Small fibre neuropathy defies 'dying-back' nerve process

By Lucy Piper

Neuronal degradation in patients with small fibre neuropathy (SFN) is not dependent on nerve fibre length, study findings suggest.

The findings in 52 patients with idiopathic SFN and SFN associated with impaired glucose tolerance and diabetes showed that epidermal fibres were lost at similar rates in proximal and distal sites. This was in opposition to the expected classic "dying-back" process of slow progression from distal to proximal axonal degeneration, note the researchers.

Skin biopsies (33 mm) were obtained from the distal leg, distal thigh and proximal thigh of each patient to ascertain intraepidermal nerve fibre density at each site. The rate of nerve fibre density loss was then calculated over a 2- to 3-year period.

At baseline, there was evidence of a distal, length-dependent pattern in nerve fibre density reduction, with lower density at the distal leg in all patients, at an average of 6.48 fibres/mm, compared with 13.32 fibres/mm and 19.98 fibres/mm at the distal and proximal thigh, respectively.

Also, the 13 patients with SFN associated with impaired glucose tolerance and the 14 with SFN due to diabetes had significantly lower nerve fibre density at all three biopsy sites than the 25 with idiopathic SFN at baseline.

But, over time, nerve fibre density declined at a similar rate in all three groups of patients, compared with no change in 10 healthy controls, and irrespective of biopsy site, indicating a "uniform reduction in [intraepidermal nerve fiber density] at proximal and distal sites regardless of cause", say Michael Polydefkis (Johns Hopkins University, Baltimore, Maryland, USA) and team.

The mean yearly rates of nerve fibre density decline irrespective of SFN cause were 1.42 fibres/mm at the distal leg, 1.59 fibres/mm at the distal thigh and 2.80 fibres/mm at the proximal thigh.

The mean slopes of decline in nerve fibre density over time regardless of biopsy site were 0.179, 0.164 and 0.198 for idiopathic SFN, impaired glucose tolerance-associated SFN and diabetes-associated SFN, respectively.

"The pattern of disease progression in our patients with SFN is a non-length-dependent distal axonopathy and could be interpreted as evidence of the interaction between SFN terminals and its target (the skin) playing a critical role", the researchers write in JAMA Neurology.

They add: "Together, these observations are consistent with the increasing impression that distal portions or axons are selectively vulnerable in peripheral neuropathy."

The researchers highlight the important clinical implications of their findings, given that current diagnostic criteria and identification for an accurate cutoff for intraepidermal nerve fibre density are based on the assumption that the SFN process is dependent on nerve length.

"Our data suggest that [intraepidermal nerve fiber density] from proximal sites can be informative as well, including cases that clinically present as a classic distal symmetric SFN with a stocking-and-glove distribution", they note.

However, in a related editorial, John Kissel (The Ohio State University Wexner Medical Center, Columbus, USA) and Gordon Smith (University of Utah School of Medicine, Salt Lake City, USA) point out some study limitations, including the small numbers of patients and the "surprisingly high" nerve fibre density values, which they say mean the "results are not sufficient to set aside clinical terms such as length dependent or stocking and glove."

They note: "Even if skin biopsy is not a length-dependent biomarker, the clinical scenario remains almost uniformly a length-dependent process."

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