Subscribe to eTOC

For Your Patients-Small Fiber Sensory Neuropathy
New Questions About the Diagnostic Sensitivity of Skin Biopsies for Small Fiber Sensory Neuropathy, Particularly for Chinese-Americans

ARTICLE IN BRIEF

Figure

DR. LAN ZHOU: “Our retrospective study was the first to determine whether the diagnostic sensitivity of using the worldwide normative values of IENFD was reduced in Chinese-American patients when compared to non-Chinese-American patients.”

A new analysis reports that skin biopsy values for intraepidermal nerve fiber density at the distal leg were significantly lower in Chinese-American patients, raising questions about the sensitivity of the test across different patient groups.

New research suggests that the worldwide normative reference values used to compare patient's intraepidermal nerve fiber density (IENFD) at the distal leg may not be sensitive enough to detect small fiber sensory neuropathy in ethnic Chinese groups.

Chinese-Americans may have significantly higher baseline IENFD at the distal leg than primarily Caucasian Americans, according to a paper published in the online September 2018 Journal of Clinical Neuromuscular Disease.

“Our retrospective study was the first to determine whether the diagnostic sensitivity of using the worldwide normative values of IENFD was reduced in Chinese-American patients when compared to non-Chinese-American patients,” lead investigator Lan Zhou, MD, PhD, professor of neurology and pathology at the University of Texas Southwestern Medical Center, told Neurology Today.

Dr. Zhou referred to a few previous studies that have compared IENFD values at the distal leg in different ethnic groups. One study published in 2013 in Muscle Nerve found that healthy ethnic Thais had significantly higher baseline IENFD values than a healthy control group in the United States. The other study published in 2015 in the European Journal of Neurology included only 6.5 percent non-Caucasians and 1.6 percent Asians in their sample, which didn't allow for a meaningful comparison, according to Dr. Zhou.

The finding suggest the need for tighter standards for skin biopsy interpretation, independent experts told Neurology Today.

STUDY DESIGN

Dr. Zhou perceived the low sensitivity of using the worldwide normative reference values of IENFD in diagnosing ethnic Chinese patients with small fiber sensory neuropathy when she saw patients at the Manhattan Chinatown clinic affiliated with Icahn School of Medicine at Mount Sinai, where she previously worked. “Despite my strong suspicion that certain patients had small fiber sensory neuropathy based on clinical symptoms and examination findings, their skin biopsies would often be normal. This led to my interest in conducting this study.”

The investigators conducted a retrospective chart review of subjects who underwent skin biopsies and clinical evaluations by neuromuscular experts at Mount Sinai between 2013 and 2017. All the skin biopsies and IENFD evaluation were performed by the Mount Sinai skin biopsy service and Mount Sinai Cutaneous Nerve Laboratory following the published guidelines.

“We selected the final study subjects, 23 in the Chinese-American group and 32 in the non-Chinese-American group, based on the high clinical suspicion of a pure distal small fiber sensory neuropathy,” said Dr. Zhou. This was defined as “the presence of both small fiber sensory symptoms (pain, burning, tingling, and/or numbness) and signs (reduced pinprick sensation or hyperalgesia to pinprick) bilaterally in a length-dependent manner.” The researchers excluded subjects with large fiber involvement or a nerve conduction study and/or electromyography findings suggestive of a large fiber polyneuropathy.

The age at skin biopsy ranged from 35 to 85 years (mean 66.0 years) in the Chinese-American group and 34 to 87 years (mean 58.6 years) in the non-Chinese American group. The two groups had comparable female predominance (69.6 percent in Chinese and 62.5 percent in non-Chinese). The non-Chinese group was 78.1 percent Caucasian, 9.4 percent African-American, 9.4 percent Hispanic, and 3.1 percent Asian Indian.

The investigators found that the diagnostic sensitivity of skin biopsy using the bright-field immunohistochemistry protocol and the worldwide normative reference values of IENFD at the distal leg was significantly lower (26.1 percent) in the Chinese American patients than in the non-Chinese-American patients (62.5 percent; p=0.01).

“Therefore, the worldwide normative values appear insensitive for diagnosing a pure distal SFSN in Chinese-Americans,” said Dr. Zhou.

The limitations were the small sample size and retrospective aspect of the study. “In the future, we need to conduct a large-scale study to confirm the ethnic differences in baseline IENFD in healthy Asians as well as other ethnic groups including Caucasians, African-Americans and Hispanics. Then, we can develop more accurate normative values for each group to improve the diagnostic sensitivity,” said Dr. Zhou.

EXPERT COMMENTARY

“I very much agree with the authors of this study. The published norms most skin biopsy labs use to decide whether specific patient's biopsies are normal or diagnostic for small fiber polyneuropathy are often rudimentary,” said Anne Louise Oaklander, MD, PhD, FAAN, associate professor of neurology at Harvard Medical School and an assistant in neuropathology at Massachusetts General Hospital in Boston where she directs the neurology skin biopsy lab.

Figure

DR. ANNE LOUISE OAKLANDER: “The normative criteria most labs use will have unacceptably high false negative diagnostic rates for Asians, females, and especially children. This is because their epidermal neurite densities are normally higher than in non-Asians, males, and older adults.”

“The normative criteria most labs use will have unacceptably high false negative diagnostic rates for Asians, females, and especially children,” said Dr. Oaklander, who was not involved with the study. “This is because their epidermal neurite densities are normally higher than in non-Asians, males, and older adults.”

In the posters Dr. Oaklander and her colleagues presented to the 2015 Society for Neurosciences and 2014 American Neurology Association, they reported that “the original single-threshold norm (3.8 EN/linear mm) would have falsely diagnosed as normal three-quarters of all 173 biopsies we had interpreted in 2012-2013.”

They also reported statistically higher densities in normal Asians than in other races, and in females compared to males. The norms are highest of all in young children and teens, said Dr. Oaklander. Consequently, “we use statistical multivariate regression that uses each patient's age, sex, and race to generate a predicted normal distribution for them and to calculate what the fifth centile would be for them. The diagnostic threshold calculated for an Asian girl is very different than that for a 70-year-old Caucasian man.”

Dr. Oaklander recommends that patients ask their neurologists which lab is actually analyzing their skin biopsies and what diagnostic algorithms they apply. For best accuracy, the norms should be generated from within the same lab analyzing their skin biopsy. “Our reports specify that our norms come from a within-lab normative database that's updated multiple times each year with newer values,” she said.

Patients can also request that their slides be sent from the lab that originally analyzed them to another lab for a second interpretation, Dr. Oaklander suggested. “False positive and false negative diagnoses of small fiber polyneuropathy can both lead to serious problems. When a disease is not diagnosed in a timely manner and remains untreated, it can have devastating consequences for patients,” said Dr. Oaklander.

She emphasized the need for tighter standards for skin biopsy interpretation. For this reason, she and co-author Max Klein submitted a Letter of Intent to the FDA's Biomarker Qualification Program regarding the diagnostic context of using PGP 9.5 immunolabeled skin biopsies. Their decision is expected within the month.

Figure

DR. MICHAEL J. POLYDEFKIS: “This is an important study as it points to the limitations of our diagnostic tests and that we need to continue to refine them for diverse populations. It also emphasizes that we need to continue to be good physicians and take the entire clinical picture into account: patients symptoms, examination results, and test results.”

Michael J. Polydefkis, MD, FAAN, professor of neurology at Johns Hopkins University School of Medicine and director of the Johns Hopkins Cutaneous Nerve Laboratory, commented: “This is an important study as it points to the limitations of our diagnostic tests and that we need to continue to refine them for diverse populations. It also emphasizes that we need to continue to be good physicians and take the entire clinical picture into account: patients' symptoms, examination results, and test results.”

Dr. Polydefkis agreed with the study authors that a limitation of the study was the small sample size. In addition, there were several differences between the Chinese-American and non-Chinese-American populations including, age, distributions, average weight, and symptoms of neuropathy.

“It was not clear if the researchers addressed other risk factors such as hypertension, and impaired glucose tolerance. Also, I would have expected neuropathy to present with similar symptoms between Chinese-Americans and non-Chinese-Americans. That makes me wonder if the populations are truly comparable or if there was a difference in how symptoms were reported and/or ascertained,” said Dr. Polydefkis.

LINK UP FOR MORE INFORMATION:

•. Jin P, Cheng L, Chen M, Zhou L. Low sensitivity of skin biopsy in diagnosing small fiber neuropathy in Chinese Americans https://journals.lww.com/jcnmd/fulltext/2018/09000/Low_Sensitivity_of_Skin_Biopsy_in_Diagnosing_Small.1.aspx. J Clin Neuromuscul Dis 2018: 20(1): 1–6.
•. Lauria G, Bakkers M, Schmitz C, et al. Intraepidermal nerve fiber density at the distal leg: A worldwide normative reference study https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1529-8027.2010.00271.x. J Peripher Nerv Syst 2010; 15:202–207.
•. Shikuma CM, McArthur JC, Ebenezer GJ, et al. Ethnic differences in epidermal nerve fiber density https://onlinelibrary.wiley.com/doi/abs/10.1002/mus.23834. Muscle Nerve 2013; 48:462–464.
•. Provitera V, Gibbons CH, Wendelschafer-Crabb G, et al. A multi-center, multinational age- and gender adjusted normative dataset for immunofluorescent intraepidermal nerve fiber density at the distal leg https://onlinelibrary.wiley.com/doi/abs/10.1111/ene.12842. Eur J Neurol 2016; 23:333–338.