Evidence of small-fiber neuropathy in neurofibromatosis type 1
Corresponding Author
Carolina Barnett MD, PhD
Elisabeth Raab Neurofibromatosis Clinic, Toronto General Hospital, University Health Network, Toronto, Ontario, Canada
Division of Neurology, Department of Medicine, University of Toronto and University Health Network, Toronto, Ontario, Canada
Correspondence
Carolina Barnett, Division of Neurology, Department of Medicine, University of Toronto and University Health Network, 200 Elizabeth Street, 5EC Room 334, Toronto, ON M5G 2C4, Canada.
Email: [email protected]
Search for more papers by this authorTayir Alon MD
Elisabeth Raab Neurofibromatosis Clinic, Toronto General Hospital, University Health Network, Toronto, Ontario, Canada
Division of Neurology, Department of Medicine, University of Toronto and University Health Network, Toronto, Ontario, Canada
Search for more papers by this authorAlon Abraham MD
Neuromuscular Diseases Unit, Department of Neurology, Tel Aviv Sourasky Medical Center, The Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
Search for more papers by this authorRaymond H. Kim MD, PhD
Elisabeth Raab Neurofibromatosis Clinic, Toronto General Hospital, University Health Network, Toronto, Ontario, Canada
Division of Medical Oncology and Hematology, Department of Medicine, University of Toronto and University Health Network, Toronto, Ontario, Canada
Search for more papers by this authorJeanna M. McCuaig MSc
Elisabeth Raab Neurofibromatosis Clinic, Toronto General Hospital, University Health Network, Toronto, Ontario, Canada
Division of Medical Oncology and Hematology, Department of Medicine, University of Toronto and University Health Network, Toronto, Ontario, Canada
Search for more papers by this authorPaul Kongkham MD, PhD
Elisabeth Raab Neurofibromatosis Clinic, Toronto General Hospital, University Health Network, Toronto, Ontario, Canada
Division of Neurosurgery, Department of Surgery, University of Toronto and University Health Network, Toronto, Ontario, Canada
Search for more papers by this authorCatherine Maurice MD
Elisabeth Raab Neurofibromatosis Clinic, Toronto General Hospital, University Health Network, Toronto, Ontario, Canada
Division of Neurology, Department of Medicine, University of Toronto and University Health Network, Toronto, Ontario, Canada
Search for more papers by this authorSuganth Suppiah MD
Elisabeth Raab Neurofibromatosis Clinic, Toronto General Hospital, University Health Network, Toronto, Ontario, Canada
Division of Neurosurgery, Department of Surgery, University of Toronto and University Health Network, Toronto, Ontario, Canada
Search for more papers by this authorGelareh Zadeh MD, PhD
Elisabeth Raab Neurofibromatosis Clinic, Toronto General Hospital, University Health Network, Toronto, Ontario, Canada
Division of Neurosurgery, Department of Surgery, University of Toronto and University Health Network, Toronto, Ontario, Canada
Search for more papers by this authorVera Bril MD, FRCP
Elisabeth Raab Neurofibromatosis Clinic, Toronto General Hospital, University Health Network, Toronto, Ontario, Canada
Division of Neurology, Department of Medicine, University of Toronto and University Health Network, Toronto, Ontario, Canada
Search for more papers by this authorCorresponding Author
Carolina Barnett MD, PhD
Elisabeth Raab Neurofibromatosis Clinic, Toronto General Hospital, University Health Network, Toronto, Ontario, Canada
Division of Neurology, Department of Medicine, University of Toronto and University Health Network, Toronto, Ontario, Canada
Correspondence
Carolina Barnett, Division of Neurology, Department of Medicine, University of Toronto and University Health Network, 200 Elizabeth Street, 5EC Room 334, Toronto, ON M5G 2C4, Canada.
Email: [email protected]
Search for more papers by this authorTayir Alon MD
Elisabeth Raab Neurofibromatosis Clinic, Toronto General Hospital, University Health Network, Toronto, Ontario, Canada
Division of Neurology, Department of Medicine, University of Toronto and University Health Network, Toronto, Ontario, Canada
Search for more papers by this authorAlon Abraham MD
Neuromuscular Diseases Unit, Department of Neurology, Tel Aviv Sourasky Medical Center, The Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
Search for more papers by this authorRaymond H. Kim MD, PhD
Elisabeth Raab Neurofibromatosis Clinic, Toronto General Hospital, University Health Network, Toronto, Ontario, Canada
Division of Medical Oncology and Hematology, Department of Medicine, University of Toronto and University Health Network, Toronto, Ontario, Canada
Search for more papers by this authorJeanna M. McCuaig MSc
Elisabeth Raab Neurofibromatosis Clinic, Toronto General Hospital, University Health Network, Toronto, Ontario, Canada
Division of Medical Oncology and Hematology, Department of Medicine, University of Toronto and University Health Network, Toronto, Ontario, Canada
Search for more papers by this authorPaul Kongkham MD, PhD
Elisabeth Raab Neurofibromatosis Clinic, Toronto General Hospital, University Health Network, Toronto, Ontario, Canada
Division of Neurosurgery, Department of Surgery, University of Toronto and University Health Network, Toronto, Ontario, Canada
Search for more papers by this authorCatherine Maurice MD
Elisabeth Raab Neurofibromatosis Clinic, Toronto General Hospital, University Health Network, Toronto, Ontario, Canada
Division of Neurology, Department of Medicine, University of Toronto and University Health Network, Toronto, Ontario, Canada
Search for more papers by this authorSuganth Suppiah MD
Elisabeth Raab Neurofibromatosis Clinic, Toronto General Hospital, University Health Network, Toronto, Ontario, Canada
Division of Neurosurgery, Department of Surgery, University of Toronto and University Health Network, Toronto, Ontario, Canada
Search for more papers by this authorGelareh Zadeh MD, PhD
Elisabeth Raab Neurofibromatosis Clinic, Toronto General Hospital, University Health Network, Toronto, Ontario, Canada
Division of Neurosurgery, Department of Surgery, University of Toronto and University Health Network, Toronto, Ontario, Canada
Search for more papers by this authorVera Bril MD, FRCP
Elisabeth Raab Neurofibromatosis Clinic, Toronto General Hospital, University Health Network, Toronto, Ontario, Canada
Division of Neurology, Department of Medicine, University of Toronto and University Health Network, Toronto, Ontario, Canada
Search for more papers by this authorAbstract
Introduction
Large-fiber neuropathy is rare in neurofibromatosis type 1, but small-fiber neuropathy has not been studied.
Methods
Patients with neurofibromatosis type 1 underwent nerve conduction studies for large-fiber assessment. Small-fiber tests included quantitative thermal thresholds, laser Doppler flare imaging, intraepidermal nerve fiber density, and corneal nerve fiber length.
Results
Of the 52 patients enrolled, 31 (60%) were female and the mean age was 33.0 ± 12.3 years. Four (8%) patients had abnormal nerve conduction studies. Small-fiber tests were frequently abnormal: thermal thresholds in 7 (13%); laser Doppler flare imaging in 10 (19%); intraepidermal nerve fiber density in 11 (22%); and corneal nerve fiber length in 27 (52%). The mean corneal nerve fiber length was below normative level (10.1 ± 2.7 mm/mm3).
Discussion
Small-fiber neuropathy may be common in neurofibromatosis type 1, and should be investigated in symptomatic patients.
CONFLICT OF INTEREST
C.B. has served as consultant for UCB Alexion, Takeda, and Akcea, and has received research support form Octapharma and Grifols (not associated with this study). J.M. has served as a consultant to AstraZeneca for hereditary breast and ovarian cancer research (not associated with this study). V.B. has served as a consultant for UCB, Grifols, CSL, Octapharma, Argenx, Pfizer, Shire, Alnylam, and Alexion. She has received research support from Biogen, UCB, Grifols, CSL, Octapharma, and Argenx (not associated with this study).
Supporting Information
| Filename | Description |
|---|---|
| mus26687-sup-0001-FigureS1.docxWord 2007 document , 2 MB | FIGURE S1 Confocal corneal microscopy. (A) Image from a patient with normal corneal nerve fiber length. (B) Image from the same patient, but includes the automated tracing of the nerves for fiber length calculations. (C) Image from a patient with reduced corneal nerve fiber length. (D) Image from the same patient, but includes the automated tracing of the nerves for fiber length calculations. |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
REFERENCES
- 1Evans DG, Howard E, Giblin C, et al. Birth incidence and prevalence of tumor-prone syndromes: estimates from a UK family genetic register service. Am J Med Genet A. 2010; 152A: 327-332.
- 2Wolters PL, Burns KM, Martin S, et al. Pain interference in youth with neurofibromatosis type 1 and plexiform neurofibromas and relation to disease severity, social-emotional functioning, and quality of life. Am J Med Genet A. 2015; 167A: 2103-2113.
- 3Drouet A. Neurofibromatosis 1–associated neuropathies: a reappraisal. Brain. 2004; 127: 1993-2009.
- 4Ferner RE. Neurofibromatous neuropathy in neurofibromatosis 1 (NF1). J Med Genet. 2004; 41: 837-841.
- 5Sperfeld AD, Hein C, Schröder JM, Ludolph AC, Hanemann CO. Occurrence and characterization of peripheral nerve involvement in neurofibromatosis type 2. Brain. 2002; 125: 996-1004.
- 6Yerdelen D, Koc F, Durdu M, Karakas M. Electrophysiological findings in neurofibromatosis type 1. J Neurol Sci. 2011; 306: 42-48.
- 7Devigili G, Tugnoli V, Penza P, et al. The diagnostic criteria for small fiber neuropathy: from symptoms to neuropathology. Brain. 2008; 131: 1912-1925.
- 8Lauria G, Cornblath DR, Johansson O, et al. EFNS guidelines on the use of skin biopsy in the diagnosis of peripheral neuropathy. Eur J Neurol. 2005; 12: 747-758.
- 9Ahmed A, Bril V, Orszag A, et al. Detection of diabetic sensorimotor polyneuropathy by corneal confocal microscopy in type 1 diabetes: a concurrent validity study. Diabetes Care. 2012; 35: 821-828.
- 10Lovblom LE, Halpern EM, Wu T, et al. In vivo corneal confocal microscopy and prediction of future-incident neuropathy in type 1 diabetes: a preliminary longitudinal analysis. Can J Diabetes. 2015; 39: 390-397.
- 11Stumpf D. Consensus development conference of neurofibromatosis. Arch Neurol. 1988; 45: 575-578.
- 12 American Association of Neuromuscular and Electrodiagnostic Medicine. Guidelines in electrodiagnostic medicine. Recommended policy for electrodiagnostic medicine. Muscle Nerve. 1999; 8(suppl): S91-S105.
- 13Bolton CF, Benstead TJ, Grand'Maison F, Tardif GS, Weston LE. Minimum standards for electromyography in Canada: a statement of the Canadian Society of Clinical Neurophysiologists. Can J Neurol Sci. 2000; 27: 288-291.
- 14Kramer HH, Rolke R, Bickel A, Birklein F. Thermal thresholds predict painfulness of diabetic neuropathies. Diabetes Care. 2004; 27: 2386-2391.
- 15Abraham A, Alabdali M, Alsulaiman A, et al. Laser Doppler flare imaging and quantitative thermal thresholds testing performance in small and mixed fiber neuropathies. PLoS One. 2016; 11:e0165731.
- 16Loseth S, Lindal S, Stalberg E, Mellgren SI. Intraepidermal nerve fiber density, quantitative sensory testing and nerve conduction studies in a patient material with symptoms and signs of sensory polyneuropathy. Eur J Neurol. 2006; 13: 105-111.
- 17Lysy Z, Lovblom LE, Halpern EM, et al. Measurement of cooling detection thresholds for identification of diabetic sensorimotor polyneuropathy in type 1 diabetes. PLoS One. 2014; 9:e106995.
- 18Green AQ, Krishnan ST, Rayman G. C-fiber function assessed by the laser Doppler imager flare technique and acetylcholine iontophoresis. Muscle Nerve. 2009; 40: 985-991.
- 19Krishnan STM, Rayman G. The LDIflare: a novel test of C-fiber function demonstrates early neuropathy in type 2 diabetes. Diabetes Care. 2004; 27: 2930-2935.
- 20Nabavi Nouri M, Ahmed A, Bril V, et al. Diabetic neuropathy and axon reflex-mediated neurogenic vasodilatation in type 1 diabetes. PLoS One. 2012; 7:e34807.
- 21Lauria G, Bakkers M, Schmitz C, et al. Intraepidermal nerve fiber density at the distal leg: a worldwide normative reference study. J Peripher Nerv Syst. 2010; 15: 202-207.
- 22Hertz P, Bril V, Orszag A, et al. Reproducibility of in vivo corneal confocal microscopy as a novel screening test for early diabetic sensorimotor polyneuropathy. Diabet Med. 2011; 28: 1253-1260.
- 23Ostrovski I, Lovblom LE, Farooqi MA, et al. Reproducibility of in vivo corneal confocal microscopy using an automated analysis program for detection of diabetic sensorimotor polyneuropathy. PLoS One. 2015; 10:e0142309.
- 24Scarr D, Lovblom LE, Ostrovski I, et al. Agreement between automated and manual quantification of corneal nerve fiber length: implications for diabetic neuropathy research. J Diabet Complic. 2017; 31: 1066-1073.
- 25Scarr D, Lovblom LE, Lovshin JA, et al. Lower corneal nerve fiber length identifies diabetic neuropathy in older adults with diabetes: results from the Canadian Study of Longevity in Type 1 Diabetes. Diabetologia. 2017; 70: 2529-2531.
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