Assessment of Small Fiber Neuropathy in Rare Diseases Using Sudoscan
Phase: NA
Conditions: Small Fiber Neuropathy, Fabry Disease, Ehlers Danlos Syndrome, Mitochondrial Disease
Sponsor: Massachusetts General Hospital

Cover Letter 
 
Date of initial document creation: 09/21/2015 
Date of most recent IRB review (annual continuing review): 01/20/2021 
 
 
• Name: Amel Karaa, MD 
• Title: PI 
 
• Institution: Massachusetts General Hospital 
• Address: 175 Cambridge Street, Boston MA 02114 
• Telephone number: 617 726 0580 
• Email address: akaraa@mgh.harvard.edu 
 
• Proposal title: Assessment of small fiber polyneuropathy in rare disease using Sudoscan   
NCT02985710 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
Research Plan  
 
Background 
 
Small-fiber polyneuropathy, or SFPN, is the medical term for whole-body dysfunction and/or 
degeneration of small-diameter nerve fibers that transmit pain and control the body's involuntary 
(autonomic) functions.  Symptoms of SFPN include wide-spread chronic pain, low blood 
pressure and/or rapid heart rate, and gastrointestinal distress.  Abnormal sweating has also 
been associated with SFPN 1,2.  
One of the first clinical manifestations of Fabry disease include acroparesthesias (pain), 
sweating impairment, and gastrointestinal dysmotility. Up to 70% of children and adolescents 
with classical Fabry disease develop pain in hands and feet at the average age of 9 years for 
boys or 16 years for girls 3. These are the most common complaints by Fabry patients and the 
ones that impact their quality of life the most; long before kidney, heart and central nervous 
system involvement becomes apparent. These symptoms are thought to be caused by SFPN 
and improved with enzyme replacement therapy (ERT)4. Major efforts have attempted to raise 
awareness of Fabry disease and to screen high risk populations presenting with symptoms 
consistent with SFPN to promptly initiate ERT.  
 
The pathophysiology of SFPN in Fabry disease is still not fully elucidated but there is consensus 
that the dysfunction involves: 1) Hypofunction of the nerve Aδ fibers preferentially which is 
different from SFPN in diabetes and amyloidosis where both C fibers and Aδ fibers are equally 
affected5,6. This is likely related to accumulation of glycolipids and loss of cell bodies in the 
dorsal root ganglia7,8. These deposits may disrupt ion channels and/or lead to nerve tissue 
cytotoxicity which could explain why certain anti-epileptic drugs targeting ion channels work so 
well to relieve acroparesthesias in Fabry patients9.  2) Chronic nerve ischemia secondary to 
glycolipids accumulation within endothelial cells of the blood vessels supplying nerve fibers10. 
 
Being able to properly diagnosis and monitor SPFN is therefore not only important for patients 
with idiopathic SFPN to have adequate, earl diagnoses for proper treatment and counseling, but 
also for patients with established Fabry disease to have good monitoring of SFPN progression 
and 
assessment 
of 
ERT 
efficacy 
and 
adjunct 
therapy 
for 
pain 
management.  
 
Differentiating Fabry-induced SFPN from other causes (diabetes, amyloidosis, hereditary 
neuropathies and other multisystemic genetics and inflammatory/auto-immune disorders) can 
be clinically challenging early in the disease presentation when only symptoms of SFPN are 
apparent. Neuropathic pain with an onset in childhood or adolescence and/or chronic pains in 
the hands and feet exacerbated by changes in outside or body temperature, and decreased 
cold sensation on examination are strongly suggestive of Fabry disease. This data might 
however be elusive for years leading to considerable delay in diagnosis11. 
 
 
In general SFPN is diagnosed through a combination of symptoms, signs and confirmatory 
diagnostic testing. Nerve conduction studies are not sensitive enough in most of the cases 
leaving the ankle skin punch biopsy with measurement of intraepidermal nerve fiber density 
(IENFD) as the main gold standard diagnostic tool. Despite its utility and reproducibility, skin 
biopsy is invasive, expensive and requires a central laboratory for processing and interpretation. 

Sophisticated autonomic function test (AFT) equipment, which includes a quantitative 
sudomotor axon reflex testing (QSART), is already in use at major medical centers, including 
MGH, as one of several methods recommended by the American Academy of Neurology for 
diagnosing SFPN12.  However, full AFT testing takes an hour to complete and requires rigorous 
preparation to undergo the test.   
 
A new device, Sudoscan™ (Impeto Medical, Paris, France) has been cleared by the FDA as a 
non-invasive galvanic skin response method to measure sweat gland function.  There are no 
preparations required and the measurement takes about 2 minutes.  The Sudoscan device 
consists of four metal plates on which patients place their hands and feet while standing.  A 
small, low-voltage DC current is applied to the plates, which attracts chloride ions from the 
sweat glands on the palms of the hands and soles of the feet.  The resulting electrochemical 
skin conductance (ESC) is measured and related to the subject's capacity to sweat.  Normative 
scales of adult sweat function are preloaded in the device and compared to actual 
measurements to determine if a subject's sweat response is reduced, which is associated with 
neuropathy.  Thus, Sudoscan is marketed as a rapid screening test for SFPN.  Several 
researchers have shown Sudoscan to be useful for detecting early SFPN in diabetic adults, the 
largest group at risk of SFPN13-15, chemotherapy-induced SFPN as well as sudomotor changes 
in cystic fibrosis (unpublished data).  Because much of the focus has been on diabetes, there 
are no studies to-date of the feasibility of using Sudoscan for screening for other causes of 
SFPN. 
 
Sudoscan™ is a promising modality to test SFPN in Fabry disease. Defective sweating is one of 
the hallmarks of Fabry disease and  is thought to originate not only from a decrease in nerve 
fiber density of sweat gland  innervation, but also from storage of glycolipids in the sweat glands 
themselves causing sweat gland dysfunction 16 which might be unique to Fabry disease and 
contributing to a specific pattern of ESC.  Data by the Sudoscan™ manufacturer suggests 
increased sensitivity with the ability of detecting abnormalities very early in the disease process 
even when only mild fiber density changes are seen on skin biopsy and long before any 
significant change can be detected by AFT (unpublished data).   This modality; if proven useful 
in detecting SFPN in Fabry disease could be used not only as a diagnostic tool but also as 
monitoring tool to evaluate the effect of ERT and other adjunct therapy. 
 
In the Neuro-genetics unit at the Massachusetts General Hospital (MGH), we also follow 
hundreds of patients with rare diseases such as mitochondrial disease and connective tissue 
disorders. Despite the variable pathophysiology of these disorders SFPN seems to be a 
common pathogenic pathway shared with Fabry disease and leading to the same multiple 
complaints from the patients. In mitochondrial disease, SFPN is thought to be the result of lack 
of energy production and abnormal nerve metabolism, whereas in connective tissue disease, 
the abnormal structural proteins within the tissues are likely the cause. Because of these very 
different mechanisms and the fact that Sudoscan may be more sensitive to subtle SFPN 
changes, one might speculate that there are possibly discriminating ESC parameters (intensity, 
slope and pattern of conductance on the hands and feet) that might be able to distinguish SFPN 
within these 3 disease groups.  
 
Thus we seek to find faster, less-invasive ways to diagnose and monitor small-fiber 
polyneuropathy in Fabry disease as well as identify a signature pattern of Fabry-induced SFPN 
in comparison to other rare diseases.  Since Sudoscan measurement is non-invasive and takes 
only 2 minutes, it is an attractive potential add-on to the routine clinical care of our patients. 
 
Aims: 

The aims of this preliminary study are to:  
 
Aim 1.  
Analyze electrochemical skin conductance and compare data to SFPN standard of care 
diagnostic testing (QSRT and skin biopsy) in patients with Fabry disease and evaluate the 
reliability and sensitivity of SUDOSCANTM. as a new method to asses sweat gland function for 
the screening of Fabry disease. 
  
Aim 2.  
Determine whether there is a specific signature pattern of the ESC (intensity, slope and pattern 
of conductance on the hands and feet) that distinguishes Fabry disease from other disorders 
causing SFPN such as mitochondrial disease and connective tissue disorders. 
Methods 
 
Study population 
Adults and children ages 4 to 65 years recruited at MGH Neurogentics clinic. If local recruitment 
is incomplete, advertisement will be made on patient support groups for broader national 
patients’ enrollment. Informed consent will be obtained from all participants prior to the 
measurement with SUDOSCANTM.  Young participants age 17 and below will provide Assent in 
addition to Consent from their parents. 
Submission to the Institutional Review Board (IRB) for this protocol will be initiated once this 
proposal has been approved. 
 
A.  Study groups - Inclusion criteria 
-Patients (males and females) with confirmed Fabry disease (by GLA enzymes and/or DNA 
testing) naïve and on ERT, mitochondrial diseases (electron transport chain and/or DNA testing) 
and connective tissue diseases (clinical criteria and/or DNA testing when available) 
-Consenting adults and children who are old enough to stand with hands and feet on the 
Sudoscan plates for at least 2 minutes. 
B.  Subject population - Exclusion criteria 
- In general we exclude potential subjects with cognitive, psychiatric, or other problems that 
preclude informed consent.   
- Patients with history of glucose intolerance or diabetes. 
- Patient on chemotherapy 
- Other exclusion criteria are: 
• 
People with any open or bleeding wounds at any sensor plate contact surface location 
• 
People with any type of implantable device 
• 
People with missing hand(s) and/or leg(s) 
• 
Pregnant women or women who are uncertain about a possible pregnancy 

 
  
Study Design 
Aim 1.  
Analyze electrochemical skin conductance and compare data to SFPN standard of care 
diagnostic testing (QSRT and skin biopsy) in patients with Fabry disease and evaluate the 
reliability and sensitivity of SUDOSCANTM. as a new method to asses sweat gland function for 
the screening of Fabry disease. 
 
- Thirty patients with Fabry disease will be enrolled. Emphasis will be given to treatment-naïve 
patients but we expect the majority of the patients to be on ERT. We will proactively seek 
patients who have been on ERT for a short period of time (less than 1 year) and patients who 
are on ERT with persistent acroparesthesia to maximize the yield of SFPN findings.  
- Patients’ charts will be reviewed for pertinent medical history, inclusion/exclusion criteria 
assessment and demographic data (age, gender, body mass index (BMI)). Medications intake 
will also be reviewed to eliminate patients who are on neurotoxic drug that might cause 
neuropathies. 
- All subjects will receive a complete neurological examination comprising: the neurological 
symptom score, cranial nerve function, and an evaluation of muscle weakness, muscular 
atrophy, bilateral reflexes, and sensory function of upper and lower extremities.  
 
-SUDOSCANTM will be used on all patients at baseline to collect ESC. A subset of these 
patients (15) will also undergo standard of care diagnostic testing for SFPN: QSART at the 
MGH neuromuscular clinic’ AFT suit as well as skin biopsy interpreted in Dr. Anne Louise 
Oaklander’s laboratory. Dr. Oaklander is the director of the neuropathology laboratory and has 
tremendous expertise in SFPN with normative data for both children and adults17.  
 
Results of QSRT, skin biopsy and ESC output from SUDOSCANTM will be compared at 
baseline.  
Aim 2.  
Determine whether there is a specific signature pattern of the ESC (intensity, slope and pattern 
of conductance on the hands and feet) that distinguishes Fabry disease from other disorders 
causing SFPN such as mitochondrial disease and connective tissue disorders. 
- Twenty patients with mitochondrial disease and 15 with connective tissue disease will be 
enrolled.  Patients’ charts will be reviewed for pertinent medical history, inclusion/exclusion 
criteria assessment and demographic data (age, gender, body mass index (BMI)). Medications 
intake will also be reviewed to eliminate patients who are on neurotoxic drug that might cause 
neuropathies. 

- All subjects will receive a complete neurological examination comprising: the neurological 
symptom score, cranial nerve function, and an evaluation of muscle weakness, muscular 
atrophy, bilateral reflexes, and sensory function of upper and lower extremities.  
 
-SUDOSCANTM will be used on all patients at baseline to collect ESC. A subset of these 
patients (8 to 10) will also undergo standard of care diagnostic testing for SFPN: QSART at the 
MGH neuromuscular clinic’ AFT suit as well as skin biopsy interpreted in Dr. Anne Louise 
Oaklander’s laboratory. Results of QSRT, skin biopsy and ESC output from SUDOSCANTM from 
each group will be compared to the Fabry patients group to assess for any signature pattern of 
ESC in Fabry disease. 
Study Procedure 
1) SUDOSCANTM  
Subjects will be studied at MGH at a time convenient to them.  No special preparations are 
required.  This study is accomplished in a single session lasting less than 30 minutes including 
paperwork.  Study staff will explain the study and gather informed consent.  Subjects will then 
remove their shoes and socks and stand on two metal plates on the floor while placing the 
palms of their hands on two metal plates on a table.  The plates are connected to the 
SUDOSCANTM  device.  The subject stands still for two minutes while skin conductance data are 
gathered.  There is no perceptible sensation.  Results are expressed immediately as 
Electrochemical Skin Conductance (ESC, µS) representing the ratio between the current 
generated and the constant DC stimulus (lower than 4 V) applied on the electrodes. Sudomotor 
dysfunction is evaluated according to the ESC measured on the limbs: > 60 lS = no dysfunction; 
60–40 lS = moderate dysfunction; and < 40 lS = severe dysfunction (normative database on 
>300 subjects). 
The SUDOSCANTM apparatus is small and can be transported in a small case. This will be 
available at each clinic and will be used to screen every patient seen in the MGH neurogenetics 
clinic during their regular clinic visit. Fabry patients who are not regular MGH patients and 
enrolled for the purpose of this study will be assessed in our research center after full 
examination and comprehensive medical history is obtained.  
There are no risks or discomforts associated with sweat measurement with SUDOSCANTM . The 
procedure is similar to standing on a digital scale for 2 minutes.  The applied voltage is less than 
or equal to 4V with a current of about 0.2 mA.  At this level there is no sensation from contact 
with the electrode plates.  There is no radiation associated with the SUDOSCANTM device. 
2) QSRT 
Quantitative sudomotor axon reflex test measures axon reflex-mediated sudomotor responses 
quantitatively and evaluates postganglionic sudomotor function. The recording is typically 
performed on the forearm and three lower extremity skin sites to evaluate the distribution of 
postganglionic deficits. The test has a high sensitivity, specificity and reproducibility. The test is 
straightforward in established laboratories such as the MGH neuromuscular AFT suite18. There 
is no specific risk associated with this procedure. 
3) Skin biopsy for intraepidermal nerve fiber density (IENFD) 

IENFD and sweat gland nerve fiber (SGNF) density evaluations uses a skin biopsy and 
immunostaining of the tissue to identify and count the intraepidermal and sudomotor nerve 
fibers. Assessment of nerve fiber density typically involves a 3-mm punch biopsy of skin from 
the leg (10 cm above the external malleolus). After sectioning by microtome, the tissue is 
immunostained with anti-protein-gene-product 9.5 (PGP 9.5) antibodies and examined with 
immunohistochemical or immunofluorescent methods.  
Skin biopsy is a well-tolerated procedure and complications which are very rare include: pain, 
infection, bleeding and delayed healing with scaring. 
Primary endpoints 
ESC output from SUDOSCANTM. . Normative ESC scales previously obtained by Sudoscan TM. 
are provided by the manufacturer for comparison. 
Secondary points 
1) Specific Fabry disease ESC signature pattern on SUDOSCANTM testing comparison to other 
rare diseases with SFPN.  
2) ESC characteristics within the Fabry group with assessment of specific phenotypic features 
of Fabry disease such as disease severity, kidney and cardiac involvement to evaluate any 
meaningful correlation between the degree of ESC derangement to the disease 
severity/progression. 
Statistical analysis 
For a p value <1% at 99.5 power a sample size of 20 patients is sufficient (taking into account 
standard deviations and data variation from diabetes studies). Multivariate analysis will be used 
to uncover any ESC variation correlating with the severity of Fabry disease and the different 
phenotypic variability of the disease. 
Anticipated results 
We expect SUDOSCANTM results to be in accordance with the decrease in total sweat response 
measured by QSART and skin biopsy small fiber neuropathy low density. We expect to see an 
improvement of ESC in patients on ERT. We expect to see a specific ESC pattern in patients 
with Fabry disease as compared to other diseases with SFPN. 
Potential benefits to society 
We anticipate adding to the body of knowledge about SFPN.  This method may in time develop 
into a clinical diagnostic tool with the potential to supplement or replace more arduous tools 
such as skin biopsy or AFT. 
 (1 page) 
I. Attachments 
 
 
 
 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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