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Primary Raynaud phenomenon and small-fiber neuropathy: is there a connection? A pilot neurophysiologic study

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Abstract

The pathophysiologic factors of primary Raynaud phenomenon (RP) are unknown. Preliminary evidence from skin biopsy suggests small-fiber neuropathy (SFN) in primary RP. We aimed to quantitatively assess SFN in participants with primary RP. Consecutive patients with an a priori diagnosis of primary RP presenting to our outpatient rheumatology clinic over a 6-month period were invited to participate. Cases of secondary RP were excluded. All participants were required to have normal results on nailfold capillary microscopy. Assessment for SFN was accomplished with autonomic reflex screening, which includes quantitative sudomotor axonal reflex test (QSART), and cardiovagal and adrenergic function testing, thermoregulatory sweat test (TST), and quantitative sensory test (QST) for vibratory, cooling, and heat-pain sensory thresholds. Nine female participants with a median age of 38 years (range 21–46 years) and a median symptom duration of 9 years (range 5 months–31 years) were assessed. Three participants had abnormal results on QSART, indicating peripheral sudomotor autonomic dysfunction. Two participants had evidence of large-fiber involvement with heat-pain thresholds on QST. Heart rate and blood pressure responses to deep breathing, Valsalva maneuver, and 70° tilt were normal for all participants. Also, all participants had normal TST results. In total, three of the nine participants had evidence of SFN. The presence of SFN raises the possibility that a subset of patients with primary RP have an underlying, subclinical small-fiber dysfunction. These data open new avenues of research and therapeutics for this common condition.

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Abbreviations

QSART:

Quantitative sudomotor axonal reflex test

QST:

Quantitative sensory test

RP:

Raynaud phenomenon

SFN:

Small-fiber neuropathy

TST:

Thermoregulatory sweat test

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Conflict of interest statement

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Author information

Authors and Affiliations

  1. Division of Rheumatology, Mayo Clinic, 200 First St SW, Rochester, MN, 55905, USA

    Nisha J. Manek & Thomas G. Osborn

  2. Rheumatology CentraCare Clinic, 1200 Sixth Ave North, St. Cloud, MN, 56303, USA

    Aaron R. Holmgren

  3. Department of Neurology, Mayo Clinic, Rochester, MN, USA

    Paola Sandroni

  4. Department of Dermatology, Mayo Clinic, Rochester, MN, USA

    Mark D. P. Davis

Authors
  1. Nisha J. Manek
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  2. Aaron R. Holmgren
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  3. Paola Sandroni
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  4. Thomas G. Osborn
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  5. Mark D. P. Davis
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Corresponding author

Correspondence to Nisha J. Manek.

Appendix: Protocol of history and clinical investigation for study participants presenting with primary Raynaud phenomenon

Appendix: Protocol of history and clinical investigation for study participants presenting with primary Raynaud phenomenon

  • Criteria for the diagnosis of primary Raynaud phenomenon included the following:

    • Symmetrical, repetitive episodic attacks with definite biphasic skin color changes (at least 2 of pallor, cyanosis, or erythema) in either cold or normal temperature environment occurring for >3 months

    • No evidence of peripheral vascular disease, with strong symmetrical peripheral pulses

    • No tissue injury, skin ulcers, or gangrene

    • Normal nailfold capillaroscopy

    • Normal antinuclear antibody test result and a normal erythrocyte sedimentation rate

    • Not a current or past smoker

  • History focusing on secondary causes of Raynaud phenomenon included the following:

    • Connective tissue diseases (systemic lupus erythematosus, scleroderma, mixed connective tissue disease, overlap syndromes, polymyositis, dermatomyositis, rheumatoid arthritis, Sjögren syndrome, undifferentiated connective tissue disease, and vasculitis

    • Occlusive vascular disease (arteriosclerosis, atheroemboli, and thromboangiitis obliterans)

    • Drug-induced Raynaud phenomenon (use of amphetamines, β-blockers, ergotamines, interferon-α, or cocaine: chemotherapy, such as vinblastine sulfate

    • Hematologic disorders and cold agglutinins (cold agglutinin disease, cryofibrinogenemia, cryoglobulinemia, paraproteinemia, and polycythemia)

    • Occupational vibration-induced (with use of drills and electric hammers) causes

    • Vascular trauma

    • Frostbite

  • History focusing on causes of small-fiber neuropathy included the following:

    • No history of diabetes mellitus or impaired glucose handling

    • Alcohol intake

    • Familial neuropathy

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Manek, N.J., Holmgren, A.R., Sandroni, P. et al. Primary Raynaud phenomenon and small-fiber neuropathy: is there a connection? A pilot neurophysiologic study. Rheumatol Int 31, 577–585 (2011). https://doi.org/10.1007/s00296-009-1293-9

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  • DOI: https://doi.org/10.1007/s00296-009-1293-9

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