Temporal Vascular Changes in Leg with Ulcer Due to Autonomic Neuropathy

Abstract

Background  Vascular dysfunction dominates the clinical picture of peripheral autonomic neuropathy in lower extremity.

Patients and Methods  We have studied functional changes of leg vasculature in 30 patients with chronic ulceration due to peripheral autonomic neuropathy between clinical stages 1 and 3. They suffered from lower extremity wounds. After sympathetic skin response test, pedal arterial blood flow analysis including peak systolic velocity (PSV) and pulsatility index (PI) was made by duplex ultrasonography (DUS) in involved legs. Vascular anatomy of leg was also examined by magnetic resonance angiography.

Results  The mean PSV value was found 58.32 cm/s in stage 1, 35.31 cm/s in stage 2, and 15.71 cm/s in stage 3. The mean PI value was observed 1.17 in stage 1, 1.43 in stage 2, and 1.87 in stage 3. In chronic stage 3, three patients had inadequate arterial blood supply and recurrent ulcer.

Conclusions  We suggest that reduced sympathetic activity due to small fiber neuropathy causes temporal variations in leg blood flow. There was a nonlinear relationship between vascular functional changes and stages of disease with increased, intermediate, and decreased blood flow, respectively. DUS assessment of pedal arteries contributed to differentiation of clinical stages and permitted vascular evaluation in the course of peripheral autonomic neuropathy.

Autonomic neuropathy presents in many diseases and the small lightly myelinated and unmyelinated nerve fibers are involved in pathogenesis. Especially, sympathetic nerve failure initiates temporal vascular alterations and leads to venous stasis. ¹ It has a tendency with a lower leg distribution, regardless of the origin of the precipitating pathology which are immune-mediated, paraneoplastic, infectious, toxic and drug-induced, hereditary, nutritional, traumatic, and idiopathic. Sympathetic postganglionic sudomotor fibers are affected in dysautonomia that occurs in isolation, but it can also happen in conjunction with a somatic neuropathy. Symptomatic variability among patients makes it difficult to establish firm conclusions about mechanisms of the clinical situation. Patients progress through three stages in time and lower venous noradrenalin level remains unchanged at all stages, thus, clinical findings depend on developing vascular changes during the course. ² In clinical practice, impairments in vascular and sudomotor functions provide clinical findings such as pain, edema, skin warming, and sweating abnormalities. Detecting a nerve lesion is not obligatory to confirm diagnosis. Measurement of changes in blood flow is a more reliable method for monitoring the sympathetic hypoactivity than that of changes in temperature and sweating. ³ Vascular impairment from sympathetic dysfunction was reported to be a higher frequency in the lower limbs than cardiovascular involvement. ⁴ A variety of symptoms occurs only with advanced sympathetic denervation and may be disabling. Earlier in the course of the disease, the diagnosis is missed often since the lack of evidence of peripheral sympathetic nerve failure that may be subclinical or clinically irrelevant. Despite the use of methods such as the quantitative sudomotor axon reflex test, the sympathetic skin response (SSR), the skin blood flow study with the Laser Doppler device and the skin biopsy examinations, clinical method to diagnose reduced sympathetic activity easily in lower limbs has not been established yet due to technical difficulties in quantification of measurements. ⁵ Neuropathic pain and vascular dysfunction influence the clinical picture of sympathetic dysautonomia. These patients have an increased risk of leg ulcer and limb loss following an abnormal flow redistribution and a defect in sympathetic thermoregulation. ⁶

Today, Doppler flow analysis is an effective method in clinical use for assessing the quantitative arterial functional changes. Evaluation of arterial flow waveform pattern via transcutaneous Doppler devices provides valuable diagnostic and prognostic information related to vascular disturbances in lower leg. Changes in arterial blood flow are affected by segmental interaction between proximal compliance and distal vascular resistance. ⁷ As the severity increases, proximal arterial compliance raises and distal vascular resistance diminishes. This condition results in dilatation of the arteries and arterioles associated with arteriolovenular communications that rush blood from the arterial to the venous side of circulation due to decreased sympathetic activity. ⁸ Higher venous pressure causes dilatation and tortuosity of crural and pedal veins and is transmitted to the capillaries of the subcutaneous tissues and the skin. Increased capillary filtration results in subcutaneous edema and skin ulceration. In lower limb, a remarkable increase in pedal blood flow was shown by using Doppler ultrasonography ⁹ and laser Doppler flowmetry ¹⁰ and pletysmography. ¹¹ At the onset of disease, hyperperfusion leads to venous distension and warmth in lower calf and foot. Subsequently, blood samples from pedal veins show higher oxygen concentration that indicates concept of arteriolovenular shunting. ^{12 13} Venous stasis ulcer seems to be present due to prolonged venous hypertension and edema. With time, small distal arterial sclerosis develops following vascular remodeling and structural abnormalities. Thus, venous distension and skin edema lessen in chronic stage 3. Abnormal blood flow can lead to recurrence of ischemic ulceration during the course of disease. We intended to evaluate the alterations in vascular abnormalities during the clinical stages of pathological process.

Materials and Methods

From 2017 to 2018, a series of 30 patients admitted to the outpatient clinic for chronic leg ulceration with or without edema due to sympathetic mediated vascular changes and their involved legs were treated. The average age of patients was 57 years (range: 32–74 years). Previous clinical course of patients had been complicated by slow wound healing for > 3 months and they were still undergoing wound care. The vital signs of patients were stable on presentation. Pain, long-lasting burning feel, and paresthesia were the major symptoms in the leg. Skin changes manifest as warm, erythematous tenderness with pitting edema over the calf and foot in stage 1 patients. There were diminished edema and normothermia in the stage 2. In stage 3, the skin becomes cold, clammy, and cyanotic. In stage 1, examination of the foot demonstrated palpable arterial pulses and brisk capillary refill to the digits. There were diabetes in 8 patients, trauma in 4, rheumatoid arthritis in 4, lymphoma in 1, Systemic lupus erythematosus in 1, alcoholism in 1. Etiology was idiopathic in 11 cases. All patients had negative sera for antibodies against acetylcholine-receptors.

The management of leg ulcer arising from autonomic neuropathy requires daily dressings, debridement when necessary, and proper antibiotherapy in the presence of infection, regardless of stage and depth. Treatment of underlying causative etiology was attempted, when possible in cooperation with medical specialists from the appropriate disciplines. A symptomatic therapy was vitally important which was given to relieve pains with respect to underlying pathological conditions such as autonomic neuropathy, venous edema, and ischemia in affected leg. A nonsteroidal anti-inflammatory drug, diclofenac potassium (Cataflam) 50 mg, twice daily; and an anticonvulsant agent, pregabalin (Lyrica) 300 mg, twice daily, were administered to alleviate neuropathic pain in all patients. In addition to mainstay compression bandage therapy, a venotonic drug, oxerutin (Venoruton) 500 mg, twice daily, was used to decrease pain from venous stasis edema in stage 1 patients. An antiplatelet agent, cilostazol (Platel) 100 mg, twice daily, was administered to decrease intermittent claudication and ischemic rest pain in stage 3 patients.

After confirmation of patient eligibility and procurement of informed consent, an electrophysiologic test, SSR and continuous wave (CW) Doppler, duplex ultrasonography (DUS) and magnetic resonance angiography (MRA) were performed to evaluate lower limb. Sympathetic dysfunction was diagnosed on the basis of clinical findings and Doppler flow studies in pedal arteries by means of an initial evaluation of hand-held CW Doppler instrument and a more detailed DUS under conditions at rest. SSR test indicating sympathetic cholinergic activity to sweat glands was also used to verify the condition by measuring the conduction velocity of postganglionic sympathetic sudomotor C fibers in leg in suitable conditions. SSR measurements were performed using Medelec Synergy device on Nicolet AT2 EMG/EP system (Nicolet Biomedical, Madison, WI). The electromyography parameters employed in our SSR study were as follows: Sweep speed: 1 ms/Division; sensitivity: 500 mV/Division; filtering: 0.5 to 2 kHz; stimulation duration: 0.2 ms; stimulation intensity: 20 mA. The electrical stimulation was applied with standard surface electrodes at the ankle posterior to the medial malleolus for the tibial nerve to evoke SSR. We attempted to obtain the wave with shortest latency by using an active recorder electrode placed at the plantar surface among three stimuli that were required to prove reproducibility. Repetitive stimuli were applied to prevent habituation at irregular intervals with a minimum 60 seconds between the consecutive two stimuli. When there was no wave recorded, it was considered as absent. Pathologic criteria in SSR measurements were determined as follows: any absent wave and tibial nerve latency > 1.88 seconds. ¹⁴

Fırst, the dorsalis pedis artery was insonated with an 8 MHz CW Doppler instrument probe (Hadeco, ES-100V3, Hayashi Denki Co., Kawasaki, Japan) in the examination room. Moreover, patients were subjected to insonation with a 7.5 MHz linear DUS (Toshiba Aplio 500, Canon Medical Co., Tochigi, Japan) probe for arterial and venous evaluation of lower limb in radiology unit. A 8 MHz pencil CW Doppler probe was used to examine dorsalis pedis artery. Flow velocities and pulsatility index (PI) were measured at room temperatures ranging from 22 to 25°C. The lowest insulation angle was provided to read the maximal rate of peak systolic velocity (PSV). In Doppler flow assessment, normal values of PSV of dorsalis pedis artery range between 10 and 20 cm/sec due to synchronous fluctuations which is made possible by spontaneous opening and closing of skin arteriovenous anastomoses. ¹⁵ PI is normally consistent with values between 5 and 10 for pedal arteries that are more oscillatory and high resistant. ¹⁶ The PI value of 5 was applied as a threshold to determine the decreased resistance resulting from sympathetic hypoactivity in pedal Doppler tracings. ¹⁷ Staging was performed on the basis of wound bed temperature assessment via a hand-held noninvasive infrared thermometer and velocimetric values of dorsalis pedis artery. Patients with PSV above 40 cm/sec and PI < 2 were accepted as stage 1 sympathetic dysfunction ( Fig. 1A ). These 15 patients had warmer and severe edematous skin in the leg than other patients in this entity. In this patient, the wound bed temperature was above 37°C. Patients with PSV between 20 and 40 cm/sec and PI < 2 were diagnosed as stage 2 ( Fig. 2A ). These seven patients had mild edema and normal wound bed temperature between 35 and 37°C. Eight patients with PSV below 20 cm/sec and PI between 2 and 3 were evaluated as stage 3 ( Fig. 3A ). These patients had lower wound bed temperature below 35°C. Five of them had lower perfusion. Only three patient had unhealed ulcer with PSV below critical value, 10 cm/sec. In stage 1 patients, PSV values were significantly higher than other stages ( p  = 0.0001). They ranged from 44 to 83 cm/sec with a mean 58.32 cm/sec. PI values were observed between 0.89 and 1.38 with a mean 1.17. The PSV values above 40 cm/sec and PI values below 2 have been interpreted as a consequence of maximal hyperperfusion due to diminished sympathetic activation. PSV were ranged from 27 to 38 cm/sec with mean 35.31 cm/sec in stage 2. PI values were between 1.24 and 1.72 with a mean 1.43 in these patients. In stage 3 patients, PSV was remarkably lower than other stages ( p  = 0.0001). PSV values ranged from 8.5 to 19 cm/sec with a mean 15.71 cm/sec. PI was ranged from 1.56 to 2.34 with a mean of 1.87 ( Table 1 ). DUS investigation was diagnostic for vascular abnormalities encountered in the autonomic neuropathy. In both stage 1 and 2, blood flow waveform of dorsalis pedis artery was characteristically high volume and monophasic in shape. There were an elevated PSV and a diminished PI. Long-term sympathetic nerve failure caused a change in the shape of monophasic antegrade flow waveform. In stage 3, There was a decrease in both systolic and the diastolic velocities. Thus, PSV reflecting proximal compliance was found to be diminished and PI indicating distal vascular resistance was observed not to be changed remarkably in stage 3 patients. In five of them, intermittent claudication or critical ischemia was not present. Because they had PSV values above 10 cm/sec indicating minimal blood perfusion and vascular reconstruction, it was not necessary to maintain blood supply. There were three patients with unhealed wound due to ischemia. In venous DUS examination of the leg, there were superficial venous insufficiency alone in 21 cases, and deep and superficial venous insufficiency in four cases. There was no any venous pathology in five patients.

Fig. 1.

( A ) Pedal arterial duplex ultrasonography showed a monophasic pattern with significant increased peak systolic velocity in stage 1 patients. ( B ) Magnetic resonance angiography of the leg revealed bright contrast enhancement in vascular structures and enlarged draining calf veins in stage 1 patients.

Fig. 2.

( A ) Pedal arterial duplex ultrasonography displayed a monophasic pattern with mild increased peak systolic velocity in stage 2 patients. ( B ) Magnetic resonance angiography of the calf revealed mild decreased arterial contrast density and contrast pooling in dilated stagnant veins in stage 2 patients.

Fig. 3.

( A ) Pedal arterial duplex ultrasonography demonstrated a monophasic pattern with diminished peak systolic velocity in stage 3 patients. ( B ) Magnetic resonance angiography of the leg showed severe arterial stenoses with venous contamination in stage 3 patients.

Table 1. CW Doppler velocity parameters and waveform analysis.

No. of measurements	PI	PSV (cm/sec)	Waveform analysis
15 (Stage 1, hyperthermia)	0.89–1.38 (mean: 1.17)	44–83 (mean: 58.32)	Monophasic form with significant increased flow
7 (Stage 2, normothermia)	1.24–1.72 (mean: 1.43)	27–38 (mean: 35.31)	Monophasic form with mild increased or normal flow
8 (Stage 3, hypothermia)	1.56–2.34 (mean: 1.87) flow	8.5–19 (mean: 15.71)	Monophasic form with decreased flow

Abbreviations: PI, pulsatility index; PSV, peak systolic velocity.

We preferred qualitative evaluation of SSR disturbances, that is, the absence of SSR. We thought that SSR could be a useful complimentary method for detecting patients by measurement of latency prolongation and amplitude decrease. In all of cases, the absence of SSR was also observed in all stages of disease.

MRA of leg showed vascular and soft tissue contrast enhancement that indicated fast blood flow and early venous return in stage 1 patients ( Fig. 1B ). MRA of calf revealed decreased vascular contrast density that reflected hypoperfusion and venous stagnation in stage 2 ( Fig. 2B ). In stage 3 patients, MRA demonstrated infragenicular arterial stenosis in a variety degree and venous contamination ( Fig. 3B ).

Data were entered into a database and analyzed by using IBM version 16.0 statistical soft-ware (SPSS Inc., IL). A Mann–Whitney U test was performed for statistical significance to compare differences between stages with respect to values of PSV and PI in all patients. A probability of 5% was considered statistically significance.

Discussion

Existence of sympathetic hypoactivity on the basis of arterial dysfunction in the lower limb increases the severity of venous stasis and related skin pathology. In this trial, vascular DUS examination and MRA have supplied a great deal of information about the presence and severity of the sympathetic vascular abnormalities. In stage 1, the presence of blood overflow causing stasis ulcer is irrespective of whether the demonstrable cardiovascular disease exists or not. Overperfusion makes the limb warmer and edematous following venous blood congestion. In this stage, hyperperfusion was also shown by 99mTc-labeled human serum albumin dynamic vascular scintigraphy. ¹⁸ DUS examination provides an indirect assessment of blood perfusion. Differences in arterial Doppler flow patterns are generally attributed to segmental interaction between distal vascular resistance and proximal compliance. Modulation of arterial compliance is largely realized by autonomic innervation of arterial smooth muscle with intrinsic elastic properties. In sympathetic nerve failure, a blood overflow due to increased proximal arterial compliance and reduced distal arteriolar resistance following arteriovenular shunting would be expected to cause a higher capillary pressure that promotes fluid transfer into the interstitium and edema formation. An increased arterial blood flow is present at an early stage of sympathetic neuropathy without occurring symptoms and developing ulcer. In CW Doppler examination and DUS evaluation of pedal arteries, there was a significant increase in the PSV that reflected proximal compliance and a decrease in PI which indicated sensitivity of distal vascular resistance. While autonomic dysfunction extends proximally, the increase in proximal arterial compliance causes an elevation in the systolic blood flow with a rise in PSV. The decrease in distal resistance produces a rise in the diastolic blood flow with a fall in PI.

In Doppler flow analysis, systolic flow pattern above the baseline is merged into the diastolic portion of the cycle without clear border between phases and increased forward flow passes throughout diastole. Precapillary arterioles regulated by sympathetic nerves seem to be dilated and higher pressure at thevenous end of the capillaries and the venules produces venous enlargement and following elevated blood volume. Loss of venoarteriolar reflex also causes venous hypertension and stasis in lower limb. Higher venous pressure in the diabetic leg is correlated well with the severity of sympathetic denervation with AV shunting. ¹⁹ Sympathetic neuropathy was the most encountered precipitating factor for the development of leg edema and skin ulcer which represents a leading cause of hospitalization and amputation. ²⁰ Furthermore, a clear association was determined between the autonomic neuropathy and the nature of vascular dysfunction in the leg. ²¹ There is no comparable pathologic difference between diabetic and nondiabetic patients with regard to autonomic denervation. Peripheral sympathetic denervation is required to occur diabetic foot ulcer. ²¹ Clinical profile and outcomes of venous stasis ulceration above the ankle among diabetic patients are similar to that of nondiabetic cases. ²²

Transcutaneous oximetry and laser Doppler flowmetry have limitations in predicting infrapopliteal perfusion since skin blood flow is usually unchanged until severe degree of arterial disease exists. ²³ DUS analysis of flow velocity waveforms provides remarkable data to evaluate the blood supply of arterial tree and has a great importance to understand vascular pathophysiology causing leg ulcer. DUS is a noninvasive and a highly reliable assessment for the severity and the temporal alterations of vascular dysfunctions in lower limb. Autonomic neuropathy has a divergent development and a more different course than that of peripheral somatic neuropathy. ²⁴ As the arterial compliance increases, a rounded and prolonged systolic peak becomes relatively more marked in spectral Doppler display. Last, continuous triphasic flow pattern turns into a constant positive monophasic flow pattern throughout systole and diastole phases. Clinical findings generally do not appear until long after the onset of sympathetic arterial dysfunction. In patients with traumatic sympathetic dystrophy, dynamic blood pool imaging study by using radionuclide agent, 99Tc sestamibi demonstrated a valuable information related to an increased blood supply of soft tissue and bone of limbs. ²⁵ In this study, there was an increased uptake in the delayed images of equilibrium phase due to a higher plasma volume following venous blood congestion and capillary dilatation. In stage 3, vascular alterations resulted in arterial sclerosis developing with time. Reduction in blood flow was due to increased distal vascular bed resistance following arteriolar and distal arterial occlusions which resemble to an atherosclerotic small distal arterial disease. Long-term higher resting blood flow velocity results in shear stress on arterial wall and promotes vascular remodeling. Consequently, developing platelet aggregation process and smooth muscle proliferation, known as medial sclerosis, may be responsible for decreasing distensibility and lowered diameter of small distal arteries. Reduced blood flow due to diminished proximal compliance and distal arterial occlusions also leads to persistent nonhealing ulcer which is related to age and duration or severity of disease. A good correlation exists between autonomic neuropathy and peripheral vascular dysfunction before distal arterial occlusion develops. ²⁶

In evaluation of vascular dysfunction in leg, measurement of pedal arterial blood flow parameters by using DUS has a great importance in patients with autonomic leg ulcer. It is needed to confirm or rule out the existence of hyperperfusion in pedal arterial DUS measurements at initial examination. An increased PSV value above 40 cm/sec and a reduced PI value below 2 indicates appropriate cutoff values to define the presence of an excessive blood flow in a higher degree. The treatment of these ulcers still presents a therapeutic challenge. Reducing pressure and volume overload in the crural venous system is the main causal treatment. This can be achieved using compression therapy which has also a priority in appropriate pressure relief for the management of edema due to over blood supply in stage 1. ²⁷ Diminished blood flow observed in stage 3 patients had a remarkable pain and different wound management in which compression was not used. By using DUS arterial velocity measurements and MRA, this article clarifies that severe leg edema due to increased perfusion is associated with worsening of leg ulceration in patients with acute sympathetic neuropathy. In long-term course, developing distal arterial sclerosis is considered to indicate lower perfusion that is responsible for nonhealing and recurrence of wounds.

Lastly, a meticulous effort can be made for the presence of reduced sympathetic activity causing leg ulceration. DUS evaluation of blood flow in pedal arteries is a feasible and simple test to perform and has a rational basis to assess the vascular dysfunction.