Measures of small fiber peripheral nerve integrity affected

Measures of small fiber peripheral nerve integrity were affected in persons with autism spectrum disorder (ASD) compared with age-matched controls, a small neurophysiology study found.

“The observation of reduced skin innervation in autism individuals extends our knowledge of neural substrates underlying autism somatosensory symptoms due to dysregulated skin nerve development or degeneration,” noted Sung-Tsang Hsieh, MD, PhD, of the National Taiwan University in Taipei, and coauthors.

“The demonstration of small fiber pathology in this report provides a starting point to study the peripheral nervous system in autism,” they wrote in Neurology.

Small fiber assessments included skin biopsy to quantify intraepidermal nerve fiber density, heat pulses to assess contact heat-evoked potential, and quantitative sensory testing.

Findings showed that:

  • Intraepidermal nerve fiber density was reduced in 53% of those with ASD compared to controls (mean 5.53 versus 11.13 fibers/mm, respectively; P<0.0001). Intraepidermal nerve fiber density also showed a U-shaped relationship with autistic symptoms on the 50-point autism spectrum quotient.
  • Contact heat-evoked potential was negatively correlated with intraepidermal nerve fiber density in those with ASD but positively correlated in controls, suggesting altered nociceptive afferent processing in ASD.
  • Quantitative sensory testing showed elevated thermal thresholds to warmth in about 25% of the ASD group. Tactile symptoms were correlated with intraepidermal nerve fiber density distribution, and the warmth threshold at the big toe negatively correlated with intraepidermal nerve fiber density, implying small fiber impairment.

Large-fiber physiology was evaluated with nerve conduction studies (NCS) which were uniformly normal, suggesting selective small fiber involvement.

In an accompanying editorial, Tyler Rehbein, MD, and David Herrmann, MBBCh, both of University of Rochester in New York, noted that the researchers “expand upon their earlier work demonstrating attenuated contact heat-evoked potentials in individuals with ASD by asking if there is a potential contribution of peripheral nervous system denervation and dysfunction to sensory manifestations of ASD, as opposed to the prevailing view of primarily central sensory perturbations.”

“The authors propose these findings as evidence that peripheral small fiber sensory pathology may at least partly underlie somatosensory symptoms in ASD, and that the U-shaped correlation of the intraepidermal nerve fiber density with the autistic spectrum quotient reflects different extremes of autism sensory phenotypes,” they added.

Abnormalities in sensory perception and processing have been seen in a high proportion of people with ASD. Often, they are presumed to reflect central rather than peripheral dysfunction. But the demonstration of changes in the enteric nervous system in ASD suggested other systems, including the peripheral nervous system, might also contribute to sensory dysfunction. “In peripheral neuropathy with the involvement of small-fiber sensory nerves, intraepidermal nerve fiber density is an indicator of C- and Aδ-fiber degeneration,” Hsieh and colleagues noted.

The researchers analyzed data from 32 recruited male ASD patients age 18-45 with IQ of 70 or more; of these, 40% consented to laboratory work and had no abnormal findings. Neurophysiology results were compared with 27 controls (mean age about 33, about 59% male), while symptoms on the autism spectrum quotient were compared with norms from 1,492 controls from Taiwan.

While 53% with ASD had abnormal intraepidermal nerve fiber density, 47% had adequate innervation, creating two ASD groups. Both groups had similar NCS results and similar autistic symptoms.

“The skin denervation group had a distinct psychophysical pattern with a higher warm threshold than the normal innervation group,” the authors observed. “This is similar to typical small fiber neuropathy due to peripheral nerve degeneration disorders, such as diabetic neuropathy, which manifests reduced intraepidermal nerve fiber density and elevation of the thermal threshold.”

But an important difference seen between the denervation and adequate innervation groups within ASD — and between findings in ASD and in typical small-fiber neuropathy — was the reversed relationship between decreased intraepidermal nerve fiber density and increased contact heat-evoked potential amplitude. In typical small fiber neuropathy, intraepidermal nerve fiber density is positively correlated with contact heat-evoked potential amplitude and attenuation of contact heat-evoked potential reflects denervation; the effect of skin nerve degeneration is proportionally transmitted to the brain and the lesions are peripheral.

This reversed relationship “implies a fundamental difference between typical small fiber neuropathy and autism with small fiber pathology,” the authors noted.

“Skin innervation was associated with autistic symptoms in a U-shaped fashion, supporting the observation that the severity of autistic symptoms was associated with the degree of skin innervation, particularly on the two extremes of intraepidermal nerve fiber density,” the authors wrote. “This phenomenon provides pathological substrates for previous reports indicating both hypo- and hyper-responsiveness.”

While findings support the possibility of combined central and peripheral contributions to disordered sensory processing in ASD, they “should be viewed as exploratory, and hypothesis-generating with respect to the broader understanding of disordered sensory processing in ASD,” the editorialists observed.

Limitations include a relatively small sample size and small subgroups. All ASD participants were males with mild autism in a narrow age range, limiting generalizability. While common causes of peripheral neuropathy were excluded in all controls, only 40% of ASD participants had such workup available.

  1. Measures of small fiber peripheral nerve integrity were affected in persons with autism spectrum disorder (ASD) compared with age-matched controls, a neurophysiology study found.

  2. Large-fiber physiology was evaluated with nerve conduction studies which were uniformly normal, suggesting selective small fiber involvement.

Paul Smyth, MD, Contributing Writer, BreakingMED™

The study was supported by National Taiwan University Hospital, Taiwan Ministry of Science and Technology, Ministry of Education and National Health Research Institutes.

Researchers reported no conflicts of interest.

Rehbein reported no disclosures. Herrmann reported directing an academic clinical skin biopsy laboratory for epidermal nerve fiber density analysis for diagnosis of small fiber neuropathies at the University of Rochester and grants from the Friedreich’s Ataxia Research Alliance and CMT Association, grants from Acceleron Pharma, grants from Flex Pharma, grants from NIH, personal fees from Regenacy, personal fees from Neurogene, personal fees from Sarepta Therapeutics, personal fees from Narrow River Management, personal fees from Guidepoint global, personal fees from GLG, personal fees from Slingshot Insights, personal fees from ClearView Health Partners, personal fees from DDB Health NY, personal fees from Cydan, personal fees from Trinity Partners, personal fees from Schlesinger, and personal fees from Human First therapeutics.

Cat ID: 135

Topic ID: 85,135,128,135,192,925