Not infrequently we face patients who have diabetes or other comorbid conditions with which vascular disease and neuropathy are both associated. At times, differentiating vascular pain from neuropathic pain can be difficult. In a patient with diabetes, vascular pain secondary to loss of blood flow may result from ischemia, vasculitis, vasospasm or vascular compression. Neuropathic pain may result from diabetic neuropathy, nerve entrapment such as tarsal tunnel syndrome, or spinal compression syndrome.
As a practical standpoint, neuropathy and vascular disease not infrequently coexist in the same patient. Making the differential diagnosis more difficult is the fact that the symptoms of neuropathy and vascular disease may be similar, each manifesting as nocturnal pain or cramping and pain with ambulation.
There are number of common risk factors for neuropathy and vascular disease, including hypertension, diabetes, elevated cholesterol, increasing age, elevated homocysteine levels and tobacco use, to name but a few.
Increasingly, there has been a recognition that diabetic neuropathy may be associated with endoneural ischemia with resultant oxidative stress from decreased nerve perfusion and associated neuropathy symptoms. Therefore, in many patients, both neuropathy and vascular disease may coexist, causing pain secondary to peripheral neuropathy.
There has been an expanding understanding of diabetic neuropathy and the wall of microvascular damage. The increased incidence of entrapment neuropathies, often superimposed on preexisting diffuse peripheral symmetrical polyneuropathy, also increases the difficulty in determining the etiology of pain in a patient with diabetes. Some form of entrapment neuropathy may occur in up to one-third of patients with diabetes mellitus, including entrapment of the common peroneal nerve, tarsal tunnel syndrome, carpal tunnel syndrome or lateral femoral cutaneous nerve neuritis.1 These problems may present as an acute mononeuritis. Additionally, one must consider the effects on nerves and vascular supply by medications and comorbid conditions.
It is well-established that neuropathy may occur in up to 66 percent of patients with diabetes, of whom 50 percent of patients are asymptomatic.2 The symptoms of diabetic neuropathy may include aching pain, cramping or a sensation of deep pain, which we may not think of being associated with diabetic neuropathy and mistakenly attribute instead to musculoskeletal disease.
Classically, vascular disease is associated with claudication. However, muscle cramping may be associated with etiologies other than vascular disease, including neuropathy. Pseudoclaudication may occur from lumbar spinal stenosis, disc herniation, the effects of osteoporosis, or less commonly neoplastic disease.
When considering a diagnosis of claudication, consider other common causes of muscle cramping in the legs. These would include fatigue, hyponatremia, hypokalemia, dehydration, hypocalcemia and hypomagnesemia. For many of these causes of cramping, mistaken for claudication, one may pursue electrolyte screening in addition to vascular studies. It is equally important to remember that the conditions may coexist in the same patient.
Pseudoclaudication or neurogenic claudication is not rare. It occurs in 21 percent of individuals living in retirement communities and 12 percent of community dwelling men.3 It is characterized by a history of low back pain and extremity pain. The symptoms of neurogenic claudication can mimic those of vascular disease and vascular claudication. These symptoms include leg pain, leg weakness, tingling, fatigue, a sensation of heaviness and weakness. In addition, the symptoms of neurogenic claudication may be bilateral in presentation.
In the patient presenting with neurogenic claudication, sitting frequently relieves symptoms. With vascular claudication, the patient frequently interdicts walking and allows a period of reperfusion without sitting. For those with any history of neurogenic claudication, patients tolerate walking uphill better than walking downhill. In addition, a careful history can reveal that neurogenic claudication may have radicular characteristics. One may frequently appreciate the discrimination of vascular versus neurogenic claudication by having the patient exercise on a stationary bike. In general, the patient with neurogenic claudication will lean forward on the bike in order to relieve the lower extremity pain.
Neurogenic claudication may be associated with degenerative spondylolisthesis and less commonly ankylosing spondylitis. Examination of the low back or evaluation of radiographs followed by magnetic resonance imaging (MRI) or computed tomography (CT) studies may be helpful in confirming the diagnosis.
Vascular claudication is characterized by pain in the muscle within the calf, thigh or buttocks. It is typically unilateral with femoral popliteal disease and bilateral with aortoiliac disease. The patient will give a history of a rather typical claudication distance with pain relieved by resting. The clinical evaluation will demonstrate reduced or absent pulses, or other manifestations of peripheral arterial disease (PAD).
Neurogenic claudication may not infrequently be associated with paresthesia or dysesthesia, and typically is bilateral rather than unilateral. Patients generally describe sitting down and bending forward as relieving the pain. Not infrequently, maneuvers to stress the sciatic nerve, such as a straight leg raising test, are positive.
Lastly, one should consider cramping in the legs secondary to venous disease. General indications describe a sensation of swelling or fullness. Venous associated muscle cramping is typically unilateral and occurs with a characteristic post-static dyskinesia. Clinical examination may demonstrate findings consistent with venous insufficiency, such as varicose veins, venous ulceration or chronic edema.
Nocturnal exacerbation may occur with neuropathy, restless leg syndrome, muscle cramping or rest pain associated with vascular disease. In addition, some patients suffer from restless leg syndrome (Willis-Ekbom disease) pain at night, worsening with rest and relief with motion of the legs. One diagnoses restless leg syndrome by history and physical examination. Treatments include ropinirole (Requip, GlaxoSmithKline), pramipexole (Mirapex, Boehringer Ingleheim) or rotigotine (Neupro, UCB). Personally, I have continued to have reasonable success utilizing generic diazepam (Valium, Roche USA).
Rest pain, as I noted earlier, may also be associated with venous insufficiency, renal disease, thyroid dysfunction, pregnancy, diabetic motor neuropathy, reactive hypoglycemia or hyperinsulinemia.
Many patients complain of nocturnal cramping, which is not associated with either vascular or neurogenic disease. Typically, patients complain of awakening with painful cramping in the calf or cell of their feet with residual soreness, which may remain for several hours. Nocturnal cramping is much more common in older patients. As noted earlier, nocturnal cramping is typically associated with dehydration, low calcium, low sodium, low potassium or low magnesium, which one may assess by standard laboratory studies and treat by appropriate supplement therapy.
Cramping may also be the result of medications such as diuretics or statin medications. Twenty-five percent of statin-utilizing patients and 80 percent of athletes utilizing statin drugs may experience cramping secondary to the use of statins.4 In addition, the use of long-acting adrenergic beta agonists, such as fluticasone propionate (Advair, GlaxoSmithKline), to treat asthma or chronic obstructive pulmonary disease may initiate cramping. When it comes to cramping associated with the drug effects of statin drugs, one can frequently relieve this with coenzyme Q10.
Patients may relieve vascular nocturnal pain with the use of medication such as cilostazol (Pletal, Otsuka America Pharmaceuticals), pentoxifylline (Trental, Aventis) or certain 5-HT2 receptor antagonists such as naftidrofuryl.
The symptoms of neuropathy are frequently exacerbated during the evening hours. In such cases, oral or topical medications are not infrequently helpful for resolution of symptoms although they do require appropriate monitoring for adverse sequelae. Such medications include ketamine, gabapentin (Neurontin, Pfizer), clonidine (Catapres, Boehringer Ingelheim), tricyclic antidepressants such as amitriptyline (Elavil, Pfizer) or nortriptyline (Pamelor), serotonin norepinephrine reuptake inhibitors such as duloxetine (Cymbalta, Eli Lilly) or certain analgesics such as tapentadol (NuCynta, Janssen Pharmaceuticals).
Topical medications are frequently very helpful for relieving neuropathic symptoms and avoiding side effects. Effective topical combinations include 10% ketamine, 6% gabapentin, 5% lidocaine and 3% imipramine (Tofranil), in addition to which one may add vasodilators such as nifedipine (Procardia, Pfizer).
Metabolic control of symptoms may occur with the use of L-methylfolate, pyridoxal 5’-phosphate and methylcobalamin (Metanx, Nestle Health Sciences, Pamlab) bid, alpha lipoic acid 600 mg-1,800 mg daily or the use of carnitine 2-4 g daily. The utilization of L-methylfolate is particularly attractive as it improves vascular flow to nerves, stimulating the production of nitric oxide, decreasing oxidative stress within the nerve and reducing homocysteine levels.
Studies have described a variety of other supplements such as vitamin D, vitamin C and others as useful for the resolution of neuropathy symptoms.5 Anticonvulsant drugs such as pregabalin (Lyrica, Pfizer) are helpful for symptomatic treatment but do not reverse the underlying pathologic condition.
The evaluation of neuropathy includes a history and physical examination. Following this, one may consider appropriate diagnostic studies such as electromyography/nerve conduction velocity (EMG/NCV), epidermal nerve fiber density testing, the Pressure Specified Sensory Device (PSSD, Sensory Management) or other appropriate diagnostic interventions. In general, one should obtain a proper history, perform a neurologic examination and consider a differential diagnosis. As I noted above, one should consider an evaluation of medications associated with neurologic disorders or muscle cramping.
Clinicians should also complete a complete vascular evaluation and follow this with appropriate diagnostic testing as indicated. In general, an ankle brachial index (ABI) greater than 0.90 is expected in a normal patient. Claudication typically occurs with an ABI of 0.5-0.9, rest pain of 0.21-0.49 and tissue loss at an ABI less than 0.2. The further evaluation of vascular disease may include duplex ultrasound, digital subtraction angiography, magnetic resonance angiography or CT angiography. Classify patients by the Rutherford classification system. In this system, mild claudication is stage I, moderate claudication is stage II, severe claudication is stage III and ischemic rest pain is stage IV. Determine appropriate medical, physical therapy, endovascular or surgical intervention by the classification and location of occlusive disease.
Evaluation of pain secondary to metabolic disorders, vascular disorders or neurologic disorders requires a proper history and physical examination, which are well within the purview of the podiatric physician. Vascular evaluation should include a general screening with noninvasive vascular studies. A stationary bicycle test can discriminate vascular versus neurogenic claudication. A suitable neurologic evaluation and selection of appropriate diagnostic studies when indicated is also essential.
It is always important to consider PAD as a potential etiology of signs and symptoms, remembering that neuropathy and PAD may coexist in the same patient. Consider the possible effects of drugs or metabolic problems, particularly electrolyte abnormalities. Finally, recall that entrapment neuropathy is not uncommon in a patient with diabetes.
1. Boulton AJM, Vinik AI, Arezzo JC, et al. Diabetic neuropathies: a statement by the American Diabetes Association. Diabetes Care. 2005; 28(4):956-62.
2. American Diabetes Association. National Diabetes Fact Sheet. Available at http://www.diabetes.org/diabetes-basics/diabetes-statistics/  . Published Jan. 26, 2011. Accessed Jan. 3, 2014.
3. Papanas N, Edmonds M, Maltezos E. Pseudoclaudication as a manifestation of diabetic neuropathy. Diabet Med. 2005; 22(11):1608-10.
4. Statins linked to leg pain but not weakness. Harv Mens Health Watch. 2013; 17(8):8.
5. Farvid MS, Homayouni F, Amiri Z, Adelmanesh F. Improving neuropathy scores in type 2 diabetic patients using micronutrients supplementation. Diabetes Res Clin Pract. 2011; 93(1):86-94.