Neuropathic pain in Charcot–Marie‐Tooth disease: A clinical and laser‐evoked potential study

Abstract

Background: Pain, either nociceptive or neuropathic (NP), is a common symptom in Charcot-Marie-Tooth (CMT) disease. Methods:We investigated small fibers involvement and its correlation with pain in different CMT subtypes through a systematic clinical and neurophysiological study. We enrolled 50 patients: 19 with duplication of PMP22 (CMT1A), 11 with mutation of MPZ (CMT1B, CMT2I/J, or CMTDID), 12 with mutation of GJB1 (CMTX1), and 8 with mutation of MFN2 (CMT2A and CMT2A2B). Pain was rated with the 11-point Numerical Rating Scale and characterized through Neuropathic Pain Symptoms Inventory. Laser-evoked potentials (LEPs) were recorded after right foot and hand stimulation and N2-P2 complex amplitude and latency were compared with those of 41 controls.Results: Overall pain prevalence was 36%. NP was present in 14.6% of patients, with a length-dependent distribution in 85.7% of cases, and it was significantly more frequent in CMT1A (p < 0.001). Aδ fibers involvement greatly varies between CMT subtypes, reflecting differences in molecular pathology and pathophysiologic mechanisms. Prolonged N2 latency from foot stimulation was noted in 11 CMT1A patients, 5 of which report NP. MPZ-CMTs displayed different neurophysiological phenotypes and a very low prevalence of NP. LEPs were normal in all but one CMTX1 patients, although lower limbs N2-P2 amplitude was significantly reduced in males (p = 0.043). MFN2-CMTs were NP free and LEPs recordings were all normal. NP strictly correlated with LEPs alterations (p = 0.017).Conclusions: NP prevalence varies among CMTs subtypes and is mainly related to Aδ fibers impairment.Significance: Neuropathic pain is a frequent finding in Charcot-Marie Tooth disease and is related to Aδ fibers impairment. Patients at higher risk are those belonging to certain genetic subtypes (i.e. CMT1A and CMT2J) or with laserevoked potentials abnormalities. While managing this disease, clinicians should be aware of this symptom in order to offer best treatment options to their patients.

Charcot-Marie-Tooth disease: from historical landmarks in Brazil to current care perspectives

“…Neuropathic pain prevalence varies among CMT subtypes, being significantly more frequent in CMT1A, and is related to Aδ fibers impairment. 32 This study corroborated the observation of the study of Laurà et al 30 that neuropathic pain in patients with CMT1A could have its etiology in Aδ fiber dysfunction.…”

“…Pain is a poorly studied phenomenon in CMT, with a frequency between 28.8% and 88% according to previously published works. 29 30 31 32 The study of pain in CMT patients is complex as it is necessary to consider several variables, such as genetic subtype, severity of neuropathy, history of orthopedic injuries (sprains and fractures), presence of musculoskeletal deformities, and overweight/obesity. Sometimes, differentiating pain mechanisms in this condition can be challenging, especially when there is an overlap between them.…”

“…In 2022, Peretti et al 32 investigated small fibers involvement and its correlation with pain in different CMT subtypes through a systematic clinical and neurophysiological study, including evaluation by the laser-evoked potentials (LEPs). This study enrolled 50 patients with disease causing-variants in PMP22, MPZ, GJB1, and MFN2.…”

Defect of the Endogenous Inhibitory Pain System in Idiopathic Restless Legs Syndrome: A Laser Evoked Potentials Study

“…Fila and colleagues 16 found prolonged latency and increased amplitude of LEPs recorded in lower limbs of RLS, an apparently conflicting neurophysiological result. In neuropathic patients, a prolonged N2 latency is consistent with impairment of Aδ fibers conduction, and patients with abnormal latencies generally disclose a reduction of the mean N2–P2 amplitude, which likely reflects an associated length‐dependent loss of Aδ fibers because of a secondary axonopathy 34 or temporal desynchronization of the cortical potential caused by the Aδ fibers demyelination 35 . In these patients, the coexistence of prolonged latencies and increased amplitude pointed to different pathophysiological mechanisms, like a disorder of small fiber conduction associated to a central disinhibition of lower structures by higher structures that centrally regulate nociceptive pathways.…”