Establishing Diagnosis

Peripheral vascular disease (PVD) results from progressive atherosclerosis of the arteries of the lower extremities. The presence of PVD signals an increased likelihood of disease in other regions of the body, resulting in cardiovascular and cerebrovascular morbidity and mortality. PVD affects 10% to15% of the U.S. population; the prevalence increases with advancing age.¹ Risk factors for PVD include smoking, diabetes, hypertension, dyslipidemia, age greater than 40 years, being of African origin, and previous cardiac and cerebrovascular disease.

Most patients with PVD are initially asymptomatic. However, in some patients the early presenting symptom may be intermittent claudication. Classic intermittent claudication is only present in 10% of patients with PVD, and presents as exercise-induced pain; cramping; or discomfort in the hip, buttock, thigh, calf, or foot that is relieved with rest. One of the main differential diagnoses to be considered in vascular claudication is neurogenic claudication, which results from spinal compression caused by conditions such as spinal stenosis, herniated disc, and spondylolisthesis. The pain of neurogenic claudication results from ischemia and swelling of nerve roots at the site of compression. Neurogenic claudication can be differentiated from vascular claudication by the following features:

Neurogenic claudication is more commonly bilateral.

The pain associated with neurogenic claudication is relieved by bending over while walking.

The individual with neurogenic claudication who walks for a long time is able to walk shorter and shorter distances at the expense of longer and longer periods of rest. This is in contrast to the patient with vascular claudication, who can walk the same distance with equal rest periods in between.

The severity of the symptoms in vascular claudication is governed by the amount of stenosis, presence of collateral circulation, and vigor of exercise. The classification systems used to stage severity of disease are the Fontaine and the Rutherford systems, with the Fontaine system used more widely (Table 10-1). Stenoses in the arterial tree secondary to atherothrombosis are responsible for the underlying pathophysiology of this disease. As the disease advances, the resistance in the vascular system increases, and the system is unable to provide oxygenation to the muscles, especially during exercise. This results in claudication, ischemia, ulceration, and eventual loss of limb if left untreated.² Skeletal muscle ischemia affects muscle metabolism with the accumulation of lactate and intermediates of oxidative metabolism (acylcarnitines). This in turn causes muscle deterioration, denervation, and atrophy.³ Chronic ischemia leads to ulceration and gangrene. Pain resulting from ulcers and gangrene is caused by ischemic neuropathy and necrosis of the sensory nerves at the site of the lesion. Severe necrosis of the sensory nerves can paradoxically make gangrenous lesions insensate and anesthetic.

Table 10-1 Fontaine Classification of PAD

Investigations

In the initial stages of PVD clinical history and physical examination are generally unreliable, with the diagnosis being missed more than 90% of the time based on these two factors alone. To make an early diagnosis of PVD, measurement of the ankle-brachial index (ABI) is helpful. The ABI is a ratio of the systolic blood pressure in the ipsilateral dorsalis pedis and posterior tibial arteries to that in the brachial artery (higher of bilateral brachial pressures), measured with a handheld continuous wave Doppler in the supine position. Normal ABI ranges between 1.0 and 1.3. An ABI <0.9 is 95% sensitive and 100% specific for PVD. Angiograms completed in these patients show more than 50% stenosis in one or more major blood vessels.⁴ The lower the ABI score, the more severe the PVD, with ABI <0.4 representing advanced ischemia. Segmental limb pressure, segmental volume plethysmography, duplex ultrasonography, computed tomography (CT) angiography, and magnetic resonance (MR) angiography are additional modalities for evaluation of the level and extent of disease (Fig. 10-1).

Fig. 10-1 Evaluation of patients with suspected peripheral vascular disease.

Adapted from Hiatt WR et al.: Medical treatment of peripheral arterial disease and claudication, N Engl J Med 344:1608, 2001.

The goals of treatment for patients with PVD are to relieve claudication, improve walking capacity, and improve quality of life. Initial management of PVD includes modification of risk factors such as smoking cessation, glycemic control, blood pressure normalization, and dyslipidemia management. Exercise rehabilitation has also been shown to be beneficial in reducing the symptoms of intermittent claudication by improving collateral circulation and thus improving functional status. Medical treatment of PVD includes antiplatelet and vasodilatory drugs. Revascularization is indicated when ischemic pain is severe, indicated by disabling claudication that prevents the patient from performing daily activities of living, rest pain, ischemic ulcers, or gangrene. Amputation is indicated in approximately 5% of patients with nonreconstructible critical limb ischemia and extensive tissue necrosis or life-threatening infection.⁵

Spinal cord stimulation (SCS) was first shown to be effective in relieving claudication symptoms and increasing blood flow to lower extremities by Cook and associates⁶ in 1976, who were using SCS to treat limb pain in patients with multiple sclerosis. During the late 1980s to early 1990s, the use of SCS as an alternative treatment measure for PVD rapidly advanced, especially in Europe. Currently SCS is the most promising neuromodulatory treatment for ischemic pain, and the overall beneficial effects last for at least 1 year in 80% of patients and for up to 5 years in 60% of patients.⁷ The beneficial effects of SCS in the treatment of ischemic pain include pain relief, ulcer healing, decreased oxygen requirement, and increased claudication distance.

Basic Science

There are no established animal models with PVD that give rise to ischemic pain. Therefore normal Sprague-Dawley rats are used for research into the mechanisms of action of SCS for PVD. These rats are used to study acute changes in peripheral blood flow during SCS. SCS intensity in the rat is determined by the motor threshold (MT), which is the stimulation required for muscle contraction to be observed. Experimental SCS is performed at 30%, 60%, 90%, and 300% of MT. Stimulation at 30% MT is the minimum stimulus that produces vasodilation, with 60% MT being the level that approximates the stimulation parameters in clinical applications in humans. SCS at the upper lumbar spinal segments such as L2-L3 produces the largest increase in cutaneous blood flow in the lower limbs in the rat.⁸ There are several proposed theories as to the mechanism of action of SCS in the treatment of PVD:

With regard to pain control, the action of SCS falls back on the Wall-Melzack gate control theory of pain, which proposes that stimulation of large diameter afferent fibers such as those in the dorsal columns of the spinal cord would close notional gates in lamina V of the dorsal horn. This would prevent the ascent of impulses that mediate pain and that originate in small-diameter afferents from ascending to higher levels.⁹ Relief from pain decreases the vasoconstriction that occurs as a reflex response.

SCS-induced vasodilation occurs via suppression of sympathetic activity. The sympathetic nervous system causes vasoconstriction via stimulation of α₁– and α₂-adrenoreceptors. Linderoth, Herregodts, and Meyerson¹⁰ observed that cutaneous vasodilation after SCS in the rat hind paw was eliminated by complete surgical sympathectomy. Administration of ganglionic blocker, hexamethonium, or neuronal nicotinic ganglionic blocker, chlorisondamine, had the same effect. High-dose adrenergic receptor blockers phentolamine and prazosin also suppressed SCS-induced vasodilation. Inhibition of vasodilation was not observed after administration of muscarinic receptor antagonists. However, there are conflicting data with the sympathetic mechanism because some patients demonstrate vasodilation with SCS even after chemical or surgical sympathectomy¹¹ and some incompletely sympathectomized rats in Linderoth, Herregodts, and Meyerson’s study still retained the effects of SCS.

The antidromic mechanism was first proposed by Bayliss in 1901,¹² who noted that dorsal root stimulation at high intensity induced peripheral vasodilation mediated by thin fibers. SCS antidromically activates afferent fibers in dorsal roots, causing the peripheral release of calcitonin gene-related peptide (CGRP), a powerful microvascular vasodilator. Since this time there has been intensive research into the types of fibers that mediate vasodilation and the vasodilators that are released during SCS. CGRP is found in small, myelinated Aδ fibers and unmyelinated C fibers in dorsal root ganglia. By stimulating at various thresholds and blocking C-fiber conduction with the application of capsaicin, Tanaka and colleagues¹³ determined that SCS-induced vasodilation at ≤60% MT is mediated by antidromic activation of myelinated fibers, whereas vasodilation at ≥90% is mediated by both myelinated and unmyelinated C-fibers.¹³ Wu and associates¹⁴ further characterized that SCS-induced vasodilation is predominantly mediated by those sensory fibers that contain transient receptor potential vanilloid-1 (TRPV1).¹⁴

Several vasodilators, including CGRP, are contained within the terminals of TRPV1 sensory nerve endings. Antidromic activation and depolarization of these nerve endings cause release of vasodilators into muscle tissue. CGRP is a potent vasodilator that is tenfold more powerful than prostaglandins and 100 to 1000 times more effective than other typical vasodilators such as acetylcholine, adenosine, and substance P.¹⁵ CGRP binds to CGRP-1 receptor of smooth muscle cells and causes direct relaxation or can bind to CGRP-1 receptor of endothelial cells, which causes release of nitric oxide, which leads to vasodilation. Adrenomedullin is a peptide that co-localizes with CGRP in perivascular nerves and dorsal root ganglia and is involved with angiogenesis and endothelial protection.⁸

Despite the intense research into the mechanisms of action of SCS for the treatment of PVD, the theories are incompletely understood, and there is much more to explore. It is very likely that reduction in pain transmission, the sympathetic theory, and the antidromic theory act in concert to provide pain relief and vasodilation in patients suffering from PVD. The relative weight of one mechanism over another may depend on the patient’s personal set of risk factors, sympathetic activity, and stimulation parameters. The mechanisms of SCS on the peripheral vascular system are summarized in Fig. 10-2.

Fig. 10-2 Proposed mechanisms of action of spinal cord stimulation. SCS, Spinal cord stimulation; TRPV1, transient receptor potential vanilloid-1.

From Wu et al: Putative mechanisms behind effects of spinal cord stimulation on vascular diseases: a review of experimental studies, Autonomic Neurosci 138:14, 2008.

Indications and Contraindications

General criteria for consideration of a spinal cord stimulator include¹⁶:

Nonmalignant cause of pain.

Failure of medical management.

Remedial surgical procedure not feasible.

Absence of a major psychiatric disorder, including somatization of symptoms.

Elimination of inappropriate drug use before implantation.

Absence of unresolved issues of secondary gain or litigation that potentially could be central to the propagation of the pain complaint.

Capacity to give informed consent for the procedure.

SCS is considered specifically for PVD when critical limb ischemia becomes surgically nonreconstructible. Critical limb ischemia is defined as the presence of rest pain or tissue necrosis (ulceration or gangrene) with an ankle systolic pressure of ≤50 mm Hg or a toe pressure of ≤30 mm Hg. In patients in whom it is not possible to obtain pressure measurements, absence of lower-extremity pulsations on physical examination qualifies as selection criteria. Critical limb ischemia corresponds to Fontaine stages III and IV, in addition to the blood pressure criteria. Surgically nonreconstructible disease is characterized by ischemia in which angioplasty and bypass grafting is not possible, ABI <0.4, or great toe pressures <30 mm Hg. Patients being considered for SCS also must have ischemic rest pain that persists for more than 2 weeks.

SCS is not indicated in PVD for patients who have¹⁷:

Ulcerations deeper than the fascia or gangrene with a diameter larger than 3 cm².

Superimposed infections on ulcerations or gangrene.

Co-morbid disease restricting life expectancy to less than a year.

Presence of a cardiac pacemaker.

Poor compliance caused by psychological or social incompetence.

Based on a critical review of available literature on the topic of SCS for PVD, Spincemaille and associates¹⁸ have proposed an algorithm for successful patient selection. This has been adapted and modified (Fig. 10-3). The patient selection algorithm has not been tested by a randomized controlled trial.

Fig. 10-3 Proposed selection criteria for patients considering treatment with SCS for PVD.

Adapted from Spincemaille GH et al: The results of spinal cord stimulation in critical limb ischaemia: a review, Eur J Vascular Endovascular Surg 20:103, 2001.

Technique

SCS hardware consists of an electrode lead, an extension lead, and an implantable pulse generator. There are two main types of electrodes used:

Cylindrical electrodes with multiple contact points can be introduced in the epidural space percutaneously using a Tuohy type needle. The commonly used percutaneous leads have four or eight contact points.

Because of their larger size, surgical or paddle electrodes need a small laminotomy for the introduction into the epidural space. These electrodes also can have multiple contact points in various types of configurations. These electrodes can have 4, 8, or 16 contact points (Fig. 10-4).

Fig. 10-4 Cluster of various types of spinal cord stimulation leads. Types of leads used may be percutaneous, quadripolar or octipolar, or a surgical paddle lead. These can be used for the treatment of peripheral vascular disease.

Image provided courtesy of Medtronic Inc.

The procedure for insertion of a cylindrical lead is performed in the operating room under sterile conditions with local anesthesia supplemented by conscious sedation. Access to the epidural space is gained with a Tuohy needle, introduced either at L2-L3 or L4-L5 space. A paramedian approach is preferred over a midline approach. Entry into the epidural space is judged by loss of resistance technique and confirmed by taking a lateral x-ray film of the spine.

Positioning of the lead must be performed under fluoroscopic control with lead placement either in the midline if the pain is bilateral, or slightly off of midline to the symptomatic side (Fig. 10-5). Intraoperative stimulation is then carried out. The tip of the electrode position should be such that stimulation induces paresthesias. For best results the stimulation-induced paresthesias should cover the entire territory of the pain. Results may be less than satisfactory if stimulation covers <80% of pain territory. The Tuohy needle and the stylet of the electrode are removed, and the lead is then fixed into the deep fascia. For this purpose an anchoring device is used. The lead is then externalized, and a trial of stimulation is initiated. The trial period in North America usually lasts approximately 1 week. In certain European countries (e.g., Belgium) by law the trial must last for 4 weeks.

Fig. 10-5 A, Quadripolar percutaneous lead implanted in epidural space, in case of peripheral vascular disease, left leg, anteroposterior view. B, Lateral view.

There is controversy in the literature whether or not a trial of stimulation is beneficial. An analysis of multiple pathologies treated with SCS showed that approximately 18% to 20% of patients fail trial stimulation in spite of the best efforts in selecting candidates for SCS therapy.¹⁶ This emphasizes the importance of screening with trial stimulation before permanent implantation. This approach reduces the rate of failed permanent implants and improves cost-effectiveness. The trial stimulation also allows for a period of patient adjustment to stimulation-induced paresthesia and counseling by the neurosurgical team. The main disadvantages of this process are that it is an added procedure with associated costs and minimal risks such as root irritation, hematoma, or infection, which may add to the hospital stay.

If trial stimulation is successful in relieving at least 50% of pain and in improving microcirculatory status, the lead is internalized by connecting to a pulse generator, which is implanted subcutaneously in the anterior abdominal wall or in the gluteal region in the area of the hip pocket below the belt line.

Effective stimulation parameters vary with each patient and can range from amplitudes between 1.5 and 6 V, frequencies of 55 to 60 Hz, and pulse widths of 210 to 300 ms. Stimulation can be performed continuously or with cyclical use to preserve the life of the pulse generator battery. Kumar and colleagues¹⁹ found that optimal results were achieved with a cycling mode of 1 minute on, 2 minutes off.¹⁹ With the advent of rechargeable pulse generators, this issue has been resolved. The new pulse generators also allow for multiple programming.

Patient Management and Evaluation

Several parameters are used to evaluate the efficacy of SCS for PVD. Improvements in macrocirculation can be measured by (1) Doppler peak blood flow velocities at the common femoral, popliteal, and dorsalis pedis arteries and the digital arteries in the great toe; (2) pulse volume recording at the midthigh, calf, foot, and big toe; (3) ABIs; and (4) claudication distance evaluated by walking on a treadmill with no incline at 2 miles/hr. Microcirculation is assessed using the transcutaneous partial pressure of oxygen (TcpO₂) over the dorsum of the foot with a portable oximeter. Improvement in circulation can also be monitored by documenting healing of ulcers and gangrene.

Pain relief is usually assessed using a visual analog scale and monitoring the patient’s narcotic and nonnarcotic analgesic use.

Patients with spinal cord stimulators require lifelong evaluation to review the adequacy of pain relief and address concerns such as fractured or displaced electrodes, hardware malfunction, or exhausted battery life. Stimulation parameters may also require adjustment and refinement at follow-up appointments to better meet the patient’s evolving pain experience.

Tolerance is defined as a progressive loss of efficacy in the presence of functional hardware. Gradual loss of pain control after a successful period is a multifactorial problem involving physiological, pathological, and psychological factors. Development of tolerance is most common in the first 2 years of implantation, but it can occur at any point in treatment. Tolerance remains a challenge to the maintenance of high rates of long-term success, regardless of early successful results. Tolerance may be caused by plasticity of pain pathways in the spinal cord, thalamus, or cortex. Fibrosis around the stimulating tip has also been implicated but has not been proven by autopsy or surgical exploration.

A review of the literature fails to provide an adequate explanation or guidance in treatment of tolerance. Stimulation “holidays” of up to 6 weeks have met with minimal success, and addition of adjuvant medications, such as amitriptyline or L-tryptophan, has also been met with equally poor results.¹⁶

Outcome Evidence

Outcome measures commonly evaluated in clinical studies include pain reduction, macrocirculatory and microcirculatory data, percentage of limb salvage, and clinical improvement in Fontaine classification.

Spinal Cord Stimulation for Nonatherosclerotic Peripheral Vascular Disease

SCS also has beneficial effects in the treatment of nonatherosclerotic PVD such as Buerger disease or Raynaud phenomenon. Unfortunately there are only a few published studies on this topic, and the studies do not have large samples of patients. In a prospective study by Donas and colleagues,²⁹ patients with Buerger disease received SCS treatment. Microcirculation was measured using the regional perfusion index (RPI), which is the ratio between the foot and chest transcutaneous oxygen pressure. Baseline RPI was recorded to be 0.27, which improved to 0.41 at 3 months, and was sustained at 1 and 3 years at 0.49 and 0.52, respectively. Limb survival rate was 93.1%. Claudication symptoms were also improved, and healing of trophic lesions was noted. Thus SCS can also be considered as an alternative treatment for patients with vascular disorders of nonatherosclerotic origin.

Little data are available in the literature with respect to SCS for Raynaud phenomenon, except for several case reports that report successful results.

Risk and Complication Avoidance

Complications with SCS are generally related to the hardware and are similar, regardless of the indication for treatment. In a retrospective analysis of 410 patients over a period of 22 years, Kumar, Hunter, and Demeria¹⁶ found the following types and incidence of complications: displaced electrode (21.5%), fractured electrode (5.9%), other hardware malfunction (8.1%), subcutaneous hematomas (4.4%), infection (3.4%), cerebrospinal fluid leak (0.5%), rotation of the pulse generator (0.7%), and discomfort at the pulse generator site (1.2%). The most common fracture site was distal to the point of anchor where the lead exits from the deep fascia; a bend or kink is created at this point, increasing the stress on the lead. In cases of lead migration, the need for surgical revision is decreasing because of the use of octipolar leads and multichannel pulse generators.

Summary

SCS is currently the most promising neuromodulatory measure for the treatment of PVD. The mechanism of action behind SCS for PVD is still incompletely understood. The theories of reduction in pain transmission, sympathetic suppression, and antidromic activity likely act in concert to provide the beneficial effects of SCS.

Overall SCS has been shown to be an effective alternative for the treatment of nonreconstructible critical limb ischemia. SCS significantly improves pain, microcirculation, limb survival, and Fontaine clinical stage compared to conservative treatment. Selection of patients using improvement in TcpO₂ and pain relief during trial stimulation can further improve the success of SCS. However, there is no linear correlation between the degree of pain relief and improvement in TcpO₂. It appears that the use of SCS is more effective in patients with rest pain before ulceration takes place.