of the result or inference—negative because the tests showed no evidence of regeneration anywhere. Nevertheless, Case 8 does provide strong evidence for the conjectures (note particularly Fig. 8 B). Although regenerating fibers had bridged the gap where the 2nd dorsal ganglion had been removed and proceeded through the intact stellate ganglion to the brachial nerves and down to the finger tips, the skin zone over the back representing the segmental distribution of D2 always remained completely anhidrotic to both heat and drugs. It may be concluded from this striking picture that none of the regenerating fibers found their way down the 2nd intercostal nerve.

INFERENCES

After analyzing the results in the above cases the following inferences are drawn:

  1. Preganglionic neurones do not regenerate to replace postganglionic neurones.

  2. Preganglionic neurones do not regenerate to activate the cell bodies of postganglionic neurones. Therefore, a zone after preganglionic sympathectomy should not be expected to recover function as a result of regeneration of sympathetic nerves.

  3. It appears that while postganglionic axons may regenerate across gaps in the sympathetic cords, they do not tend to grow down the old paths in peripheral nerves if the grey rami to these nerves have been cut.

  4. As a corollary to (3) regeneration does not occur down a peripheral nerve if the ganglion or ganglia supplying rami to that nerve have been excised.

The conclusions that we draw depend upon the validity of one proposition,4 the proposition that cholinergic drugs (pilocarpine and mecholyl) when used in the manner and under the conditions described, will stimulate sweating indefinitely in skin where the postganglionic neurones are intact and will not stimulate sweating in skin where the postganglionic neurones have degenerated. We have as yet sensed no flaw in the proposition, and when a final analysis of all the cases presented in this paper is made, the results appear to be consistent and the conclusions logical. The drug test provides a means of differentiating preganglionic from postganglionic sympathectomy, and when used in conjunction with the thermoregulatory sweating test as a control, offers a method of procuring data concerning cell stations. At present we know of no other valid or dependable method of obtaining this information.

After this paper was finished the authors had the pleasure of reading a recent report by Ray and Console9 in which they postulate not only the possibility of accessory sympathetic fibers which reside somewhere afield of the well-known paravertebral system but conclude that they consistently supply the zone corresponding to the Th12-L3 distribution, which is predominantly the anterior aspect of the thigh. We feel that the report deserves special comment, not only because it has a bearing on the validity of our conclusions, but because it embodies a departure from accepted principles in the anatomy and physiology of the sympathetic nervous system. If their conclusions be valid, one could not expect to sever sympathetics from their central connections just by removing appropriate paravertebral ganglia, a procedure heretofore relied upon. Particular reference is made to the anterior thigh.

The concept of a system of fibers accessory to the known sympathetic system was proposed by List and Peet in 1938.7 They assumed that cholinergic fibers coursed with cranial nerves because they obtained pilocarpine sweating on the face after cervicodorsal sympathectomy. In 1941 Hyndman and Wolkin4 gave evidence to show that it was not necessary to postulate an unknown system of fibers to explain the apparently discrepant findings. The thesis is founded on a recognition of the pathophysiologic differences between preganglionic and postganglionic sympathectomy.

The authors feel that the findings of Ray and Console may also be explained without postulating a system of fibers foreign to the known anatomic scheme. The fundamental proposition given by Ray and Console is as follows: Removal of paravertebral ganglia from Th8 to L3, inclusive, does not sever the anterior thigh, Th12 to L3 zone, from central connections and hence sympathetic activity may persist. A variable period of time from 3 days to 3 months is required for readjustment, that is, for accessory sympathetic activity to become manifest. In searching for an explanation for this unexpected finding they assume that accessory ganglia exist remote from the paravertebral chain and that the postganglionic fibers course with the genitofemoral, ilioinguinal and iliohypogastric nerves to supply the skin of the anterior thigh.

In respect to their conclusions the entire weight of the evidence rests upon whether, by the operation cited, the sympathetics innervating the anterior thigh are severed from their central connections. We feel they have not given adequate evidence for this for the following reasons: They used measurement of skin resistance as an indicator for sympathectomized and non-sympathectomized zones. High resistance is characteristic of the former and low resistance is characteristic of the latter. All the factors that relate to and determine skin resistance are admittedly not known. Low resistance in a skin zone after operation may not necessarily mean persistence of central connections but may characterize, as we believe to be the case here, a pre-ganglionectomized zone. In our opinion, thermoregulatory sweating is, at present, the only clearly objective and unassailable indicator of the presence or absence of central connections. Ray and Console did not check their findings by this test. One of the present authors (O. H.) removed the ganglia from Th11 to L3 in 3 patients and obtained unequivocal anhidrosis of the lower extremity including the T12-L3 zone as indicated by the Minor starchiodine sweating test. The tests were made not sooner than 2 weeks after operation.

As an alternative explanation for their findings we believe it probable that postganglionic fibers from the lower lumbar and sacral ganglia join and course with the nerves that supply the skin of the anterior thigh. This zone along with the lower sacral distribution would thus be preganglionectomized after the operation cited and may account for the results. In the present paper we have pointed out that drug sweating on the upper anterior chest after cervicodorsal sympathectomy may be due to intact postganglionic fibers that course with the supraclavicular nerves. The same analogy may hold for the anterior thigh.

ADDENDA

It has been thought by some that the preganglionic sympathetic supply to the upper extremity is mediated through the 1st thoracic ganglion. If this were true, a removal of only the 2nd dorsal ganglion would not completely sympathectomize the upper extremity. To put it another way, sympathectomy of the upper extremity would not be complete so long as the 1st dorsal root and the 1st dorsal sympathetic ganglion with its rami were left intact. Kuntz and Dillon6 performed experiments on cats and rhesus monkeys which indicated that some preganglionic supply does go through the 1st thoracic segment. They utilized reflex alterations in volume pulse wave of finger pads as an indicator. The results of our heat sweating tests after interrupting the sympathetic chain just below the 1st dorsal ganglion (or any equivalent operation) indicate that this premise does not hold true for man. Hence, in man a removal of the 2nd dorsal ganglion alone has in our experience constituted a complete sympathectomy to the upper extremity insofar as central connections are concerned.

As a further test of this proposition the patient R. McC, Case 8, was placed in a Burdick heat cabinet on Jan. 26, 1943, 4 months after the 2nd operation, and the body temperature was raised. Both upper extremities were outside of the cabinet so that the hands were exposed at room temperature. A record was made of the cabinet temperature, mouth temperature and temperature of the finger tips as the cabinet temperature was raised. It will be recalled that on April 1, 1942 the inferior cervical and upper 2 dorsal ganglia were removed on the left whereas only the 2nd dorsal ganglion was removed on the right. On Sept. 25, 1942 the 3rd and 4th dorsal ganglia were removed on the right. Hence, the 1st dorsal pathways were left intact on the right and eliminated on the left. Under the conditions of this experiment, if uninterrupted sympathetic connections resided in the 1st dorsal path, the fingers on the right should have become warmer while those on the left would not be expected to respond. The experiment was carried on for 100 minutes during which time the cabinet temperature was raised to 111°F., and the mouth temperature rose from 98.6° to 99.8°F. During this experiment the temperature of the fingers of both hands actually dropped. We feel that the drop in temperature is not particularly significant and was only a manifestation of Raynaud's syndrome which the patient had. The significant fact is that the temperature of the finger tips did not elevate on the right. In fact, the temperature on the right dropped 1.9° lower than that on the left. However, we do not feel that this in itself is significant either. It is significant that the pattern of the curves for the right and left sides is essentially the same, thus furnishing additional evidence that there is no direct sympathetic supply to the upper extremity in man through the 1st dorsal path (Fig. 11).

Fig. 11.
Fig. 11.

Case 8 (R.McC). Curves representing temperature change in the finger tips when the body was heated and the upper extremities exposed to room temperature. The values represent averages for the tips of the 5 digits of each hand. The unbroken line represents the right side and the broken line represents the left. The temperature of the finger tips was recorded with a Tycos dermatherm (Taylor Instrument Co., Rochester, N. Y.).

CONCLUSIONS

  1. Cell stations of postganglionic neurones to sweat glands of the face (especially the forehead) may reside entirely in the stellate ganglion in some cases or largely in the superior cervical ganglion in other cases. There appears to be a variation. Cell stations to the neck and shoulder reside largely in the stellate ganglion. Cell stations to the upper extremity reside in the 2nd dorsal ganglion and/or below.

  2. While a removal of only the 2nd dorsal ganglion constitutes as complete a sympathectomy as removal of the inferior cervical and upper 2 dorsal ganglia insofar as central connections are concerned, regeneration may occur to the upper extremity after removal of only the 2nd ganglion and provision should be made to prevent it.

  3. Evidence thus far indicates the probability that the axons of post-ganglionic fibers only are capable of functional regeneration in man.

It is hoped that more studies of this kind will be stimulated in order to test this apparent law.

REFERENCES

  • 1.

    EcclesJ. C. The actions of antidromic impulses on ganglion cells. J. Physiol.193688: 139.EcclesJ. Physiol.88: 1–39.

  • 2.

    GibsonW. C. Degeneration and regeneration of sympathetic synapses. J. Neurophysiol.19403: 237247.GibsonJ. Neurophysiol.3: 237–247.

  • 3.

    HyndmanO. R.WolkinJ. Sweat mechanism in man. Study of distribution of sweat fibers from the sympathetic ganglia, spinal roots, spinal cord and common carotid artery. 194145: 446467.HyndmanWolkin45: 446–467.

  • 4.

    HyndmanO. R.WolkinJ. The pilocarpine sweating test. 1. A valid indicator in differentiation of preganglionic and postganglionic sympathectomy. 194145: 9921006.HyndmanWolkin45: 992–1006.

  • 5.

    HyndmanO. R.WolkinJ. Sympathectomy of the upper extremity. Evidence that only the second dorsal ganglion need be removed for complete sympathectomy. 194245: 145155.HyndmanWolkin45: 145–155.

  • 6.

    KuntzA.DillonJ. B. Preganglionic components of the first thoracic nerve. Their role in the sympathetic innervation of the upper extremity. 194244: 772778.KuntzDillon44: 772–778.

  • 7.

    ListC. F.PeetM. M. Sweat secretion in man. III. Clinical observations on sweating produced by pilocarpine and mecholyl. 193840: 269290.ListPeet40: 269–290.

  • 8.

    MinorV. Ein neues Verfahren zu der klinischen Untersuchung der Schweissabsonderung. Dtsch. Z. Nervenheilk.1928101: 302308.MinorDtsch. Z. Nervenheilk.101: 302–308.

  • 9.

    RayB. S.ConsoleA.D. Residual sympathetic pathways after para vertebral sympathectomy. J. Neurosurg.19485: 2550.RayConsoleJ. Neurosurg.5: 25–50.

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Headings

Figures

  • View in gallery

    Case 5 (G.M.). Pilocarpine sweating test 79 days after removal of the right superior cervical ganglion. The upper pole of the ganglion was left intact. There is anhidrosis on the right side of the face except for a few small spots on the right forehead, which could be accounted for by cell bodies in the intact upper pole of the ganglion.

  • View in gallery

    Case 3 (M.G.). Mecholyl sweating test. On the right side the sympathetic chain was cut below the D3 ganglion and all rami of D2 and D3 were. Severed. On the left side the chain was cut below D2 and all rami of D2 were severed. See text for description of sweat pattern. Note band of anhidrosis in D2 and 3 distribution on the right and in D2 on the left in relation to the inferences at the end of the paper.

  • View in gallery

    Case 4 (M.S.). Pilocarpine sweating test. See text for significance of sweat pattern. On the right the sympathetic chain was cut below D3 and all rami of D2 and 3 were severed. On the left the chain was cut below D2 and all rami of D2 were severed.

  • View in gallery

    Case 6 (D.C.). A mecholyl sweating test 6 days after complete removal of the left superior cervical ganglion. The appearance of sweat was delayed on the left but ultimately was equal on the two sides. See Fig. 5, a later test.

  • View in gallery

    Case 6 (D.C.). A mecholyl sweating test repeated 25 days after removal of the left superior cervical ganglion. There is complete anhidrosis on the left side of the face identical with the anhidrosis from a heat sweating test. Compare with the mecholyl test done 6 days after operation as shown in Fig. 4.

  • View in gallery

    Case 7 (N.B.). A pilocarpine sweating test 72 days after removal of only the 2nd dorsal ganglion on the right. There is anhidrosis of the right arm to the level of the axilla, See text for description of a heat sweating test.

  • View in gallery

    Case 8 (R.McC). A heat sweating test 4 months after removal of the inferior cervical and upper 2 dorsal ganglia on the left and removal of only the 2nd dorsal ganglion on the right. A heat test made 10 days after the operation showed an anhidrosis of the right upper extremity also. The recurrent sweating is evidence of regeneration to the right upper extremity only. The black strip in the midline of the chest is an artefact.

  • View in gallery

    Case 8 (R.McC). Mecholyl sweating test done before the 2nd operation and on the same day that the heat test shown in Fig. 7 was done. A) Front view. There is abundant sweating on both sides of the forehead, right upper extremity and right side of neck and chest. B) Back view. Note the strip of anhidrosis on the right corresponding to the distribution of D2 and which is bounded above and below by sweating. The margin of sweating below is faint but definite.

  • View in gallery

    Case 8 (R.McC). A heat sweating test following reoperation on the right at which time only the 3rd and 4th dorsal ganglia were removed. The right upper extremity is again anhidrotic. The right chest is now anhidrotic down to the level of D5. We feel that the result from this operation is incontrovertible evidence that the recurrent sweating shown in Fig. 7 was due to regeneration of sympathetic fibers to the upper extremity.

  • View in gallery

    Case 8 (R.McC). A mecholyl test 15 days after removal of the 3rd and 4th dorsal ganglia (and the 1st, 2nd and 3rd lumbar ganglia) on the right and 52 days after removal of the 10th and 11th dorsal and 1st, 2nd and 3rd lumbar ganglia on the left. A) Front view. The only change from the pattern shown in Fig. 8-A is that now the right upper extremity is anhidrotic to the level of the axilla. Compare with Fig. 6. B) Back view. The band of anhidrosis on the right back has widened to include the distribution of D2, 3 and 4. Note the band of anhidrosis on the left in the distribution of D10 and 11.

  • View in gallery

    Case 8 (R.McC). Curves representing temperature change in the finger tips when the body was heated and the upper extremities exposed to room temperature. The values represent averages for the tips of the 5 digits of each hand. The unbroken line represents the right side and the broken line represents the left. The temperature of the finger tips was recorded with a Tycos dermatherm (Taylor Instrument Co., Rochester, N. Y.).

References

1.

EcclesJ. C. The actions of antidromic impulses on ganglion cells. J. Physiol.193688: 139.EcclesJ. Physiol.88: 1–39.

2.

GibsonW. C. Degeneration and regeneration of sympathetic synapses. J. Neurophysiol.19403: 237247.GibsonJ. Neurophysiol.3: 237–247.

3.

HyndmanO. R.WolkinJ. Sweat mechanism in man. Study of distribution of sweat fibers from the sympathetic ganglia, spinal roots, spinal cord and common carotid artery. 194145: 446467.HyndmanWolkin45: 446–467.

4.

HyndmanO. R.WolkinJ. The pilocarpine sweating test. 1. A valid indicator in differentiation of preganglionic and postganglionic sympathectomy. 194145: 9921006.HyndmanWolkin45: 992–1006.

5.

HyndmanO. R.WolkinJ. Sympathectomy of the upper extremity. Evidence that only the second dorsal ganglion need be removed for complete sympathectomy. 194245: 145155.HyndmanWolkin45: 145–155.

6.

KuntzA.DillonJ. B. Preganglionic components of the first thoracic nerve. Their role in the sympathetic innervation of the upper extremity. 194244: 772778.KuntzDillon44: 772–778.

7.

ListC. F.PeetM. M. Sweat secretion in man. III. Clinical observations on sweating produced by pilocarpine and mecholyl. 193840: 269290.ListPeet40: 269–290.

8.

MinorV. Ein neues Verfahren zu der klinischen Untersuchung der Schweissabsonderung. Dtsch. Z. Nervenheilk.1928101: 302308.MinorDtsch. Z. Nervenheilk.101: 302–308.

9.

RayB. S.ConsoleA.D. Residual sympathetic pathways after para vertebral sympathectomy. J. Neurosurg.19485: 2550.RayConsoleJ. Neurosurg.5: 25–50.

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