C-Fiber Loss as a Possible Cause of Neuropathic Pain in Schwannomatosis.

Said Farschtschi,Said Farschtschi,Hildegard Kehrer-Sawatzki,Victor-Felix Mautner,Victor-Felix Mautner,Christian Hagel,Christian Hagel,Alexander Schulz,Mathias Gelderblom,Mathias Gelderblom,Reinhard Friedrich,Reinhard Friedrich,Anna-Lena Hannekum,Anna-Lena Hannekum,Christian Gerloff,Christian Gerloff,Markus Glatzel,Markus Glatzel,Martin Schuhmann,Jan Luhmann,Jan Luhmann,Helen Morrison,Philipp Bäumer,Philipp Bäumer,Philipp Bäumer,Michael Hauck,Michael Hauck,Tina Mainka,Tina Mainka,Martin Bendszus,Martin Bendszus

doi:10.3390/ijms21103569

Abstract

Schwannomatosis is the third form of neurofibromatosis and characterized by the occurrence of multiple schwannomas. The most prominent symptom is chronic pain. We aimed to test whether pain in schwannomatosis might be caused by small-fiber neuropathy. Twenty patients with schwannomatosis underwent neurological examination and nerve conduction studies. Levels of pain perception as well as anxiety and depression were assessed by established questionnaires. Quantitative sensory testing (QST) and laser-evoked potentials (LEP) were performed on patients and controls. Whole-body magnetic resonance imaging (wbMRI) and magnetic resonance neurography (MRN) were performed to quantify tumors and fascicular nerve lesions; skin biopsies were performed to determine intra-epidermal nerve fiber density (IENFD). All patients suffered from chronic pain without further neurological deficits. The questionnaires indicated neuropathic symptoms with significant impact on quality of life. Peripheral nerve tumors were detected in all patients by wbMRI. MRN showed additional multiple fascicular nerve lesions in 16/18 patients. LEP showed significant faster latencies compared to normal controls. Finally, IENFD was significantly reduced in 13/14 patients. Our study therefore indicates the presence of small-fiber neuropathy, predominantly of unmyelinated C-fibers. Fascicular nerve lesions are characteristic disease features that are associated with faster LEP latencies and decreased IENFD. Together these methods may facilitate differential diagnosis of schwannomatosis.

Highlights

Schwannomatosis is a newly identified hereditary tumor predisposition disorder [1] with an estimated incidence of about one in 60,000 individuals [2]
All 20 patients enrolled in this study fulfilled the current clinical diagnostic criteria for schwannomatosis [11], three of which exhibited segmental schwannomatosis
We hereby provide evidence that point toward a C-fiber neuropathy as the underlying cause for the pain experienced by most schwannomatosis patients

Summary

Introduction

Schwannomatosis is a newly identified hereditary tumor predisposition disorder [1] with an estimated incidence of about one in 60,000 individuals [2]. The clinical diagnostic criteria for schwannomatosis have changed over time since its first description as separate disease entity besides neurofibromatosis type 2 (NF2) [1,4,5]. In contrast to neurofibromatosis type 1 (NF1) and NF2, schwannomatosis is characterized by genetic heterogeneity. Disease-causing germline mutations have been identified in the genes SMARCB1 and LZTR1 [6,7,8,9]. In approximately 60% of sporadic and 14% of familial schwannomatosis cases, the disease-causing genes have not been identified yet [10]

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