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Peripheral Sensory Nerve Pathology Contributes to Autism Symptoms, Researchers Find

Article In Brief

A new study documents small fiber pathology and functional impairments as the major presentations underlying autism symptoms. But the findings may have limited value until more research is conducted in this area, independent experts said.

A substantial portion of people with autism have pathology of the peripheral sensory nerves that is associated with their autism symptoms, according to new research reported online on October 14 in Neurology.

The findings, which the researchers said are the first report of peripheral nerve involvement in autism, add a new dimension to the understanding of sensory phenomena seen in patients with the disorder. They also point to potentially important areas of research and could eventually help clinicians tailor treatments for their patients, said the researchers from the National Taiwan University Hospital.

But independent experts told Neurology Today these observations may have limited value until more research is performed in this area.

“This study documents small fiber pathology and functional impairments as the major presentations underlying autistic symptomatology,” wrote the research team, led by Sun-Tsang Hsieh, MD, PhD, attending neurologist at National Taiwan University Hospital.

“Neuropathic pain is uncommon in most autism patients,” Dr. Hsieh told Neurology Today. “Nevertheless, the presence of small fiber pathology may hint at the potential of applying or extending similar principles (that are already established) in designing assessments and therapeutic strategies.”

Study Details

To study the association, researchers took biopsies and assessed the nerve fiber density of 32 patients with autism, who were all male and on average 27-years-old. They compared those results with 27 matched controls. They also conducted sensory testing and profiled their autism symptoms.

The intraepidermal nerve fiber (IENF) density of the autism patients was significantly lower than that of the controls, with 5.53 fibers per millimeter on average, compared with 11.13 fibers per millimeter (p<0.0001).

Of the 27 autism subjects who underwent quantitative sensory testing, nine had abnormal detection of warmth at the index finger, foot dorsum or big toe. The IENF density was correlated with the warm threshold at the toe, researchers found.

Testing large nerve fibers, responsible for the perception of position and movement, showed no difference between autism subjects and controls.

The small nerve fiber density was not uniform among those with autism: 17 had reduced IENF density while the others had adequate density, and researchers assessed these subgroups. Those with reduced small nerve fiber density showed symptoms associated with a lower tactile sensitivity, with participants in this group saying they preferred going barefoot over wearing shoes and reporting being unaware of scratches or bruising. The individuals with autism who had normal IENF density, on the other hand, reported a dislike of being touched and of being uncomfortable with certain textures of clothing, researchers said.

Overall, IENF density correlated with autism symptoms, as measured by the Autism-Spectrum Quotient, in a U-shaped fashion, such that those with lower density had higher scores, those in the middle had lower scores, and those with higher densities in the autism cohort had higher scores (p=0.014).

When researchers assessed contact heat-evoked potential (CHEP), which reflects the transmission of pain signals from the periphery to the brain, they came away with a novel finding. In typical subjects, the density of small nerve fibers is positively correlated with CHEP amplitude. But in the autism subjects assessed in this study, researchers found that as the small nerve fiber density went up, CHEP amplitude went down.

“The inverse correlation between IENF density and CHEP might hint at changes developed not only in the periphery but also in the brain,” Dr. Hsieh said. “Our study indicated that the autism patients might be further grouped into different phenotypes. This strategy will help to identify biomarkers for designing new therapies.”

The findings could result in a more immediate clinical impact for some patients, Dr. Hsieh suggested. “At this stage, some patients have the manifestations of small fiber pathology, and we can take advantage of available medications, such as neuropathic pain treatments,” he said. Also, he said, “We can apply the findings in this study to explore new molecular targets for treatment.”

The researchers acknowledged that the study had several limitations. The participants who had autism were all male, and the average IQ was within the normal range; therefore, the findings might not be generalizable to the whole autism population, they wrote. In addition, the mean age of the controls were older (at approximately 32.8-years-old) than the participants who had autism. They noted that based on previous research that IENF density decreases as individuals age, older controls were supposed to have lower IENF density, and so the true difference between the participants with autism and age-matched healthy controls may be larger than reported.

Expert Commentary

Charles D. Smith, MD, FAAN, who recently retired as a professor of neurology at the University of Kentucky, said there are several possible explanations for the findings. While cautioning that he was speculating, he said that “the small-nerve pathology could be part of the same developmental defect that is responsible for classic autism symptoms. Among possible explanations, it could reflect a secondary biological consequence of autism, such as an undetermined nutritional defect causing nerve-ending loss or be the result of an autoimmune attack on the nerve endings.”

He added that the pathology may possibly be a secondary effect of autistic symptoms, such as fluctuating stress hormone levels due to severe anxiety or related to the subtle effects of autism medications.

“I doubt the study was sufficiently powered to differentiate among these possibilities,” he said. For instance, matching was not done for fluctuating anxiety or medications. “So, the significance is minimal currently.”

Nancy Minshew, MD, director the National Institutes of Health Autism Center of Excellence at the University of Pittsburgh, acknowledged that she is not an expert in the methodology used in the study. But she cautioned that any toxins, including certain medications, or trauma to the toe, foot, or ankle, could potentially confound the findings. She added that data on nerve conduction velocity would be helpful to know.

Since this is the first paper of its kind in autism, confirmation will be needed, she said. “One paper on anything needs independent verification to have any traction.”


Drs. Hsieh, Smith, and Minshew reported no relevant disclosures.

Link Up for More Information

• Chien YL, Chao CC, Wu SW, et al. Small fiber pathology in autism and clinical implications,peripheral%20sensory%20nerves%20in%20autism. Neurology 2020; Epub 2020 Oct 14.