Emerging Insights On Interdigital Neuromas And Metabolic Syndrome

The prevalence of metabolic syndrome and diabetes is increasing at a startling rate, and there is a high occurrence of neuroma pain with patients who exhibit symptoms of metabolic syndrome. Taking a closer look at the research and offering insights from their own experience, these authors suggest that clinicians should consider any patient with “neuroma pain” as being at risk for pre-diabetes.

Morton is well known for his observation of intermetatarsal space pain of neural origin, commonly termed “Morton’s neuroma.”¹ In the medical community, we often view this painful entity as a “neuroma” and frequently treat it by surgical excision. However, contrary to popular belief, this is not a true “neuroma” but rather reactive changes due to surrounding constraints on axoplasmic flow in a plantar digital nerve. Thus, Morton’s neuroma is a compression neuropathy of the third common plantar digital nerve.²

This concept originated with Morton in 1876 when he advocated decompression of the third interspace by resecting the fourth metatarsal head and surrounding tissues.1 He realized that external mechanical forces applied to the neural tissue would cause irritation, hyperplasia and fibrosis. A true neuroma, by contrast, forms only after a peripheral nerve has been transected or injured, and we commonly term this a “stump neuroma.”

The underlying pathology in nerve compressions is hypoxia, which is primarily caused by mechanical constraints on the affected nerve, factors that lead to “syndrome X” or metabolic syndrome, and/or a reduction in nitric oxide, which can have a direct link to lower levels of L-arginine.

Ischemia of the common plantar digital nerve is the primary cause of symptoms in patients with intermetatarsal pain as Nissen noted in 1948.³ Rydevik and colleagues further supported this hypothesis when they performed an in vivo study of compression on the tibial nerves of rats.⁴ Utilizing a microscope and mini-compression device, the authors found venous blood flow was impaired within the tibial nerve at a pressure of 20 to 30 mmHg. At 40 to 50 mmHg of pressure, they found that arteriolar and intrafascicular capillary flow were impaired. Total occlusion of all intraneural blood flow occurred at 60 to 80 mmHg.⁴

In 1940, Betts and coworkers described proximal tethering of the common plantar distal nerve about the flexor digitorum brevis and distal stretching of the nerve due to extension of the digits, causing compression on the nerve.⁵ In 1978, Gauthier developed this theory further by surgically releasing the deep transverse metatarsal ligament and decompressing the interspace in 206 patients, achieving “rapid and stable improvement” in regard to pain reduction for 83 percent of those who participated in the study.⁶

What You Should Know About Nerve Compression And The Double Crush Syndrome

MacKinnon and Dellon recognized the importance of nerve compression and neuropathies in multiple locations within the peripheral nervous system, including the common plantar digital nerve.⁷ Dellon pioneered surgical decompression at multiple sites of anatomical narrowing, where the peripheral nerve is subject to compression, for the treatment of distal polyneuropathy. The pathophysiology of a “Morton’s neuroma” is analogous to that of other chronic peripheral nerve compressions such as carpal tunnel, tarsal tunnel and the fibular tunnel, all of which we treat by surgical decompression. Barrett was the first to use endoscopy to decompress an intermetatarsal space for a compression neuropathy of a distal nerve.^8,9 Both external and internal compressions are factors that can play a role in neuropathy.

Upton and McComas described the double crush syndrome in 1973, hypothesizing that “serial constraints on axoplasmic flow, each insufficient by itself to cause a symptomatic neural dysfunction,” cause double crush syndrome.¹⁰ In addition to these compression neuropathies, an underlying metabolic neuropathy may combine additional compressive forces to cause a multiple crush. This additional crush described by Kaplan is known as “syndrome X” and “pre-diabetic syndrome,” and is defined as the quartet of hypertension, hyperlipidemia, glucose intolerance and an increase in the body mass index (BMI).¹¹ Metabolic syndrome can lead to a diabetic state if it goes undiagnosed and untreated. Internal compression or expansion within the peripheral nerves in the patient with hyperglycemia results from the accumulation of sorbitol within the nerve and subsequent endoneurial edema from osmotic water retention.¹²

Nitric oxide has been called the “miracle molecule” for its role as an essential mediator in numerous biological processes in the human body. One of these roles is a neurotransmitter contributing to sensory transmission in the peripheral nervous system. Nitric oxide also plays a vital role in vasodilation within the blood vessels that directly affect blood flow and pressure. When the body is deficient in the semi-essential amino acid L-arginine, which is the precursor for nitric oxide, functional amounts of nitric oxide are not produced and neuropathy can develop. In patients with metabolic syndrome or diabetes, there is a decrease in production and utilization of L-arginine, and an increase in neuropathy.¹³

Why Intermetatarsal Pain May Indicate Metabolic Syndrome

To date, the literature has been devoid of any studies linking the incidence of intermetatarsal pain and metabolic syndrome. We feel that intermetatarsal “neuroma” pain can be an indicator of metabolic syndrome. Intermetatarsal pain is very common in the medical community. In fact, Youngswick reported that out of 4,000 patients who presented to his podiatric practice, 372 (9.3 percent) got a diagnosis of a neuroma.¹⁴ Fifty-four of these patients were male and 318 were female, indicating a high propensity for females to be afflicted with this condition.

Out of the multiple nerve tunnels Dellon described, the tunnel that surrounds the common plantar digital nerve is the most susceptible to subtle changes in the metabolic state and mechanical irritation from the intermetatarsal ligament. The state of this tunnel can therefore act as a first-line marker of the pre-diabetic state. We must recognize this fact in those patients who exhibit symptoms or have elevated levels of glucose, cholesterol, blood pressure or an increased BMI with a high index of suspicion for metabolic syndrome. Patients will often present with complaints of pain in their lower extremity. Conversely, few will present with a suspicion of high cholesterol or blood pressure. Therefore, external symptoms are crucial in diagnosing the high-risk patient early in the disease process.

The double crush syndrome is a vital factor affecting the condition known as “Morton’s neuroma” as it relates to the diagnosis of pre-diabetes. The external factors affecting the intermetatarsal space nerves such as ligaments, bones, tendons and fibrous bands act as one crush with the additional crush resulting from the metabolic state (hypertension, hyperlipidemia, elevated BMI and elevated blood glucose). These restraints on axoplasmic flow, especially at the deep transverse metatarsal ligament, are the cause of subsequent hypertrophy and pain of the third common plantar digital nerve.

Similar to the findings of most studies performed on Morton’s neuroma, the percentage of females with double crush syndrome is very high, around 80 percent.¹⁰ This may be due to physiological or biomechanical differences in comparison to males. Women also tend to wear high-heeled, narrow, restrictive shoes.

A Closer Look At The Authors’ Research

We performed two unpublished studies to elucidate this theory. First, we performed a retrospective study to establish the concept and determine if it was a plausible theory. Then we used a prospective study to validate the retrospective study and theory.

The randomized, retrospective study consisted of 53 patients whom we had seen over the past two years with at least one area of intermetatarsal space pain. We checked the patient charts carefully for metabolic risk factors including hypertension with systolic hypertension >140 mmHg, diastolic hypertension >90 mmHg, or use of anti-hypertension medication); lipid lowering medication or total cholesterol >200 mg/dL and low-density lipoprotein (LDL) >100 mg/dL; and elevated BMI >25.0 kg/m².^15,16

Of the 53 patients, 26 had hypertension, 25 exhibited hypercholesterolemia and 35 had a BMI of 25.0 kg/m² (overweight) or greater. Seventeen patients had a combination of hypertension and hyperlipidemia while 12 patients had hypertension, hyperlipidemia and a high BMI.

The prospective study was based on the first 26 consecutive new patients we saw beginning in October 2003. The criteria established for the retrospective study also applied to the prospective study with the addition of a fasting glucose tolerance test and fasting serum insulin that we obtained for all patients. We assessed these two latter tests for a hyperglycemic state in patients with frank diabetes. All patients came from our private practices.

Out of the 26 patients, 21 had hypertension, 15 exhibited hypercholesterolemia and 19 had a BMI of 25.0 kg/m² (overweight) or greater. Fourteen patients had a combination of hypertension and hyperlipidemia while 11 patients had elevated hypertension, hyperlipidemia and a high BMI. Nine patients had impaired glucose tolerance and 12 percent had an increase in fasting serum insulin. Four patients had factors of having frank diabetes with hypertension, hyperlipidemia, a high BMI and glucose tolerance test.

Metabolic factors that lead to diabetes were present in at least 47 percent of the patients. Hypertension was the highest factor at 81 percent. The majority of patients had only one or two factors. However, the percentage of those with all three factors, excluding glucose tolerance, was 42 percent in the prospective study. This is significant. These patients are at high risk for developing diabetes if their risk factors continue unchanged. Sixteen percent of the patients had frank diabetes with an abnormal glucose tolerance and elevation of the three other factors. The highest overall factor in both studies was BMI at an average percentage of 69.5 percent with most patients categorized as being “overweight.”

There was a substantial difference in our studies between most retrospective and prospective study risk factors. These differences are especially evident with hypertension and the combinations of hypertension + hyperlipidemia, and hypertension + hyperlipidemia + BMI. The reason for this increase in the prospective study may be due to the larger patient numbers in the retrospective study and the change within the general health of the population over the past few years. Overall, there was a significant percentage of risk factors associated with pre-diabetic syndrome in the population of patients with intermetatarsal space pain. Therefore, intermetatarsal space pain can be a marker at some level of metabolic syndrome. Physicians can use this marker as an aid in detecting diabetes and with a strong clinical suspicion should perform diagnostic tests for a definitive diagnosis.

In Conclusion

Given the high incidence of pre-diabetic factors found in this study, one should consider any patient with “neuroma pain” at potential risk for pre-diabetes. However, if the patient exhibits no risk factors (hyperlipidemia, hypertension and/or an elevated BMI), the compression neuropathy may be primarily due to biomechanical factors. The results of this study confirm the importance of considering patients with intermetatarsal space pain and metabolic factors at high risk for developing diabetes and its complications. To establish this theory more fully, a multicenter prospective study must take into account the demographic and medical differences that exist.

Dr. Jacoby is in private practice in Phoenix. He is a Past President of the Association of Extremity Nerve Surgeons and the Arizona Podiatric Medical Association.

Dr. Thomas is a Fellow at the Scottsdale Neuropathy Institute.

References

1.     Morton TG. A peculiar and painful affection of the fourth metatarsophalangeal articulation. Am J Med Sci. 1876; 71:35.
2.     MacKinnon SE, Dellon AL. Surgery of the Peripheral Nerve, Ch. 13, Thieme Medical Publishers, New York, 1988, p. 339.
3.     Nissen KI. Plantar digital neuritis: Morton’s metatarsalgia. J Bone Joint Surg. 1948; 30B(1):84-94.
4.     Rydevik B, Lundborg G, Bagge U. Effects of graded compression on intraneural blood flow. J Hand Surg. 1981; 6(1):3-12.
5.     Betts LO. Morton’s metatarsalgia: neuritis of the fourth digital nerve. Med J Aust. 1940; 1:514-515.
6.     Gauthier G. Thomas Morton’s disease: a nerve entrapment syndrome. A new surgical technique. Clin Orthop. 1979; 142:90-92.
7.     MacKinnon SE, Dellon AL. Surgery of the Peripheral Nerve. Ch. 12 and 13, Thieme Medical Publishers, New York, 1988, pp. 305-345.
8.     Barrett SL, Pignetti TT. Endoscopic decompression for intermetatarsal nerve entrapment – The EDIN technique 1: preliminary study with cadaveric specimens; early clinical results. J Foot Ankle Surg. 1999; 33(5):503-508.
9.     Instratek Incorporated. Available at https://www.instratek.com/epf.php .
10.     Upton AR, McComas AJ. The double crush in nerve entrapment syndromes. Lancet. 1973; 2(7825):359-62.
11.     Kaplan NM. The deadly quartet: upper-body obesity, glucose intolerance, hypertriglyceridemia, and hypertension. Arch Intern Med. 1989; 149(7):1514-1520.
12.     Jakobsen J. Peripheral nerves in early experimental diabetes. Diabetolgia. 1978; 14(2):113-119.
13.     Moncada S, Higgs A. The L-arginine-nitric oxide pathway. N Engl J Med. 1993; 329(27):2002-2012.
14.     Youngswick FD. Intermetatarsal neuroma. Clin Podiatr Med Surg. 1994; 11(4):579-592.
15.     Drozda J Jr., Messer JV, Spertus J, et al. ACCF/AHA/AMA–PCPI 2011 performance measures for adults with coronary artery disease and hypertension. J Am Coll Cardiol. 2011; 58(3):316–36.     
16.     Smith SC Jr, Blair SN, Bonow RO, et al. AHA/ACC guidelines for preventing heart attack and death with atherosclerotic cardiovascular disease: 2001 update. J Am Coll Cardiol. 2001;38(5):1581-1583.

For further reading, see “A Closer Look At Endoscopic Nerve Decompression For Morton’s ‘Neuroma’” in the July 2012 issue of Podiatry Today, “A Guide To Endoscopic Decompression For Intermetatarsal Neuromas” in the September 2011 issue, or “Understanding The Relationship Of Metabolic Syndrome And Pre-Diabetes” in the April 2017 issue.