Nerve Decompression Debate Continues in Diabetic Neuropathy

Miriam E. Tucker

February 17, 2014

Adding operative nerve decompression to usual foot-ulcer treatment in patients with diabetic sensorimotor polyneuropathy (DSP) significantly reduces ulcer recurrence compared with patients' own unoperated legs, a new analysis from a multicenter cohort study finds.

"Almost every amputation is preceded by an ulcer wound. If we can do something that changes the risk of having a repeat ulcer or a first ulcer event, we can probably do something to greatly reduce the risk of an amputation," lead author D. Scott Nickerson, MD, from Northeast Wyoming Wound Clinic, Sheridan, told Medscape Medical News in an interview.

Results of the 42-patient study are published in the January/February 2014 issue of the Journal of the American Podiatric Medical Association by Dr. Nickerson and Andrew J. Rader, DPM, from the Wound Care Center, Memorial and Healthcare Center, Jasper, IN.

But the topic of whether operative nerve decompression is of benefit in DSP is controversial, and the new study may not convince those who say that there is insufficient randomized-controlled-trial evidence to support its use. Critics say that claims of its success are based on imprecise and subjective DSP assessments and flawed assumptions about the prevalence of nerve entrapment and the extent to which it contributes to the condition's morbidity.

After reviewing the new study, Aaron I. Vinik, MD, PhD, director, research & neuroendocrine unit, at Eastern Virginia Medical School, Norfolk, who coauthored a commentary on the subject in 2007, told Medscape Medical News: "I did not notice anything that would change my mind." His 2007 piece concluded that "until such time as definitive randomized trials are conducted and the supporting evidence is stronger, surgical decompression should not be recommended for patients with DSP."

And a 2006 practice advisory by the American Academy of Neurology as well as a 2008 Cochrane review call the treatment modality "unproven."

However, Dr. Nickerson said the dramatic difference in ulcer recurrence — a hard end point — in his new study provides strong objective prospective evidence in support of the procedure. He also pointed to a December 2013 prospective study from China involving microsurgical peripheral nerve decompression in 516 patients with DSP, which showed a 0% ulcer rate 18 months after surgery. And several other studies have documented subjective improvements in pain and sensitivity scores following nerve decompression in patients with DSP, he noted.

Dr. Nickerson, who retired from performing orthopedic surgery due to DSP, is now medical director of a recently launched randomized controlled clinical trial aimed at testing the procedure's benefit with objective outcome measures.

A Leg Up on Ulcer Recurrence

Dr. Nickerson had previously published retrospective results from 65 patients (8 with type 1 and 57 with type 2 diabetes) who had neuropathic foot ulcers in 75 legs. With pain as the indication, all had undergone operative decompression of the common peroneal and tibial nerve branches in the anatomical fibro-osseous tunnels. Ulcer recurrence rates in the feet of operated limbs remained at less than 5% at 2.5 years and 5 years of follow-up, "more than 80% lower than the literature leads us to expect," they write in the current paper.

The new prospective analysis includes 42 of those patients who underwent only unilateral decompression, thereby allowing for the nonoperated leg to serve as a control that is perfectly matched for duration and severity of diabetes and DSP neuropathy, as well as other clinical characteristics. All patients had a positive Tinel's sign (when tapping over the anatomical tunnels with the foot flexed or extended elicits a tingling sensation), suggesting nerve entrapment.

From year 2 to 5 postdecompression, there were 2 foot-ulcer recurrences (1 at the previous site, the other at a new site; neither led to amputation) in the operated legs (4.8%), compared with 9 ulcers in the contralateral nonoperated legs (21.4%), of which 3 required amputation.

The ulcer risk during the 3-year period was 1.6% per patient per year in the limbs with nerve decompression vs 7% in the control limbs, a significant difference (P = 0.048). The hazard ratio for ulcer recurrence in nonoperated vs operated legs was 5.5 (95% CI, 3.6–7.0).

The Controversy

However, in an email to Medscape Medical News, Dr. Vinik faults the new study for not having a "definitive diagnosis of neuropathy," not using nerve-conduction studies to demonstrate entrapment, and lacking appropriate controls.

In the 2007 commentary, he and his coauthors — including diabetic foot expert Andrew J. M. Boulton, MD, from the University of Manchester, United Kingdom, the current president of the European Association for the Study of Diabetes — said that Tinel's sign "is poorly standardized and lacks sensitivity and specificity. The proponents of the subjective Tinel's sign ignore the proven value of electrodiagnostic studies, an objective test of nerve function."

But Dr. Nickerson counters that although neurologists typically rely on nerve-conduction testing, it doesn't pick up early changes and is not a better predictor of entrapment than Tinel's sign or other clinical assessments that evoke symptoms.

"Nerve conduction studies aren't the be all and end all. The people who will get better can be nicely identified by Tinel's sign," he stressed.

He cited a 2002 study in which electrodiagnostic testing failed to differentiate DSP alone from carpal tunnel syndrome, considered to be an analogous upper-extremity nerve-entrapment condition of the median nerve.

That study, which included 478 individuals with and without diabetes and DSP, also found that nerve entrapment is common among patients with diabetes. Carpal tunnel syndrome was present in 30% of patients with DSP, 14% of patients with diabetes but without DSP, and 2% in the nondiabetic reference group.

Dr. Vinik and his coauthors argue, however, that the distal neuropathy that characterizes DSP is due to progressive axonal loss and that "the proposed pathophysiological mechanism of entrapment cannot explain sensory or motor symptoms or signs above the anatomic levels of the 'entrapped' nerves." Moreover, they say, "the actual frequency of peripheral nerve entrapment in diabetic individuals is small."

But Dr. Nickerson told Medscape Medical News that it's logical that high blood glucose levels in patients with diabetes could cause both neuropathy and other tissue changes that lead to nerve entrapment. "If you believe that the neuropathy causes the nerve to be fat, it's not a big leap to think that things are entrapped."

And it follows, then, that "decompression takes away the sensory deficit that has taken away the ability to recognize a hole in your foot."

He endorses the concept as first described by A. Lee Dellon, MD, professor of plastic surgery and neurosurgery, from Johns Hopkins University, Baltimore, MD, who observed in the early 1990s that both hand and foot symptoms respond to decompression of the affected nerves as assessed with Tinel's sign among patients with diabetic peripheral neuropathy.

Since that time, Dr. Dellon has published hundreds more papers on the subject and now heads his own peripheral nerve surgery institute, which specializes in decompression procedures.

Dr. Vinik and his commentary coauthors were critical of this development, writing in 2007 that "numerous centers have sprung up around the US and the world promoting their specially trained surgeons and touting the benefits of these procedures. One can only guess the medical costs of these unproven procedures."

An End in Sight to the Controversy?

The randomized controlled clinical trial that Dr. Nickerson is now directing began in June 2013 at 6 US sites. Sponsored by the Extremity Nerve Research Foundation of the Association of Extremity Nerve Surgeons, the study is currently enrolling 120 patients with type 1 or 2 diabetes who have DSP and a plantar neuropathic diabetic foot ulcer that has healed within the previous 12 months.

Patients will be randomized to "best care" standard postulcer treatment or best care plus bilateral nerve decompression at 4 fibro-osseous tunnel sites in the leg and foot.

Primary outcome measures are ulcer recurrence or appearance of any other nontraumatic pressure wound or ulcer over a 2-year period. A variety of other subjective and objective outcomes will be measured.

Results are expected in December 2016.

Dr. Nickerson has reported no relevant financial relationships. Dr. Vinik has reported receiving honoraria/expenses from Sanofi and consulting for Abbott, Ansar, AstraZeneca, Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, KV Pharmaceuticals, Merck, Novartis, Pfizer, R.W. Johnson Pharmaceutical Research Institute, Takeda, and Tercica. Dr. Vinik has reported severing on advisory boards for Pfizer and Merck; serving as a consultant for Pfizer, Merck, ISIS Pharmaceuticals, and Pamlab; receiving research support from Pfizer, Tercica, ViroMed, Intarcia, Impeto Medical, th eNational Institutes of Health, and the American Diabetes Association; and serving on speaker bureaus for Merck and Pamlab.

J Am Podiatr Med Assoc. 2014;104:66-70. Abstract

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