Small-Fiber Neuropathy Common at 40 Years of Type 1 Diabetes

Miriam E. Tucker

September 18, 2013

After 40 years of living with type 1 diabetes, nearly all patients have small-fiber sensory neuropathy and a majority also has large-fiber nerve     dysfunction, a small prospective study has found.

Results of the trial, one of the first to distinguish among affected nerve-fiber types in diabetic polyneuropathy, were    published online September 11 in Diabetes Care by Kari     Anne Sveen, MD, from Oslo University Hospital, Norway, and colleagues.

Most important, the researchers documented a relationship between HbA1c and nerve damage, which lends further support to the importance of intensive insulin treatment, particularly early in the course of type 1 diabetes, to preserve both large- and small-fiber nerve function, Dr. Sveen told    Medscape Medical News.

"It was a bit surprising for us initially that small-fiber dysfunction was even more prevalent than large-fiber neuropathy in these type 1 diabetes     patients of 40 years' duration of their disease. However, it is believed that small-fiber changes are a precursor of later large-fiber involvement," said     Dr. Sveen, who is also a PhD student at the University of Oslo.

And she noted that because patients with small-fiber nerve damage often have no neuropathic symptoms, "annual screening with simple nerve-function testing     — monofilament and vibration perception — is very important to find patients at risk for foot ulcers and so on."

"Metabolic Memory" Supports Early Glycemic Control

Peripheral neuropathy is one of many complications of type 1 diabetes, resulting in significant morbidity and mortality, but it remains unknown how     hyperglycemia causes damage to the nervous system or whether there is a definitive threshold of glycemic exposure needed for it to develop.

Sveen and colleagues set out to study large- and small-fiber nerve function in type 1 diabetes of long duration and associations with HbA1c and     advanced glycation end products (AGEs). They explain that specific function tests to distinguish between the different nerve fibers damaged in diabetic     polyneuropathy — large myelinated, small thinly myelinated, or small nonmyelinated nerve fibers — have only recently become available.

They examined 27 patients (12 women, 15 men), aged 53 years on average, who had had type 1 diabetes for a mean duration of 40 years and who were part of     the Oslo Study, a larger ongoing prospective trial.

Signs or symptoms of neuropathy were present in almost 60%, including sensory neuropathy symptoms reported by 9 patients, pain in 3, and carpal-tunnel     symptoms in 5. There were 2 patients without symptoms but who had abnormal neurological tests.

Of the patients, 22 (81%) were diagnosed with small-fiber dysfunction by quantitative sensory testing (QST), which assesses thresholds of temperature     detection. Among those, 15 also were found to also have large-fiber neuropathy via nerve-conduction studies (NCS).

And in another small-fiber assessment, intraepidermal nerve-fiber density (IENFD) measurement, abnormal results — which were significantly lower than in     age-matched controls (4.3 mm vs 11.2 mm; P < .001) — were recorded in 19 patients (70%).

IENFD correlated negatively with HbA1c over 27 years, although the relationship was no longer significant after adjustment for age, body mass     index, and height. But 1 AGE — N-ε-(carboxymethyl) lysine (CML), which has previously been linked to painful diabetic neuropathy — was independently     associated with IENFD, even after adjustment for these same variables.

And although large-fiber neuropathy, assessed by NCS and electromyography, was less common, it was still detected in 16 (59%) of the patients.

The authors point out that the relationship between HbA1c and both small- and large-fiber neuropathy was stronger for the first 17 years than at     27 years. This finding may be due to the phenomenon known as "metabolic memory" and points to the importance of early glycemic control, they assert.

"This study supports the importance of good glycemic control even in long-term type 1 diabetes for preserving small- and large-fiber function and that     early good glycemic control may have an especially important impact on later neuropathy development," they state.

Referral Essential if Doubt About Patient Management

Dr. Sveen told Medscape Medical News that, although intensive glycemic control remains the most important tool in the management of peripheral     diabetic neuropathy, there is also some hope that certain compounds could prove to be neuroprotective, including oral benfothiamine and erythropoietin (in     animals). "More research in this field is warranted. Treatment of neuropathic pain is essential," she observed.

She advises that referral to a neurologist for nerve-conduction studies is indicated if physicians are in any doubt about how they should manage their     patients; "especially with symptoms of pain, a small-fiber test may be necessary for a correct diagnosis and optimal treatment."

The next step will be to see whether the peripheral changes in the nervous system parallel changes in the central nervous system, she concluded.

        This work was supported by the South-Eastern Norway Regional Health Authority and Oslo Diabetes Research Center. The authors have reported no relevant         financial relationships.    

Diabetes Care. Published onlineSeptember 11, 2013. Abstract

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