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Dorsal Root Ganglion Stimulation in Chronic Painful Polyneuropathy: A Potential Modulator for Small Nerve Fiber Regeneration

  • Eva Koetsier
    Correspondence
    Address correspondence to: Eva Koetsier, MD, PhD, Centro per la Terapia del Dolore, Ente Ospedaliero Cantonale, Ospedale Italiano, Via Capelli, Lugano 6962, Switzerland.
    Affiliations
    Pain Management Center, Neurocenter of Southern Switzerland, Ente Ospedaliero Cantonale, Lugano, Switzerland

    Faculty of Biomedical Sciences, Università della Svizzera Italiana, Lugano, Switzerland
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  • Elena Vacchi
    Affiliations
    Faculty of Biomedical Sciences, Università della Svizzera Italiana, Lugano, Switzerland

    Laboratories for Translational Research, Neurocenter of Southern Switzerland, Ente Ospedaliero Cantonale, Bellinzona, Switzerland
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  • Paolo Maino
    Affiliations
    Pain Management Center, Neurocenter of Southern Switzerland, Ente Ospedaliero Cantonale, Lugano, Switzerland

    Faculty of Biomedical Sciences, Università della Svizzera Italiana, Lugano, Switzerland
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  • Jasmina Dukanac
    Affiliations
    Pain Management Center, Neurocenter of Southern Switzerland, Ente Ospedaliero Cantonale, Lugano, Switzerland
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  • Author Footnotes
    a Indicates shared last authorship.
    Giorgia Melli
    Footnotes
    a Indicates shared last authorship.
    Affiliations
    Faculty of Biomedical Sciences, Università della Svizzera Italiana, Lugano, Switzerland

    Laboratories for Translational Research, Neurocenter of Southern Switzerland, Ente Ospedaliero Cantonale, Bellinzona, Switzerland

    Neurology Department, Neurocenter of Southern Switzerland, Ente Ospedaliero Cantonale, Lugano, Switzerland
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  • Author Footnotes
    a Indicates shared last authorship.
    Sander M.J. van Kuijk
    Footnotes
    a Indicates shared last authorship.
    Affiliations
    Pain Management Center, Neurocenter of Southern Switzerland, Ente Ospedaliero Cantonale, Lugano, Switzerland

    Department of Clinical Epidemiology and Medical Technology Assessment, Maastricht University Medical Center+, Maastricht, The Netherlands
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  • Author Footnotes
    a Indicates shared last authorship.
Open AccessPublished:September 30, 2022DOI:https://doi.org/10.1016/j.neurom.2022.08.455

      Abstract

      Objectives

      Neuromodulatory treatments like spinal cord stimulation and dorsal root ganglion stimulation (DRGS) have emerged as effective treatments to relieve pain in painful polyneuropathy. Animal studies have demonstrated that neurostimulation can enhance nerve regeneration. This study aimed to investigate if DRGS may impact intraepidermal nerve fiber regeneration and sensory nerve function.

      Materials and Methods

      Nine patients with chronic, intractable painful polyneuropathy were recruited. Intraepidermal nerve fiber density (IENFD) quantification in 3 mm punch skin biopsy was performed 1 month before DRGS (placed at the level of the L5 and S1 dorsal root ganglion) and after 12- and 24-month follow-up. Quantitative sensory testing, nerve conduction studies, and a clinical scale score were also performed at the same time points.

      Results

      In 7 of 9 patients, DRGS was successful (defined as a reduction of ≥ 50% in daytime and/or night-time pain intensity), allowing a definitive implantable pulse generator implantation. The median baseline IENFD among these 7 patients was 1.6 fibers/mm (first and third quartile: 1.2; 4.3) and increased to 2.6 fibers/mm (2.5; 2.9) and 1.9 fibers/mm (1.6; 2.4) at 1- and 2-years follow-up, respectively. These changes were not statistically significant (p = 1.000 and 0.375). Sensory nerve tests did not show substantial changes.

      Conclusions

      Although not significant, the results of this study showed that in most of the patients with implants, there was a slight increase of the IENFD at the 1- and 2-year follow-up. Larger-scale clinical trials are warranted to explore the possible role of DRGS in reversing the progressive neurodegeneration over time.

      Clinical Trial Registration

      The Clinicaltrials.gov registration number for the study is NCT02435004; Swiss National Clinical Trials Portal: SNCTP000001376.

      Keywords

      Introduction

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      Therefore, we hypothesized that neurostimulation for pain treatment at the level of the DRG might also lead to intraepidermal nerve fiber regeneration in SFN. The primary aim of this study was to assess the impact of DRGS treatment in chronic, intractable painful polyneuropathy in the limbs on the pathologic progression of clinical confirmed SFN, comparing IENFD by skin biopsy at baseline and after 1 year of treatment with DRGS. Furthermore, with this study, we aimed to quantify the impact of DRGS on sensory nerve function, evaluated by nerve conduction studies, QST, and the total neuropathy score (TNS).

      Materiald and Methods

      Patients’ Enrollment

      Inclusion criteria were age ≥ 18 years and diagnosis of chronic, intractable painful polyneuropathy, either small fiber or mixed fiber neuropathy in the lower limbs, based on typical clinical signs and symptoms,
      • Callaghan B.C.
      • Price R.S.
      • Feldman E.L.
      Distal symmetric polyneuropathy: a review.
      supported by skin biopsy and/or nerve conduction studies. Eligible patients had a pain intensity of ≥ 5 on the numeric rating score (NRS) (ranging from 0 to 10) for at least 3 months, and previous drug therapy (including at least antidepressants and/or alpha-2-delta agonist) was unsuccessful. Key exclusion criteria were coagulation disorders, life expectancy of < 2 years, addiction to drugs or alcohol, and severe foraminal stenosis at the expected target level for DRGS lead implantation. Blood tests were undertaken to screen for common etiologies of polyneuropathy as part of the standard diagnostic work-up of patients with polyneuropathy in our Neurology Department.
      This study was based on the same patients as in Koetsier et al
      • Koetsier E.
      • van Kuijk S.M.J.
      • Melli G.
      • et al.
      Dorsal root ganglion stimulation for the management of intractable painful polyneuropathy: a prospective pilot study.
      and approved by the ethics committee of the Canton Ticino, Switzerland. All patients provided written informed consent before participation in the study. The study was registered at the Swiss National Clinical Trials Portal (SNCTP000001376) and ClinicalTrials.gov (NCT02435004).

      DRGS Lead Implantation

      The procedure of DRGS lead implantation was previously published.
      • Koetsier E.
      • van Kuijk S.M.J.
      • Melli G.
      • et al.
      Dorsal root ganglion stimulation for the management of intractable painful polyneuropathy: a prospective pilot study.
      In short, DRGS was delivered by the ProclaimTM DRG Neurostimulator System (manufactured by St Jude Medical, now Abbott, Sunnyvale, CA, USA). Between two and four quadripolar percutaneous DRGS leads were placed in the lateral epidural space at the level of the L5 and S1 DRG, depending on the dermatomal area of pain.
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      • Russo M.
      • Huygen F.J.
      • et al.
      A multicenter, prospective trial to assess the safety and performance of the spinal modulation dorsal root ganglion neurostimulator system in the treatment of chronic pain.
      • Liem L.
      • Russo M.
      • Huygen F.J.
      • et al.
      One-year outcomes of spinal cord stimulation of the dorsal root ganglion in the treatment of chronic neuropathic pain.
      • van Velsen V.
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      • Chapman K.B.
      Creating a strain relief loop during S1 transforaminal lead placement for dorsal root ganglion stimulation for foot pain: a technical note.
      For the trial phase, the leads were connected by extension leads to an external pulse generator. The trial was defined to be successful if there was a reduction of ≥ 50% in pain intensity and if the patient was expressing a desire to be implanted with an implantable pulse generator (IPG). The average trial stimulation phase was eight (SD = 2) days. In the subjects with a successful trial, the extension leads were removed, and the leads were connected to an IPG. Post implantation device programming proceeded according to standard practice by employees of the device company in collaboration with the hospital staff. Device programming settings were adjusted for paresthesia to overlap the painful areas. After programming, the amplitude was reduced to remain subthreshold but therapeutic.

      Skin Biopsy

      The patients underwent a skin biopsy within 1 month before the start of the study and after 12 and 24 months. As previously described,
      • Lauria G.
      • Hsieh S.T.
      • Johansson O.
      • et al.
      European Federation of Neurological Societies/Peripheral Nerve Society Guideline on the use of skin biopsy in the diagnosis of small fiber neuropathy. Report of a joint task force of the European Federation of Neurological Societies and the Peripheral Nerve Society.
      • Melli G.
      • Vacchi E.
      • Biemmi V.
      • et al.
      Cervical skin denervation associates with alpha-synuclein aggregates in Parkinson disease.
      • Vacchi E.
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      • Melli G.
      Targeting alpha synuclein aggregates in cutaneous peripheral nerve fibers by free-floating immunofluorescence assay.
      a 3 mm punch skin biopsy was performed at the ankle site (10 cm proximal to the lateral malleolus) on the body side with more prominent clinical symptoms, if not symmetrical. To provide information about non-length-dependent neuropathy and the extension of axonal degeneration, 4 of 7 patients who were implanted underwent an additional 3 mm punch skin biopsy at the thigh (10 cm above the knee) at the same time points.
      • Lauria G.
      • Hsieh S.T.
      • Johansson O.
      • et al.
      European Federation of Neurological Societies/Peripheral Nerve Society Guideline on the use of skin biopsy in the diagnosis of small fiber neuropathy. Report of a joint task force of the European Federation of Neurological Societies and the Peripheral Nerve Society.
      Skin samples were fixed in periodate-lysine-paraformaldehyde 2% fixative and sent to the laboratory.

      Intraepidermal Nerve Fiber Density Quantification

      An immunofluorescence assay to visualize intraepidermal nerve fibers was performed as previously described.
      • Melli G.
      • Vacchi E.
      • Biemmi V.
      • et al.
      Cervical skin denervation associates with alpha-synuclein aggregates in Parkinson disease.
      ,
      • Vacchi E.
      • Pinton S.
      • Kaelin-Lang A.
      • Melli G.
      Targeting alpha synuclein aggregates in cutaneous peripheral nerve fibers by free-floating immunofluorescence assay.
      Briefly, at least three nonconsecutive 50 μm thin skin sections were incubated overnight with the primary antibody against the panaxonal marker protein gene product 9.5 (PGP 9.5, Abcam, Cambridge UK, 1:1000 rabbit, polyclonal). The day after, sections were incubated with fluorescently tagged secondary antibody (Goat Anti-Rabbit, Jackson ImmunoResearch, West Grove USA, 1.700) for 90 minutes at room temperature, and cell nuclei were counterstained with 4′,6-diamidino-2-phenylindole dihydrochloride (DAPI). Sections were analyzed under an inverted fluorescence microscope (Nikon Eclipse Ti-E, Tokyo, Japan) and the IENFD was quantified according to published standard protocols.
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      • Cornblath D.R.
      • Johansson O.
      • et al.
      EFNS guidelines on the use of skin biopsy in the diagnosis of peripheral neuropathy.
      ,
      • Provitera V.
      • Gibbons C.H.
      • 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.
      The number of PGP 9.5 positive nerve fibers crossing the dermal-epidermal junction was counted and divided for the length of the section. At least 3 sections were counted, and the average was expressed as “number of fibers/mm.” Skin biopsies were rated by a qualified and experienced operator blinded to experimental conditions. Pathological IENFD was defined based on published normative data for distal leg adjusted for age and sex.
      • Lauria G.
      • Hsieh S.T.
      • Johansson O.
      • et al.
      European Federation of Neurological Societies/Peripheral Nerve Society Guideline on the use of skin biopsy in the diagnosis of small fiber neuropathy. Report of a joint task force of the European Federation of Neurological Societies and the Peripheral Nerve Society.

      Nerve Conduction Studies

      Sensory and motor nerve conduction studies were performed in the lower limbs according to published standardized protocols.
      • Cornblath D.R.
      The electrophysiology of axonal and demyelinating polyneuropathies.
      In particular, peroneal, tibial, and sural nerves conduction velocities, amplitude, and distal latency were measured in all patients included in the study, before DRGS implantation and after 1-year follow-up.

      QST

      A specially trained research associate performed QST, to determine cold detection threshold (CDT) and warm detection threshold (WDT). The measurement was performed, with stimulation “on”, on the dorsal site of both feet in case of implantation at the L5 DRG and on dorsal and plantar site in case of implantation at the L5 and S1 DRGS. Measurements were performed with the Medoc Pathway (Medoc, Israel) device with a cutaneous thermode (square surface-active area 30 × 30 mm) in a quiet office while maintaining a constant, comfortable temperature. Cold detection was defined as the highest temperature at which patients can detect a cold stimulus. Warm detection was defined as the lowest temperature at which patients can detect a warm stimulus. For each threshold, four series of increasing intensities were given at random intervals. CDT and WDT were determined as the mean of the four measurements. The baseline was set at 32 °C, and the temperature was decreased at a constant rate of 1 °C/s until patients perceived the thermode as cold. The temperature was increased at a constant rate of 2 °C/s until patients perceived the thermode as warm. The lower cutoff value was 20 °C, and the upper cutoff value was 50 °C. We considered 1.2 °C in mean temperature to be an important difference.
      • Ahmed S.U.
      • Zhang Y.
      • Chen L.
      • et al.
      Effects of spinal cord stimulation on pain thresholds and sensory perceptions in chronic pain patients.
      ,
      • Chen L.
      • Malarick C.
      • Seefeld L.
      • Wang S.
      • Houghton M.
      • Mao J.
      Altered quantitative sensory testing outcome in subjects with opioid therapy.

      TNS

      The TNS is a clinical scale that encompasses symptoms, signs, nerve conductions, and QST and is a validated measure of peripheral nerve function.
      • Cornblath D.R.
      • Chaudhry V.
      • Carter K.
      • et al.
      Total neuropathy score: validation and reliability study.
      We used the first 7 items of the scale referring to symptoms and neurological signs to grade the gravity of the polyneuropathy.

      Statistical Analysis

      Baseline characteristics of patients were described using mean and SD, or as median and first and third quartile in case of normally and skewed continuous variables, respectively, and as count and percentage for categorical variables. Ankle IENFD values were summarized at baseline and 1- and 2-year follow-up as median and first and third quartile. TNS item scores and QST cold and hot detection thresholds were summarized at baseline and 6- and 12-month follow-ups. We used the Wilcoxon signed-rank test to test paired within-patient changes. Ankle IENFD values, TNS item, total scores, and QST cold and hot detection thresholds were compared between follow-up moments and baseline. Additionally, at 6- and 12-month follow-ups, we tested differences in QST cold and hot detection thresholds between DRGS on and off. Associations between the change in pain intensity over the first 12 months of follow-up, changes in IENFD values, and changes in the sum of TNS item scores were computed using the Spearman rank correlation. All these analyses were performed using data of patients still implanted with a device unless stated otherwise.
      All statistical analyses were performed using R version 3.6.1 (R Foundation for Statistical Computing, Vienna, Austria). p Values of ≤ 0.05 were considered to indicate statistical significance. We used available cases for all analyses.

      Results

      Demographics and Clinical Data

      Between September 2016 and January 2019, we evaluated 31 patients with intractable painful polyneuropathy at our institution; 9 met the criteria for inclusion and accepted the DRGS lead implantation. Patient characteristics and the efficacy of DRGS in these patients were previously published.
      • Koetsier E.
      • van Kuijk S.M.J.
      • Melli G.
      • et al.
      Dorsal root ganglion stimulation for the management of intractable painful polyneuropathy: a prospective pilot study.
      A total of 6 (66.7%) were male, the mean age was 63 years (SD 8.7), and the median duration of pain was seven years (range, one to 20 years) at the time of inclusion. All patients included in this study were diagnosed with SFN, which was classified as being length-dependent in all 8 patients in whom skin biopsy was performed. Seven were additionally diagnosed with large fiber axonal polyneuropathy. The etiology of polyneuropathy was various: painful diabetic polyneuropathy (PDPN) (3 patients), idiopathic (3 patients), chronic inflammatory demyelinating polyneuropathy (2 patients), chemotherapy-induced peripheral neuropathy (1 patient). The DRGS trial phase was successful in 8 of 9 patients, and 7 were implanted with an IPG (Fig. 1). At six months follow-up, 6 of these 7 patients showed stable treatment success (defined as a reduction of ≥ 50% in daytime and/or night-time pain intensity) and an improvement in the patient's global impression of change. Additionally, pain extent was reduced, and the impact of pain on functioning and mood was improved significantly.
      • Koetsier E.
      • Franken G.
      • Debets J.
      • et al.
      Effectiveness of dorsal root ganglion stimulation and dorsal column spinal cord stimulation in a model of experimental painful diabetic polyneuropathy.
      ,
      • Koetsier E.
      • van Kuijk S.M.J.
      • Melli G.
      • et al.
      Dorsal root ganglion stimulation for the management of intractable painful polyneuropathy: a prospective pilot study.
      The stimulation settings were previously published.
      • Koetsier E.
      • van Kuijk S.M.J.
      • Melli G.
      • et al.
      Dorsal root ganglion stimulation for the management of intractable painful polyneuropathy: a prospective pilot study.
      The frequency was mostly set at 20 Hz. All patients used the stimulation continuously, except 1 patient who turned the device off at night, having no pain at night.
      Figure thumbnail gr1
      Figure 1Flowchart of the study design. Schematic representation of the study design and patient’s population.

      IENFD Changes After DRGS Implantation

      Skin biopsies were collected in 8 of 9 participating patients. In 1 subject, a skin biopsy was not performed because of a high risk of skin infection because of uncontrolled DM and lymphedema. The median baseline IENFD among those (still) implanted was 1.6 fibers/mm (first and third quartile: 1.2; 4.3) and increased to 2.6 fibers/mm (2.5; 2.9) and 1.9 fibers/mm (1.6; 2.4) at 1- and 2-year follow-up, respectively. These changes were not statistically significant (p = 1.000 and 0.375). At 1-year follow-up, 4 (66.7%) patients with implants improved on their IENFD compared with baseline. Of those with a biopsy available at a 2-year follow-up (n = 4), 3 (75%) had a higher IENFD than their baseline value. Figure 2a shows an immunofluorescence staining with anti-PGP 9.5 and DAPI of the ankle skin in healthy control (left) and patients with SFN (right); on the bottom, magnification shows nerve fibers crossing the dermal-epidermal junction (pink dotted line). Figure 2b shows the change in ankle IENFD values per patient over a 2-year follow-up and the high degree of heterogeneity in baseline IENFD values. Of interest, the thigh IENFD decreased in all 4 patients at 1-year follow-up and at 2-year follow-up in the 2 patients who had the biopsy available at that time.
      Figure thumbnail gr2
      Figure 2Ankle intraepidermal nerve fiber density at baseline and at 1- and 2-year follow-up. a. Immunofluorescence staining with anti-PGP9.5 and DAPI of ankle skin in a healthy control patient (left) and SFN patients (right); on the bottom, magnification showing nerve fibers crossing the dermal epidermal junction (pink dotted line). Scale bar 50 μm. b. The graph shows for each patients the ankle IENFD at baseline and after 1- and 2-year follow-up.

      DRGS Implantation Did Not Influence TNS and QST Scores

      Table 1 lists the median and first and third quartiles of baseline and 6- and 12-month TNS items. No significant changes, compared with baseline, were detected at follow-up moments. Figure 3 shows individual trajectories of the sum of TNS item scores over time. Differences between the sum of TNS item scores at baseline and six months and between baseline and 12 months were not statistically significant (p = 0.202 and p = 0.292, respectively).
      Table 1Summary of Total Neuropathy Score Items at Baseline and at 6- and 12-Month Follow-Up.
      TNS itemBaseline6 mop Value
      p Values for difference between baseline and 6-month follow-up.
      12 mop Value
      p Values for difference between baseline and 12-month follow-up.
      Sensory symptoms2.0 (1.8; 2.3)1.5 (1.0; 3.0)0.8902.5 (1.0; 3.0)0.572
      Motor symptoms0.0 (0.0; 0.3)0.0 (0.0; 0.0)1.0000.0 (0.0; 0.3)0.851
      Autonomic symptoms0.0 (0.0; 0.0)0.0 (0.0; 1.0)0.1490.0 (0.0; 1.0)0.346
      Pin sensibility2.5 (1.0; 3.0)2.0 (1.0; 3.0)0.8512.0 (1.0; 2.0)0.586
      Vibration sensibility2.0 (1.0; 3.0)1.5 (1.0; 3.0)0.8542.0 (1.0; 3.0)0.932
      Strength1.0 (0.8; 1.0)0.0 (0.0; 1.0)0.1740.0 (0.0; 0.3)0.089
      Tendon reflexes2.0 (1.8; 3.3)2.0 (2.0; 3.0)0.1002.0 (2.0; 2.5)1.000
      Sural media amplitude (μV)
      Too few observations for estimation at 6-month follow-up.
      3.5 (0.4; 5.5)3.5 (1.0; 4.5)0.371
      Motor peroneal ankle media amplitude
      Too few observations for estimation at 6-month follow-up.
      2.1 (2.0; 2.9)2.7 (1.1; 4.4)0.877
      Data are presented as median (first and third quartile).
      p Values for difference between baseline and 6-month follow-up.
      p Values for difference between baseline and 12-month follow-up.
      ˆ Too few observations for estimation at 6-month follow-up.
      Figure thumbnail gr3
      Figure 3TNS at baseline and at 6- and 12-months follow-up. The graph shows the individual trajectories of the sum of TNS item scores over time at baseline and after 6- and 12-month follow-up.
      Cold and warm detection thresholds assessed with QST did not substantially change over 12 months of follow-up (Table 2). None of the differences between six and 12 months, on the one hand, and baseline values, on the other hand, were statistically significant. Furthermore, we did not observe significant differences at six and 12 months between the device being on or off, both for hot and cold thresholds and left and right sides (p values ranged from 0.375 to 1.000).
      Table 2Summary of QST Values at Baseline and at 6- and 12-month Follow-Ups.
      MeasureLocationBaseline6 months, DRGS on6 months, DRGS offP-value
      p Values for difference between baseline and 6-month follow-up, DRGS on.
      12 months, DRGS on12 months, DRGS offP-value
      p Values for difference between baseline and 12-month follow-up, DRGS on.
      CDT (°C)L5, left20.0 (20.0; 22.4)20.0 (20.0; 26.6)20.0 (20.0; 20.9)0.31020.0 (20.0; 21.4)20.0 (20.0; 24.1)1.000
      L5, right20.0 (20.0; 20.0)21.4 (20.0; 26.8)24.3 (20.0; 27.5)0.07822.0 (20.1; 22.2)20.8 (20.0; 26.4)0.125
      WDT, mean (°C)L5, left46.0 (44.6; 47.5)43.1 (42.0 (46.6)45.0 (44.1; 45.1)0.52943.7 (43.3; 46.8)46.4 (44.6; 49.2)1.000
      L5, right43.4 (43.2; 46.9)44.0 (43.3; 45.2)46.6 (41.9; 46.7)0.52942.0 (42.8; 44.6)44.9 (43.4; 49.7)0.584
      Data are presented as median (first and third quartile).
      p Values for difference between baseline and 6-month follow-up, DRGS on.
      p Values for difference between baseline and 12-month follow-up, DRGS on.

      IENFD and Clinical Scores

      The median change in pain intensity between 12 months and baseline was −3.9 points on the NRS (first and third quartile: −5.8; −1.1). We found a strong but insignificant, positive correlation between the change in pain intensity and the change in IENFD values (Spearman’s rho: 0.70, p = 0.233). A weaker positive correlation was found with a change in the sum of TNS item scores (rho: 0.37, p = 0.497). There was a weak correlation between the change in IENFD values and the change in the sum of TNS item scores (rho: 0.25, p = 0.658).

      Discussion

      This is the first study that assessed the impact of DRGS treatment on the pathologic progression of clinically confirmed SFN, comparing IENFD by skin biopsy at baseline and after 1 (N = 6) and 2 years (N = 4) of DRGS treatment. The results of this study showed that in most patients with implants, there was a slight increase of the IENFD at 1-year and 2-year follow-ups. However, this increase was not statistically significant. The natural process of SFN is progressive axon loss, resulting in the loss of the IENFD over time.
      • Khoshnoodi M.A.
      • Truelove S.
      • Burakgazi A.
      • Hoke A.
      • Mammen A.L.
      • Polydefkis M.
      Longitudinal assessment of small fiber neuropathy: evidence of a non-length-dependent distal axonopathy.
      ,
      • Lauria G.
      • Morbin M.
      • Lombardi R.
      • et al.
      Axonal swellings predict the degeneration of epidermal nerve fibers in painful neuropathies.
      For instance, in a study of patients suffering from SFN with low-normal IENFD associated with axonal swellings (n = 15), IENFD decreased significantly during 19 months.
      • Lauria G.
      • Morbin M.
      • Lombardi R.
      • et al.
      Axonal swellings predict the degeneration of epidermal nerve fibers in painful neuropathies.
      Moreover, Khoshnoodi et al
      • Khoshnoodi M.A.
      • Truelove S.
      • Burakgazi A.
      • Hoke A.
      • Mammen A.L.
      • Polydefkis M.
      Longitudinal assessment of small fiber neuropathy: evidence of a non-length-dependent distal axonopathy.
      compared the rate of IENFD loss over time in 52 patients with idiopathic SFN (iSFN, N = 25), impaired glucose tolerance-associated SFN (IGT-SFN, n = 13), and DM-associated SFN (DM-SFN, n = 14), to ten healthy controls. Despite a relatively stable clinical course, there was a significant IENFD decrease at follow-up in all three neuropathy groups, whereas there was no change in the control group. IENFD decreased over time in all patients at a similar rate, and the mean yearly rates of IENFD change over time at the distal leg, distal thigh, and proximal thigh were −1.42, −1.59, and −2.8 IENF/mm, respectively.
      • Khoshnoodi M.A.
      • Truelove S.
      • Burakgazi A.
      • Hoke A.
      • Mammen A.L.
      • Polydefkis M.
      Longitudinal assessment of small fiber neuropathy: evidence of a non-length-dependent distal axonopathy.
      In our study, the IENFD at the thigh decreased in all patients at both time points, following the literature data. This is of particular interest because the anatomical region of the thigh, where the biopsy was performed, corresponds to the dermatomeric region innervated by L3 dorsal root ganglia, at which level no DRGS leads were implanted.
      Although the natural process of SFN is a progressive axon loss, the clinical course of SFN is known to be relatively stable.
      • Devigili G.
      • Tugnoli V.
      • Penza P.
      • et al.
      The diagnostic criteria for small fibre neuropathy: from symptoms to neuropathology.
      ,
      • Khoshnoodi M.A.
      • Truelove S.
      • Burakgazi A.
      • Hoke A.
      • Mammen A.L.
      • Polydefkis M.
      Longitudinal assessment of small fiber neuropathy: evidence of a non-length-dependent distal axonopathy.
      ,
      • MacDonald S.
      • Sharma T.L.
      • Li J.
      • Polston D.
      • Li Y.
      Longitudinal follow-up of biopsy-proven small fiber neuropathy.
      ,
      • Flossdorf P.
      • Haupt W.F.
      • Brunn A.
      • et al.
      Long-time course of idiopathic small fiber neuropathy.
      Flossdorf et al
      • Flossdorf P.
      • Haupt W.F.
      • Brunn A.
      • et al.
      Long-time course of idiopathic small fiber neuropathy.
      studied patients with iSFN (n = 16) for an average follow-up period of 5.3 years, and the clinical and electrophysiological course remained stable in 75% of patients. Furthermore, MacDonald et al
      • MacDonald S.
      • Sharma T.L.
      • Li J.
      • Polston D.
      • Li Y.
      Longitudinal follow-up of biopsy-proven small fiber neuropathy.
      described the clinical course of patients with SFN (n = 110) with an average follow-up period exceeding six years and confirmed the overall stable clinical course of SFN with their study. The correlation between IENFD and symptoms is believed to be nonlinear.
      • Khoshnoodi M.A.
      • Truelove S.
      • Burakgazi A.
      • Hoke A.
      • Mammen A.L.
      • Polydefkis M.
      Longitudinal assessment of small fiber neuropathy: evidence of a non-length-dependent distal axonopathy.
      Nevertheless, our results show a strong, but not significant, positive correlation between change in pain intensity and change in IENFD values. A weaker correlation was found between the change in pain intensity and the change in the sum of TNS item scores.
      Electrical stimulation can increase the speed and success rate of nerve repair by directly promoting axon growth and can increase the activity of Schwann cells and the secretion of neurotrophic factors, as recently demonstrated in a DRG and Schwann cell co-culture in vitro model.
      • Liang Z.
      • Lei T.
      • Wang S.
      • Luo Z.
      • Hu X.
      A simple electrical stimulation cell culture system on the myelination of dorsal root ganglia and Schwann cells.
      Furthermore, animal and human studies have demonstrated that peripheral electrical stimulation of the proximal stump of an injured peripheral nerve enhances nerve regeneration, even if the mechanisms remain relatively poorly understood.
      • Gordon T.
      • English A.W.
      Strategies to promote peripheral nerve regeneration: electrical stimulation and/or exercise.
      ,
      • Gordon T.
      Electrical stimulation to enhance axon regeneration after peripheral nerve injuries in animal models and humans.
      There is also increasing evidence that noninvasive electrical stimulation promotes neuroregeneration and neural repair after spinal cord injury.
      • Zheng Y.
      • Mao Y.R.
      • Yuan T.F.
      • Xu D.S.
      • Cheng L.M.
      Multimodal treatment for spinal cord injury: a sword of neuroregeneration upon neuromodulation.
      However, the daily requirement of long-duration peripheral electrical pulses is a practical issue for many patients.
      The precise spinal mechanisms of action of SCS are still unknown but originally emerged as an application of the Gate Control Theory of Pain of Melzack and Wall.
      • Linderoth B.
      • Foreman R.D.
      Conventional and novel spinal stimulation algorithms: hypothetical mechanisms of action and comments on outcomes.
      ,
      • Melzack R.
      • Wall P.D.
      Pain mechanisms: a new theory.
      This theory states that electrical stimulation of the large myelinated non-nociceptive Aβ fibers in the dorsal column of the spinal cord activates the inhibitory interneurons to release gamma-aminobutyric acid in the dorsal horn of the spinal cord. This leads to an inhibition (“closing of the gate”) of the spinal nociceptive signal from smaller diameter nociceptive Aδ fibers and C fibers to the brain.
      • Linderoth B.
      • Foreman R.D.
      Conventional and novel spinal stimulation algorithms: hypothetical mechanisms of action and comments on outcomes.
      ,
      • Melzack R.
      • Wall P.D.
      Pain mechanisms: a new theory.
      SCS is, additionally, known to induce orthodromic activation of a supraspinal network inhibiting the incoming nociceptive signal at spinal levels by descending tracts,
      • Linderoth B.
      • Foreman R.D.
      Conventional and novel spinal stimulation algorithms: hypothetical mechanisms of action and comments on outcomes.
      and decreasing connectivity between sensory and limbic areas,
      • Deogaonkar M.
      • Sharma M.
      • Oluigbo C.
      • et al.
      Spinal cord stimulation (SCS) and functional magnetic resonance imaging (fMRI): modulation of cortical connectivity with therapeutic SCS.
      resulting in a reduction of the affective component of pain. Moreover, there is evidence that SCS causes peripheral vasodilatation relieving ischemic pain and improving peripheral blood flow.
      • Ubbink D.T.
      • Vermeulen H.
      Spinal cord stimulation for non-reconstructable chronic critical leg ischaemia.
      • Ubbink D.T.
      • Vermeulen H.
      Spinal cord stimulation for critical leg ischemia: a review of effectiveness and optimal patient selection.
      • Deer T.R.
      • Mekhail N.
      • Provenzano D.
      • et al.
      The appropriate use of neurostimulation of the spinal cord and peripheral nervous system for the treatment of chronic pain and ischemic diseases: the Neuromodulation Appropriateness Consensus Committee.
      • van Beek M.
      • Hermes D.
      • Honig W.M.
      • et al.
      Long-term spinal cord stimulation alleviates mechanical hypersensitivity and increases peripheral cutaneous blood perfusion in experimental painful diabetic polyneuropathy.
      Considering the vascular mechanisms involved in PDPN pathology, it is expected that improved blood perfusion of tissue leads to better functioning of nervous tissue in patients with PDPN.
      • van Beek M.
      • Hermes D.
      • Honig W.M.
      • et al.
      Long-term spinal cord stimulation alleviates mechanical hypersensitivity and increases peripheral cutaneous blood perfusion in experimental painful diabetic polyneuropathy.
      ,
      Spinal cord stimulation in clinical and experimental painful diabetic polyneuropathy. van Beek M.
      A decreased sympathetic outflow during SCS is believed to cause this vasodilatation.
      • Wu M.
      • Linderoth B.
      • Foreman R.D.
      Putative mechanisms behind effects of spinal cord stimulation on vascular diseases: a review of experimental studies.
      • Linderoth B.
      • Herregodts P.
      • Meyerson B.A.
      Sympathetic mediation of peripheral vasodilation induced by spinal cord stimulation: animal studies of the role of cholinergic and adrenergic receptor subtypes.
      • Tanaka S.
      • Komori N.
      • Barron K.W.
      • Chandler M.J.
      • Linderoth B.
      • Foreman R.D.
      Mechanisms of sustained cutaneous vasodilation induced by spinal cord stimulation.
      Furthermore, peripheral vasodilatation during SCS is mediated by the antidromic release of calcitonin gene-related peptide (CGRP) through activation of predominantly small unmyelinated C fibers but also of CGRP positive Aδ fibers.
      • Tanaka S.
      • Barron K.W.
      • Chandler M.J.
      • Linderoth B.
      • Foreman R.D.
      Low intensity spinal cord stimulation may induce cutaneous vasodilation via CGRP release.
      ,
      • Wu M.
      • Komori N.
      • Qin C.
      • Farber J.P.
      • Linderoth B.
      • Foreman R.D.
      Roles of peripheral terminals of transient receptor potential vanilloid-1 containing sensory fibers in spinal cord stimulation-induced peripheral vasodilation.
      The release of CGRP from the free nerve endings and the decrease in noradrenaline release from sympathetic fibers results in peripheral vasodilation. It is likely that the vasodilating effect of SCS also occurs with the application of DRGS. Moreover, animal studies have shown sympathetic fibers to sprout into the DRG after peripheral nerve injury, thereby forming abnormal connections with sensory neurons.
      • Lee B.H.
      • Yoon Y.W.
      • Chung K.
      • Chung J.M.
      Comparison of sympathetic sprouting in sensory ganglia in three animal models of neuropathic pain.
      • Xie W.
      • Strong J.A.
      • Zhang J.M.
      Increased excitability and spontaneous activity of rat sensory neurons following in vitro stimulation of sympathetic fiber sprouts in the isolated dorsal root ganglion.
      • Ramer M.S.
      • Bisby M.A.
      Rapid sprouting of sympathetic axons in dorsal root ganglia of rats with a chronic constriction injury.
      Because it is reasonable to assume that this sympathetic fiber sprouting into the DRG also occurs in patients with SFN, the DRG might be an even better target for neurostimulation than the dorsal column in patients with SFN.
      This study has several limitations. First, it was conducted with a relatively small number of patients with heterogeneity of etiologies of polyneuropathy. The fact that the TNS scores and cold and warm detection thresholds did not improve significantly over time may be caused by a lack of statistical power for these outcomes in our study. Second, although quantification of IENFD in skin biopsies is a reliable objective measure, QST, and partially also TNS, depend on the active subjective cooperation and attention of the patient and is thus open to bias.
      • Terkelsen A.J.
      • Karlsson P.
      • Lauria G.
      • Freeman R.
      • Finnerup N.B.
      • Jensen T.S.
      The diagnostic challenge of small fibre neuropathy: clinical presentations, evaluations, and causes.
      ,
      • Provitera V.
      • Gibbons C.H.
      • 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.
      ,
      • Shy M.E.
      • Frohman E.M.
      • So Y.T.
      • et al.
      Quantitative sensory testing: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology.
      ,
      • Baron R.
      • Maier C.
      • Attal N.
      • et al.
      Peripheral neuropathic pain: a mechanism-related organizing principle based on sensory profiles.
      Moreover, a limitation of the study is related to the fact that patients with severe polyneuropathy were included, and a rapid progression because of the underlying pathology is possible. Future experiments controlling for the stability of polyneuropathy may improve overall outcomes, including nerve fiber regeneration.
      To conclude, the results of this study showed a non-significant trend toward nerve regeneration in SFN with DRGS treatment. Larger-scale clinical trials are needed to prove nerve regeneration in SFN with implantable systems like SCS and DRGS.

      Authorship Statements

      Eva Koetsier, Giorgia Melli, Paolo Maino, and Sander M.J. van Kuijk designed the study. Eva Koetsier, Elena Vacchi, Paolo Maino, Jasmina Dukanac, Giorgia Melli, and Sander M.J. van Kuijk conducted the study, including patient recruitment and data collection. Sander M.J. van Kuijk conducted the data analysis. Eva Koetsier prepared the manuscript draft with important intellectual input from Elena Vacchi, Paolo Maino, Jasmina Dukanac, Giorgia Melli, and Sander M.J. van Kuijk. Eva Koetsier and Jasmina Dukanac had complete access to the study data. All authors approved the final manuscript.

      Acknowledgements

      We would like to acknowledge Professor Roberto S.G.M. Perez who had an important role in the initiation of this study and helped substantially with the conception and design of the study. To our greatest regret, he passed away on September 7, 2017.

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