Gangrene of Toes with Normal Peripheral Pulses RAPHAEL WALDEN, M.D., RAPHAEL ADAR, M.D., MARK MOZES, M.D.
Ten patients with pregangrenous and gangrenous changes of the toes in the presence of normal peripheral pulses are described. In the absence of diabetes this is an uncommon condition and is only rarely reported upon in the literature. Four patients had non occlusive arteriosclerotic changes in large arteries; three suffered from thrombocytosis and one from polycytheniia vera; one patient had a monoclonal gamopathy and one was exposed to cold three months before the onset of gangrene. None of these patients smoked regularly. Severe pain usually preceded the gangrene. The process did not progress proximally in any patients, and in those who underwent toe amputations the healing was uneventful. Vasodilators and low-molecular dextran were not effective. Lumbar sympathectomy was performed in three patients, also with no effect on the course of the disease. Treatment of hematological disorders gave relief in three patients. Proximal arteriosclerotic changes should be corrected if possible to eliminate a source of emboli. In two patients anti-platelet aggregation agents provided relief. Toe amputation should be conservative and performed when definite demarcation appears between necrotic and viable tissue. This condition has a benign prognosis. G ANGRENE of the toes usually indicates a severe
J interference with the blood supply to the limb. In diabetic patients, distal arterial lesions are known to occur, causing gangrene of toes previous to involvement of larger vessels. This situation is rare in nondiabetic patients and only a few cases are reported in the literature. During the years 1974-1975 we treated 10 patients in whom gangrene of toes developed in the presence of good peripheral pulses and normal oscillometric readings. In one of them latent diabetes was discovered by glucose tolerance test and in the others diabetes was ruled out. A variety of possible predisposing factors was noted in these patients. As opposed to peripheral gangrene accompanying major vascular diseases, this entity seems to have a benign prognosis. Details of the 10 patients (7 men and 3 women) are given in Table 1. Clinical picture The average patient was in his 6th or 7th decade (mean age 58.9 years). One patient was an occasional Submitted for publication June 18, 1976. Reprint requests: Raphael Adar, M.D., Sheba Medical Center, Tel-Hashomer, Israel.
269
From the Department of General and Vascular Surgery, The Chaim Sheba Medical Center, Tel-Hashomer, and the Tel-Aviv University Sackler School of Medicine, Israel
smoker and all others were non smokers. Most patients reported various periods of episodic pain with red and cyanotic discoloration that preceded the onset of severe continuous pain. Deep cyanosis of a toe or toes was a common finding at admission, not necessarily in the toe that eventually became gangrenous. The lesions on the toes ranged from exquisitely painful superficial ulcerations of the tip of the toes to frankly gangrenous lesions that involved part or the whole of the toe. The gangrene was always associated with marked pain, was invariably dry and never extended beyond the proximal phalanx. Suppuration and cellulitis were notably absent in all cases. The lesion affected a single toe in three patients (patients 2, 9, 10) and several toes in one foot in one patient (patient 1.). Six patients had bilateral involvement: in two (patients 4, 7) the lesions occurred simultaneously on both sides, while in the other four (patients 3, 5, 6, 8) lesions appeared on one side and then the other over a period of 1-16 months. The common denominator in all these patients was the presence of full peripheral pulses and normal oscillometry. Noted by their absence were other stigmata of ischemia such as trophic changes in the toenails, absence of hair and atrophy of the skin. The typical sequence of color changes seen in Raynaud's phenomena was not observed. Except for one patient who had a history of prior exposure to cold, none of these lesions seemed to be affected by ambient temperature.
Ancillary tests The routine work-up included a full hematological investigation, a glucose tolerance test and several screening tests to rule out the presence of collagen diseases, proteins precipitated by cold, and other abnormal proteins. Other laboratory tests were performed as indicated. Aortography was performed in four patients to rule out a possible proximal source of emboli and in one case (patient 10) because of medico-legal implications.
270
WALDEN, ADAR AND MOZES
Ann. Surg.
*
March 1977
TABLE 1. Details of Patients with Gangrene of Toes with Normal Pulses
Case
Age,
Duration of Symptoms
Sex
Symptoms & Signs
1
65, M
Increasing pain rt. foot. Gangrene 2nd and 3rd toes
3 mon
2
74, F
Pain, gangrene rt. 3rd toe
3 wk
3
58, F
Recurrent episodes of discoloration and pain rt. 1st toe
16 mon
Cyanosis and gangrene
3 wk
1 year later-pain, cyanosis lt. 3rd toe
2 mon
Translumbar Aortography
A.S. changes in aorta, no occlusion
Treatment
Presumed Etiology
Dextran Lumbar sympathectomy Toe amputations
A.S. small vessels? Atheromatous emboli?
Toe amputation
A.S. small vessels? Atheromatous emboli?
Non occlusive stenosis SFA
Lumb. sympathect. Toe amputation
Improved on aspirin
4
68, M
While on Coumadin for susp. deep venous thrombosis-pain and cyanosis all toes, ulcerations 3rd rt.
1 mon
Ulcerations suprarenal aorta Patent aortofemoral graft
Discontinue Coumadin
Cholesterol embolism
5
49, M
Pain, cyanosis and gangrene rt. 5th toe
"Sudden"'
Normal
2nd episode 1 year later-pain, cyanosis It. 5th toe
2 wk
Toe amputation Improved on
Unknown Thrombocytosis
Recurrent episodes of pain, cyanosis and pregangrene all left toes + 1-3rd rt. toes
3 yr
6
66, M
Myleran Improved on Myleran
Thrombocytosis (latent
diabetes)
7
70, M
Pain, cyanosis and pregangrene rt. 2nd toe + It. 1st & 4th
1 mon
Improved on Cardoxin and aspirin
Thrombocytosis
8
57, F
Pain, cyanosis rt. 3rd and It. 1st toes
6 mon
Improved on Myleran Dextran (refused
Polycythemia
Pain, dry gangrene rt. 4th toe
I mon
vera
amputation) 9
10
63, M 19, M
Gangrene rt. 5th toe Cold exposure three months prior to admission. Pain, cyanosis and gangrene rt. 1st toe
1 mon 3 mon
Underlying condition In spite of the remarkable similarity in the clinical picture we did not find a single common etiology. Arteriosclerosis appeared to be the underlying condition in four cases (patients 1, 2, 3, 4). In two of them (patients 1, 2) arteriosclerotic changes were seen in the small vessels in the amputated specimens. In three (patients 1, 3, 4) arteriographic changes suggested the presence of ulcerated atheromas as a possible source of atheromatous micro-emboli. In two of these cases (patients 1, 3) only the lower extremities were involved, while in the third there was evidence of multisystem atheromatous embolization, including
Dextran Toe amputation
Normal
Lumbar sympa-
Monoclonal
gamopathy Cold injury
thectomy Toe amputation
renal failure, hypertension and G.I. bleeding. Thrombocytosis was detected in three patients (patients 5, 6, 7) and polycythemia vera in a fourth (patient 8). In all four the toe lesions were the leading symptom and the diagnosis of the hematological disorder was made 1 month, 6 months, 1 year and 3 years after the onset of symptoms in the toes. Patient 6 also had latent diabetes, however his lesions improved notably on Myleran, the improvement coinciding with the decrease in the platelet count. Patient 9 had a known monoclonal gamopathy for 6 years prior to the appearof the toe lesions. The search for cold precipitated proteins was negative in all patients, however, in patient 10 there was a ance
Vol. IN5 . No. 3
GANGRENE OF TOES
history of cold exposure three months prior to the appearance of the toe lesion. Treatment and outcome
Prior to admission a variety of vasodilator drugs was given to most patients, without any effect. Low molecular weight dextran was given to four patients and lumbar sympathectomy was performed in three. Both these therapeutical modalities failed to affect the course of the disease. Three patients with hematological disorders responded well to Myleran and the fourth to a combination of dipyridamole and aspirin. Patient 5 had his right fifth toe amputated one year previous to the discovery of the thrombocytosis; when a symmetric lesion appeared on the left side amputation was averted by treating the thrombocytosis. Toe amputation was performed in 6 patients. Relief of pain was immediate, all amputations healed primarily and no further lesions appeared proximal to the amputation sites. In three patients the gangrene remained localized and dry and no surgical intervention was necessary. Patient 4 died of generalized atheromatous emboli. Discussion Due to their distance from the heart, the toes are in a critical situation as far as blood supply is concerned. They are the first to suffer from ischemia when perfusion is decreased. The causative factor may be central, such as a drop in blood pressure, regional as in occlusion of a major artery of the limb or local as in cold or in vasospastic disorders. Conrad investigated the architecture of the vasculature of the toes using colored plastic casts.4 In cases of severe ischemia of the toes he demonstrated arteriolar occlusions, mainly in the first and fifth toes. He attributed these lesions to pressure from the shoes
during walking. Angiography will demonstrate the presence of occlusions in blood vessels but will not provide quantitative data on decreased perfusion. Bell et al.,2 Carter et al.3 and Holstein et al.'4 measured effective blood flow in ischemic toes by simultaneous differential pressure measurements in the toes, the ankle and the calf. Roddie and Sheppard found that toe arterioles are extremely susceptible to decreased perfusion: flow in these arterioles may approach zero when the perfusion pressure is still 35-60 mm Hg.20 The sequence of events in cases of gangrene of the toes is the following: 1) Considerable decrease in blood pressure and blood flow due to arterial or arteriolar occlusion; 2) Stasis and thrombosis made worse by pressure and local trauma; 3) Death of tissue in the
271
ischemic toe causing further destruction of blood vessels in the gangrenous area.4 Small vessel disease with thickening of the basement membrane is typical of diabetes mellitus. In one third of the patients, limited areas of digital gangrene may be present with palpable to normal pulses.'7 In these patients the disease is often progressive with poor healing following amputation. Goldenberg et al. stipulates that in the absence of diabetes mellitus, gangrene always indicates the presence of large vessel occlusion.9 The present series, however contradicts this sweeping statement. It is true, however, that gangrene of the toes with good peripheral pulses in non-diabetic patients is much less common. Only sporadic cases have been reported so far. Most occur as complications of severe systemic or vascular diseases. In almost none does it appear as the presenting symptom as in our series. In 1949, Fontaine et al.7 described 7 cases treated during a period of ten years; all had gangrene of toes with normal pulses. None had evidence of systemic or vascular disease, and all healed after a limited amputation or after conservative treatment as was the case in the present series. Martorell and Roca-De-Vinyals described a similar case in 1950; in this case however, only a temporary improvement was achieved by lumbar sympathectomy and several months later a high amputation was performed.'8 Microemboli from a proximal arteriosclerotic plaque are known to cause digital ischemia ("Purple toe" syndrome19). The first proven case was reported by Hoye et al. Crane described three cases of localized gangrene of toes with normal pulses in which ulcerated atheromatous plaques were demonstrated in aorta, and iliac and femoral arteries.5 In some, these are cholesterol emboli and there is circumstantial evidence that anticoagulant treatment may facilitate or precipitate embolization.6"9 Proximal atherosclerosis as a source of microemboli cannot be ruled out in any elderly patient, however aortography to prove or disprove it may not always bejustified on clinical grounds. Vreeken et al.2' followed a patient with severe toe ischemia who had thrombocytosis of 700,0001,000,000 per mm3. Clinical improvement was concomitant with a decrease in the thrombocyte count following treatment with Dextran and radioactive phosphorus, and hematological exacerbation resulted in recurrence of severe toe ischemia. The authors speculate that the thrombotic complications of polycythemia vera are due to platelet dysfunction. The high incidence of atherosclerosis in thrombocytosis and polycythemia vera should also be kept in mind in these patients. In a review by Laws et al., several other causes of localized toe gangrene are enumerated.'6 These include
272
WALDEN,
ADAR
several forms of vasculitis, usually an expression of collagen disease, as well as vasospastic and some hematologic conditions not encountered in the present series. In some of these cases the primary disease is obvious and the toe lesions are not the dominant feature. Theoretically, at least, any one of them however may present with the toe lesion before other features are obvious. The toe lesions described in this report should be distinguished from peripheral gangrene complicating severe systemic diseases-a rare but recognized phenomenon. Goodwin and Berne recently reported four cases of peripheral gangrene with no evidence of proximal arterial occlusions.10 All were secondary to hypotension and hypoperfusion due to sepsis, DIC, acute renal failure and myoglobulinuria, and all these patients died as a result of their primary disease. Hardy and Alican described a similar case in a 9year old girl following prolonged hypoglycemic shock.13 Symmetrical digital gangrene in children with normal pulses and plethysmography has been described after chickenpox, measles and also with no known primary disease.8"0'11 Severe venous thrombosis may also result in limb ischemia, however, only two cases were found in which digital gangrene was reported in the presence of normal peripheral pulses.1'22 In his monograph "Ischemic Forms of Venous Thrombosis"112 Haimovici describes 400 cases of phlegmasia cerulea dolens with venous gangrene. Patency of the arterial tree was proved in all cases either by the return of pulses after recovery or by arteriography or dissection of the amputated extremities. In all these cases however, the typical clinical picture of massive venous occlusion predominates. Reviewing the sporadic reports in the literature as well as our own cases with toe gangrene, good peripheral pulses and no obvious systemic disease, it is apparent that no single etiological factor can be implicated. Investigation should be done to discover a source of emboli, collagen diseases, hematological disorders, vasospastic conditions and, of course, diabetes. Trans-lumbar aortography is mandatory in some cases. In certain cases no definite etiological factor will be found. We may be dealing with a particular variant of arteriosclerosis obliterans or Buerger's disease in a limited peripheral location. The limited nature of this condition and its benign course in our experience dictate the therapeutic approach. Bed rest, low molecular dextran infusions and anti-platelet aggregation agents were tried first. Lumbar sympathectomy was performed in three cases. Neither dextran nor sympathectomy
AND
MOZES
Ann.
Suig. vMai-ch 1977
seemed to affect the course of the disease. Effective treatment of polycythemia and of thrombocytosis was associated with marked clinical improvement. Toe amputation should be conservative and performed when a clear demarcation appears between necrotic and viable tissue. Good healing may be expected.
References 1. Balas, P., Antonopoulos D., and Segditsas, Th.: Venous Gangrene of the Toe. Angiology, 22:491, 1971. 2. Bell, G., Nielsen, P. E., Wolfson, B., et al.: Measurements of Systolic Pressure in the Limbs of Patients with Arterial Occlusive Diseases. Surg. Gynecol. Obstet., 136:177, 1973. 3. Carter, S. A. and Lezack, J. D.: Digital Systolic Pressures in the Lower Limb in Arterial Disease. Circulation, 43:905, 1971. 4. Conrad, M. C.: Abnormalities of the Digital Vasculature as Related to Ulceration and Gangrene. Circulation, 38:568, 1968. 5. Crane, C.: Atherothrombotic Embolism to Lower Extremities in Arteriosclerosis. Arch. Surg., 94:96, 1967. 6. Feder, W. and Auerbach, R.: "Purple Toes": An Uncommon Sequela of Oral Coumarin Drug Therapy. Ann. Intern. Med., 55:911, 1961. 7. Fontaine, R., Frank, P. and Chorwath, V.: Contribution a L'etude des Gangrenes Limitees des Orteils avec Conservation du pouls et des oscillations. Arch. Mal. Coeur, 42: 240, 1949. 8. Forbes, C. D. and McNicol, G. P.: Gangrene of Digits. Br. Med. J., 4:431, 1970. 9. Goldenberg, S., Alex, M., Joshi, R. and Boumenthal, H. T.: Nonatheromatous Peripheral Vascular Disease of the Lower Extremities in Diabetes Mellitus. Diabetes, 8:261, 1959. 10. Goodwin, J. N. and Berne, T. V.: Symmetrical Peripheral Gangrene. Arch. Surg., 108:780, 1974. 11. Gyde, 0. H. B. and Beales, D. L.: Gangrene of Digits after Chickenpox. Br. Med. J., 4:284, 1970. 12. Haimovici, H.: Ischemic Forms of Venous Thrombosis. Springfield, Charles C Thomas, 1971. 13. Hardy, J. D. and Alican, F.: Ischemic Gangrene without Major Organic Vascular Occlusion: An Enlarging Concept. Surgery, 50:107, 1961. 14. Holstein, P. and Sager, P.: Toe Blood Pressure in Peripheral Arterial Disease. Acta. Orthop. Scand., 44:564, 1973. 15. Hoye, S. J., Teitelbaum, S., Gore, I. and Warren, R.: Atheromatous Embolization-A Factor in Peripheral Gangrene. New Engl. J. Med., 261:128, 1959. 16. Laws, J. W., Fred, H. L., Sharp, J.T. and Rabin, E. R.: Multiple Peripheral Gangrene. Arch. Intern. Med., 115: 547, 1965. 17. Levin, M. E. and O'Neal, L. W.: The Diabetic Foot. Saint Louis, C. V. Mosby Co., 1973. 18. Martorell, F. and Roca de Vinyals, R.: Gangrena de los Pies por Endarteriolitis Primaria Distal. Clinical y Laboratorio (Spain), 290:321, 1950. 19. Moldveen-Geronimus, M. and Merriam, J. C.: Cholesterol Embolization. Circulation, 35:946, 1967. 20. Roddie, I. C. and Sheppard, J. T.: Evidence for Critical Closure of Digital Resistance Vessels with Reduced Transmural Pressure and Passive Dilatation with Increased Venous Pressure. J. Physiol., 136:498, 1957. 21, Vreeken, J. and Van Aken, W. G.: Spontaneous Aggregation of Blood Platelets as a cause of Idiopathic Thombosis and Recurrent Painful Toes and Fingers. Lancet, 2:1394, 1971. 22. Young, T. W. and Smith, G. H.: Gangrene of the Lower Limb of Venous Origin. Br. J. Surg., 53:387, 1966.
Ten patients with pregangrenous and gangrenous changes of the toes in the presence of normal peripheral pulses are described. In the absence of diabetes this is an uncommon condition and is only rarely reported upon in the literature. Four patients had non occlusive arteriosclerotic changes in large arteries; three suffered from thrombocytosis and one from polycytheniia vera; one patient had a monoclonal gamopathy and one was exposed to cold three months before the onset of gangrene. None of these patients smoked regularly. Severe pain usually preceded the gangrene. The process did not progress proximally in any patients, and in those who underwent toe amputations the healing was uneventful. Vasodilators and low-molecular dextran were not effective. Lumbar sympathectomy was performed in three patients, also with no effect on the course of the disease. Treatment of hematological disorders gave relief in three patients. Proximal arteriosclerotic changes should be corrected if possible to eliminate a source of emboli. In two patients anti-platelet aggregation agents provided relief. Toe amputation should be conservative and performed when definite demarcation appears between necrotic and viable tissue. This condition has a benign prognosis. G ANGRENE of the toes usually indicates a severe
J interference with the blood supply to the limb. In diabetic patients, distal arterial lesions are known to occur, causing gangrene of toes previous to involvement of larger vessels. This situation is rare in nondiabetic patients and only a few cases are reported in the literature. During the years 1974-1975 we treated 10 patients in whom gangrene of toes developed in the presence of good peripheral pulses and normal oscillometric readings. In one of them latent diabetes was discovered by glucose tolerance test and in the others diabetes was ruled out. A variety of possible predisposing factors was noted in these patients. As opposed to peripheral gangrene accompanying major vascular diseases, this entity seems to have a benign prognosis. Details of the 10 patients (7 men and 3 women) are given in Table 1. Clinical picture The average patient was in his 6th or 7th decade (mean age 58.9 years). One patient was an occasional Submitted for publication June 18, 1976. Reprint requests: Raphael Adar, M.D., Sheba Medical Center, Tel-Hashomer, Israel.
269
From the Department of General and Vascular Surgery, The Chaim Sheba Medical Center, Tel-Hashomer, and the Tel-Aviv University Sackler School of Medicine, Israel
smoker and all others were non smokers. Most patients reported various periods of episodic pain with red and cyanotic discoloration that preceded the onset of severe continuous pain. Deep cyanosis of a toe or toes was a common finding at admission, not necessarily in the toe that eventually became gangrenous. The lesions on the toes ranged from exquisitely painful superficial ulcerations of the tip of the toes to frankly gangrenous lesions that involved part or the whole of the toe. The gangrene was always associated with marked pain, was invariably dry and never extended beyond the proximal phalanx. Suppuration and cellulitis were notably absent in all cases. The lesion affected a single toe in three patients (patients 2, 9, 10) and several toes in one foot in one patient (patient 1.). Six patients had bilateral involvement: in two (patients 4, 7) the lesions occurred simultaneously on both sides, while in the other four (patients 3, 5, 6, 8) lesions appeared on one side and then the other over a period of 1-16 months. The common denominator in all these patients was the presence of full peripheral pulses and normal oscillometry. Noted by their absence were other stigmata of ischemia such as trophic changes in the toenails, absence of hair and atrophy of the skin. The typical sequence of color changes seen in Raynaud's phenomena was not observed. Except for one patient who had a history of prior exposure to cold, none of these lesions seemed to be affected by ambient temperature.
Ancillary tests The routine work-up included a full hematological investigation, a glucose tolerance test and several screening tests to rule out the presence of collagen diseases, proteins precipitated by cold, and other abnormal proteins. Other laboratory tests were performed as indicated. Aortography was performed in four patients to rule out a possible proximal source of emboli and in one case (patient 10) because of medico-legal implications.
270
WALDEN, ADAR AND MOZES
Ann. Surg.
*
March 1977
TABLE 1. Details of Patients with Gangrene of Toes with Normal Pulses
Case
Age,
Duration of Symptoms
Sex
Symptoms & Signs
1
65, M
Increasing pain rt. foot. Gangrene 2nd and 3rd toes
3 mon
2
74, F
Pain, gangrene rt. 3rd toe
3 wk
3
58, F
Recurrent episodes of discoloration and pain rt. 1st toe
16 mon
Cyanosis and gangrene
3 wk
1 year later-pain, cyanosis lt. 3rd toe
2 mon
Translumbar Aortography
A.S. changes in aorta, no occlusion
Treatment
Presumed Etiology
Dextran Lumbar sympathectomy Toe amputations
A.S. small vessels? Atheromatous emboli?
Toe amputation
A.S. small vessels? Atheromatous emboli?
Non occlusive stenosis SFA
Lumb. sympathect. Toe amputation
Improved on aspirin
4
68, M
While on Coumadin for susp. deep venous thrombosis-pain and cyanosis all toes, ulcerations 3rd rt.
1 mon
Ulcerations suprarenal aorta Patent aortofemoral graft
Discontinue Coumadin
Cholesterol embolism
5
49, M
Pain, cyanosis and gangrene rt. 5th toe
"Sudden"'
Normal
2nd episode 1 year later-pain, cyanosis It. 5th toe
2 wk
Toe amputation Improved on
Unknown Thrombocytosis
Recurrent episodes of pain, cyanosis and pregangrene all left toes + 1-3rd rt. toes
3 yr
6
66, M
Myleran Improved on Myleran
Thrombocytosis (latent
diabetes)
7
70, M
Pain, cyanosis and pregangrene rt. 2nd toe + It. 1st & 4th
1 mon
Improved on Cardoxin and aspirin
Thrombocytosis
8
57, F
Pain, cyanosis rt. 3rd and It. 1st toes
6 mon
Improved on Myleran Dextran (refused
Polycythemia
Pain, dry gangrene rt. 4th toe
I mon
vera
amputation) 9
10
63, M 19, M
Gangrene rt. 5th toe Cold exposure three months prior to admission. Pain, cyanosis and gangrene rt. 1st toe
1 mon 3 mon
Underlying condition In spite of the remarkable similarity in the clinical picture we did not find a single common etiology. Arteriosclerosis appeared to be the underlying condition in four cases (patients 1, 2, 3, 4). In two of them (patients 1, 2) arteriosclerotic changes were seen in the small vessels in the amputated specimens. In three (patients 1, 3, 4) arteriographic changes suggested the presence of ulcerated atheromas as a possible source of atheromatous micro-emboli. In two of these cases (patients 1, 3) only the lower extremities were involved, while in the third there was evidence of multisystem atheromatous embolization, including
Dextran Toe amputation
Normal
Lumbar sympa-
Monoclonal
gamopathy Cold injury
thectomy Toe amputation
renal failure, hypertension and G.I. bleeding. Thrombocytosis was detected in three patients (patients 5, 6, 7) and polycythemia vera in a fourth (patient 8). In all four the toe lesions were the leading symptom and the diagnosis of the hematological disorder was made 1 month, 6 months, 1 year and 3 years after the onset of symptoms in the toes. Patient 6 also had latent diabetes, however his lesions improved notably on Myleran, the improvement coinciding with the decrease in the platelet count. Patient 9 had a known monoclonal gamopathy for 6 years prior to the appearof the toe lesions. The search for cold precipitated proteins was negative in all patients, however, in patient 10 there was a ance
Vol. IN5 . No. 3
GANGRENE OF TOES
history of cold exposure three months prior to the appearance of the toe lesion. Treatment and outcome
Prior to admission a variety of vasodilator drugs was given to most patients, without any effect. Low molecular weight dextran was given to four patients and lumbar sympathectomy was performed in three. Both these therapeutical modalities failed to affect the course of the disease. Three patients with hematological disorders responded well to Myleran and the fourth to a combination of dipyridamole and aspirin. Patient 5 had his right fifth toe amputated one year previous to the discovery of the thrombocytosis; when a symmetric lesion appeared on the left side amputation was averted by treating the thrombocytosis. Toe amputation was performed in 6 patients. Relief of pain was immediate, all amputations healed primarily and no further lesions appeared proximal to the amputation sites. In three patients the gangrene remained localized and dry and no surgical intervention was necessary. Patient 4 died of generalized atheromatous emboli. Discussion Due to their distance from the heart, the toes are in a critical situation as far as blood supply is concerned. They are the first to suffer from ischemia when perfusion is decreased. The causative factor may be central, such as a drop in blood pressure, regional as in occlusion of a major artery of the limb or local as in cold or in vasospastic disorders. Conrad investigated the architecture of the vasculature of the toes using colored plastic casts.4 In cases of severe ischemia of the toes he demonstrated arteriolar occlusions, mainly in the first and fifth toes. He attributed these lesions to pressure from the shoes
during walking. Angiography will demonstrate the presence of occlusions in blood vessels but will not provide quantitative data on decreased perfusion. Bell et al.,2 Carter et al.3 and Holstein et al.'4 measured effective blood flow in ischemic toes by simultaneous differential pressure measurements in the toes, the ankle and the calf. Roddie and Sheppard found that toe arterioles are extremely susceptible to decreased perfusion: flow in these arterioles may approach zero when the perfusion pressure is still 35-60 mm Hg.20 The sequence of events in cases of gangrene of the toes is the following: 1) Considerable decrease in blood pressure and blood flow due to arterial or arteriolar occlusion; 2) Stasis and thrombosis made worse by pressure and local trauma; 3) Death of tissue in the
271
ischemic toe causing further destruction of blood vessels in the gangrenous area.4 Small vessel disease with thickening of the basement membrane is typical of diabetes mellitus. In one third of the patients, limited areas of digital gangrene may be present with palpable to normal pulses.'7 In these patients the disease is often progressive with poor healing following amputation. Goldenberg et al. stipulates that in the absence of diabetes mellitus, gangrene always indicates the presence of large vessel occlusion.9 The present series, however contradicts this sweeping statement. It is true, however, that gangrene of the toes with good peripheral pulses in non-diabetic patients is much less common. Only sporadic cases have been reported so far. Most occur as complications of severe systemic or vascular diseases. In almost none does it appear as the presenting symptom as in our series. In 1949, Fontaine et al.7 described 7 cases treated during a period of ten years; all had gangrene of toes with normal pulses. None had evidence of systemic or vascular disease, and all healed after a limited amputation or after conservative treatment as was the case in the present series. Martorell and Roca-De-Vinyals described a similar case in 1950; in this case however, only a temporary improvement was achieved by lumbar sympathectomy and several months later a high amputation was performed.'8 Microemboli from a proximal arteriosclerotic plaque are known to cause digital ischemia ("Purple toe" syndrome19). The first proven case was reported by Hoye et al. Crane described three cases of localized gangrene of toes with normal pulses in which ulcerated atheromatous plaques were demonstrated in aorta, and iliac and femoral arteries.5 In some, these are cholesterol emboli and there is circumstantial evidence that anticoagulant treatment may facilitate or precipitate embolization.6"9 Proximal atherosclerosis as a source of microemboli cannot be ruled out in any elderly patient, however aortography to prove or disprove it may not always bejustified on clinical grounds. Vreeken et al.2' followed a patient with severe toe ischemia who had thrombocytosis of 700,0001,000,000 per mm3. Clinical improvement was concomitant with a decrease in the thrombocyte count following treatment with Dextran and radioactive phosphorus, and hematological exacerbation resulted in recurrence of severe toe ischemia. The authors speculate that the thrombotic complications of polycythemia vera are due to platelet dysfunction. The high incidence of atherosclerosis in thrombocytosis and polycythemia vera should also be kept in mind in these patients. In a review by Laws et al., several other causes of localized toe gangrene are enumerated.'6 These include
272
WALDEN,
ADAR
several forms of vasculitis, usually an expression of collagen disease, as well as vasospastic and some hematologic conditions not encountered in the present series. In some of these cases the primary disease is obvious and the toe lesions are not the dominant feature. Theoretically, at least, any one of them however may present with the toe lesion before other features are obvious. The toe lesions described in this report should be distinguished from peripheral gangrene complicating severe systemic diseases-a rare but recognized phenomenon. Goodwin and Berne recently reported four cases of peripheral gangrene with no evidence of proximal arterial occlusions.10 All were secondary to hypotension and hypoperfusion due to sepsis, DIC, acute renal failure and myoglobulinuria, and all these patients died as a result of their primary disease. Hardy and Alican described a similar case in a 9year old girl following prolonged hypoglycemic shock.13 Symmetrical digital gangrene in children with normal pulses and plethysmography has been described after chickenpox, measles and also with no known primary disease.8"0'11 Severe venous thrombosis may also result in limb ischemia, however, only two cases were found in which digital gangrene was reported in the presence of normal peripheral pulses.1'22 In his monograph "Ischemic Forms of Venous Thrombosis"112 Haimovici describes 400 cases of phlegmasia cerulea dolens with venous gangrene. Patency of the arterial tree was proved in all cases either by the return of pulses after recovery or by arteriography or dissection of the amputated extremities. In all these cases however, the typical clinical picture of massive venous occlusion predominates. Reviewing the sporadic reports in the literature as well as our own cases with toe gangrene, good peripheral pulses and no obvious systemic disease, it is apparent that no single etiological factor can be implicated. Investigation should be done to discover a source of emboli, collagen diseases, hematological disorders, vasospastic conditions and, of course, diabetes. Trans-lumbar aortography is mandatory in some cases. In certain cases no definite etiological factor will be found. We may be dealing with a particular variant of arteriosclerosis obliterans or Buerger's disease in a limited peripheral location. The limited nature of this condition and its benign course in our experience dictate the therapeutic approach. Bed rest, low molecular dextran infusions and anti-platelet aggregation agents were tried first. Lumbar sympathectomy was performed in three cases. Neither dextran nor sympathectomy
AND
MOZES
Ann.
Suig. vMai-ch 1977
seemed to affect the course of the disease. Effective treatment of polycythemia and of thrombocytosis was associated with marked clinical improvement. Toe amputation should be conservative and performed when a clear demarcation appears between necrotic and viable tissue. Good healing may be expected.
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