Home  |  Login  |  Inquiries | TOC Alerts  |  Sitemap |  

Advanced Search
J Exerc Rehabil > Volume 9(4);2013 > Article
Jeong, Shin, and Jung: Neuropathic pain in hereditary peripheral neuropathy

Abstract

Charcot-Marie-Tooth (CMT) disease is the most common inherited motor and sensory neuropathy. Previous studies have shown that neuropathic pain is an occasional symptom of CMT referred by CMT patients. However, neuropathic pain is not considered a significant symptom in CMT patient and no researchers have studied profoundly the pathophysiology of neuropathic pain in CMT. Here, we highlight the relationship between CMT disease and neuropathic pain via previous several studies.

INTRODUCTION

Charcot-Marie-Tooth (CMT) disease is known as hereditary motor and sensory neuropathy and one of the most common hereditary neuromuscular diseases, with worldwide prevalence 1/2,500 (Emery, 1991). CMT is a genetically heterogeneous group of disorders and is induced by mutations of genes, leading to a length-dependent axonal degeneration. CMT1 (demyelinating form) and CMT2 (neuronal form) are major subdivision of CMT. CMT disease is characterized by loss of touch sensation across various parts of the body and progressive muscle atrophy in the extremities. Neuropathic pain is often a symptom of CMT referred by CMT patients (Carter et al., 1998; Pazzaglia et al., 2010; Ribiere et al., 2012). Severe pain is also frequently complained by CMT patients and it interferes with quality of life. Thus, understanding this relationship may provide a novel view in identifying the main mechanism causing neuropathic pain in CMT as well as useful strategy for the treatment of neuropathic pain in peripheral neuropathies.

CHARCOT-MARIE-TOOTH DISEASE

CMT is inherited neuropathies without known metabolic unbalance. It is known that peripheral muscular atrophy occurs in this disorder. The most of CMT is frequently autosomal dominant, but may also be autosomal recessive or X-linked. Prevalence of 1/2,500 makes it one of the most frequently encountered inherited neurological syndromes (Emery, 1991). CMT influences both motor and sensory peripheral nerves and its typical symptoms are distal muscle weakness and atrophy and impaired sensation, initially involving the feet and legs and later progressing to the hands and forearms.
Depending on gene affected and the type of mutation, two main types are subdivided and subtypes are decided: CMT1 (demyelinating form) and CMT2 (neuronal form) (Berger et al., 2002; Patzko and Shy, 2011; Suter and Scherer, 2003). For example, the critical gene of CMT Type 1A (CMT1A) is peripheral myelin protein-22 (PMP-22) and the mutation of PMP-22 occurs in Schwann cells (Boerkoel et al., 2002; Smith et al., 1980). CMT1 has electro-physiologic findings of decreased motor and sensory nerve conduction velocity (NCVs; <38–40 m/s) and pathological conditions like hypertrophic demyelinating neuropathy “onion bulbs” (Wrabetz et al., 2004; Zuchner and Vance, 2005). By contrast, CMT2 shows relative preservation of the myelin sheath and these individuals have normal of near-normal NCVs (Wrabetz et al., 2004; Zuchner and Vance, 2005). Additionally, CMT3, CMT4 and CMTX refer to Déjerine-Sottas disease, autosomal recessive forms and X-linked varieties, respectively.

NEUROPATHIC PAIN

Pain is the unpleasant sensory consequence of neuronal activity in specific nociceptive pathways. Infection, nerve injury, diabetes and so on influencing peripheral nerves occasionally results in the development of chronic pain, clinically important ‘neuropathic pain’ (Baron, 2006). May patients with neuropathic pain show persistent and paroxysmal pain that is independent on a stimuli. This stimulus-independent pain ought to be shooting and lancinating or burning. Spontaneous activity in nociceptive C fibers may respond to persistent burning sensation. Spontaneous activity in myelinated A fibers is also thought to be responsible for paraesthesis and dysaesthesis. Two key features of stimulus-evoked pain is hyperalgesia and allodynia. Hyperalgesia and allodynia are and increased pains response to a suprathreshold noxious stimulus and non-noxious stimulus. Many recent studies indicate that that the abnormal excitability of dorsal horn neurons and the activation of spinal microglia by peripheral sensory input affect the induction of neuropathic pain (Costigan et al., 2009; Tsuda et al., 2003; Tsuda et al., 2005; Woolf and Salter, 2000). A variety of pathological processes affecting peripheral nerves, dorsal root ganglion neurons, spinal roots and central nervous system can induce neuropathic pain. The common denominator of these pathologies is segmental dysmyelination/demyelination and axonopathy. Interestingly, the prominent involvement of neuroglia in the pathophysiological alterations following peripheral nerve injury offers new treatment approach for intractable neuropathic pain (Dworkin et al., 2003). To date, pharmacotherapy for neuropathic pain has been disappointing. Non-steroidal anti-inflammatory drugs and resistance can not affect patient with neuropathic pain. In addition, resistance and insensitivity of opiates to neuropathic pain is also common (Kingery, 1997). Thus, there is necessary to develop more effective treatment and to understand exact etiology, mechanisms and symptoms of neuropathic pain.

NEUROPATHIC PAIN IN CHARCOT-MARIE-TOOTH DISEASE

In neuromuscular diseases, 62% of the case shows chronic pain and the mean intensity of this pain is moderate (Tiffreau et al., 2006). Few researches focused on pain in CMT and its frequency ranges from 56 to 96% (Abresch et al., 2002; Cater et al., 1998; Gemignani et al., 2004; Jensen et al., 1998; Padua et al., 2006; Padua et al., 2008; Tiffreau et al., 2006; Truini et al., 2010). Pain of CMT is usually moderate, symmetric and predominantly occurs in lower limbs. The most of pain is often neuropathic with cramps, paresthesia and restlessness. Especially, neuropathic pain in CMTA1, most the common type, is related to damages in Aδ-type nerve fibers (Pazzaglia et al., 2010). In 1998, Carter et al. reported the frequency and extent to which subject with CMT show pain and comparison of qualities of pain in CMT to other painful neuropathic disorder (Cater et al., 1998). In the study, of all CMT subjects, 71% subjects reported pain with the most severe pain sites noted as low back (70%), knee (53%) and ankles (50%), toes (46%) and feet (44%). In addition, of all CMT subjects, 39% reported interruption of activities of daily living by pain. In 2008, Paudua et al performed a multi-dimensional assessment in CMT patients and reported that pain is a relevant symptom related to gender, CMT subtypes and clinical pictures, focusing on quality of life and disability (Padua et al., 2008). However, the derangement whether neuropathic pain in CMT patients is primarily due to the neuropathy or to other causes is still unsolved.
The pharmacological care management of neuropathic pain in CMT is symptomatic. Neuropathic pain is poorly relived by common analgesics and tricyclic or serotonin and norepinephrine uptake inhibitors, antidepressants, and anticonvulsants have all limited efficacy and undesirable side-effects (Kingery, 1997). This is why physical therapy via exercise and rehabilitation is important for this disease.

CONCLUSIONS

In summary, to date, a lot of studies showed an association between the subjective pain perception and the nociceptive system function in patients with CMT. Neuropathic pain being quite common in CMT disease must be rescued from its adverse events. The treatment of neuropathic pain in CMT is symptomatic. Because neuropathic pain is poorly relived by common pharmacological treatment, physical therapy via exercise and rehabilitation is essential for managing this symptom. More research is needed to identify and develop effective treatments for neuropathic pain in CMT. Thus, in order to treat neuropathic pain correctly, it is expected that this highlight can help to discovery of a useful strategy for the treatment of neuropathic pain in peripheral neuropathies.

ACKNOWLEDGMENTS

This work was supported by the Dong-A University research fund.

Notes

CONFLICT OF INTEREST

No potential conflict of interest relevant to this article was reported.

REFERENCES

Abresch RT, Carter GT, Jensen MP, Kilmer DD. Assessment of pain and health-related quality of life in slowly progressive neuromuscular disease. Am J Hosp Palliat Care. 2002;19:39–48.
crossref pmid

Baron R. Mechanisms of disease: neuropathic pain--a clinical perspective. Nat Clin Pract Neurol. 2006;2:95–106.
crossref pmid

Berger P, Young P, Suter U. Molecular cell biology of Charcot-Marie-Tooth disease. Neurogenetics. 2002;4:1–15.
crossref pmid

Boerkoel CF, Takashima H, Garcia CA, Olney RK, Johnson J, Berry K, Russo P, Kennedy S, Teebi AS, Scavina M, Williams LL, Mancias P, Butler IJ, Krajewski K, Shy M, Lupski JR. Charcot-Marie-Tooth disease and related neuropathies: mutation distribution and genotype-phenotype correlation. Ann Neurol. 2002;51:190–201.
crossref pmid

Carter GT, Jensen MP, Galer BS, Kraft GH, Crabtree LD, Beardsley RM, Abresch RT, Bird TD. Neuropathic pain in Charcot-Marie-Tooth disease. Arch Phys Med Rehabil. 1998;79:1560–1564.
crossref pmid

Costigan M, Scholz J, Woolf CJ. Neuropathic pain: a maladaptive response of the nervous system to damage. Annu Rev Neurosci. 2009;32:1–32.
crossref pmid pmc

Dworkin RH, Backonja M, Rowbotham MC, Allen RR, Argoff CR, Bennett GJ, Bushnell MC, Farrar JT, Galer BS, Haythornthwaite JA, Hewitt DJ, Loeser JD, Max MB, Saltarelli M, Schmader KE, Stein C, Thompson D, Turk DC, Wallace MS, Watkins LR, Weinstein SM. Advances in neuropathic pain: diagnosis, mechanisms, and treatment recommendations. Arch Neurol. 2003;60:1524–1534.
crossref pmid

Emery AE. Population frequencies of inherited neuromuscular diseases--a world survey. Neuromuscul Disord. 1991;1:19–29.
crossref pmid

Gemignani F, Melli G, Alfieri S, Inglese C, Marbini A. Sensory manifestations in Charcot-Marie-Tooth disease. J Peripher Nerv Syst. 2004;9:7–14.
crossref pmid

Kingery WS. A critical review of controlled clinical trials for peripheral neuropathic pain and complex regional pain syndromes. Pain. 1997;73:123–139.
crossref pmid

Padua L, Aprile I, Cavallaro T, Commodari I, La Torre G, Pareyson D, Quattrone A, Rizzuto N, Vita G, Tonali P, Schenone A; Italian CMT QoL Study Group. Variables influencing quality of life and disability in Charcot Marie Tooth (CMT) patients: Italian multicentre study. Neurol Sci. 2006;27:417–423.
crossref pmid

Padua L, Cavallaro T, Pareyson D, Quattrone A, Vita G, Schenone A; Italian CMT QoL Study Group. Charcot-Marie-Tooth and pain: correlations with neurophysiological, clinical, and disability findings. Neurol Sci. 2008;29:193–194.
crossref pmid

Patzko A, Shy ME. Update on Charcot-Marie-Tooth disease. Curr Neurol Neurosci Rep. 2011;11:78–88.
crossref pmid pmc

Pazzaglia C, Vollono C, Ferraro D, Virdis D, Lupi V, Le Pera D, Tonali P, Padua L, Valeriani M. Mechanisms of neuropathic pain in patients with Charcot-Marie-Tooth 1 A: a laser-evoked potential study. Pain. 2010;149:379–385.
crossref pmid

Ribiere C, Bernardin M, Sacconi S, Delmont E, Fournier-Mehouas M, Rauscent H, Benchortane M, Staccini P, Lantéri-Minet M, Desnuelle C. Pain assessment in Charcot-Marie-Tooth (CMT) disease. Ann Phys Rehabil Med. 2012;55:160–173.
crossref pmid

Smith TW, Bhawan J, Keller RB, DeGirolami U. Charcot-Marie-Tooth disease associated with hypertrophic neuropathy: a neuropathologic study of two cases. J Neuropathol Exp Neurol. 1980;39:420–440.
crossref pmid

Suter U, Scherer SS. Disease mechanisms in inherited neuropathies. Nat Rev Neurosci. 2003;4:714–726.
crossref pmid

Tiffreau V, Viet G, Thévenon A. Pain and neuromuscular disease: the results of a survey. Am J Phys Med Rehabil. 2006;85:756–766.
crossref pmid

Truini A, Biasiotta A, La Cesa S, Di Stefano G, Galeotti F, Petrucci MT, Inghilleri M, Cartoni C, Pergolini M, Cruccu G. Mechanisms of pain in distal symmetric polyneuropathy: a combined clinical and neurophysiological study. Pain. 2010;150:516–521.
crossref pmid

Tsuda M, Inoue K, Salter MW. Neuropathic pain and spinal microglia: a big problem from molecules in “small” glia. Trends Neurosci. 2005;28:101–107.
crossref pmid

Tsuda M, Shigemoto-Mogami Y, Koizumi S, Mizokoshi A, Kohsaka S, Salter MW, Inoue K. P2X4 receptors induced in spinal microglia gate tactile allodynia after nerve injury. Nature. 2003;424:778–783.
crossref pmid

Wrabetz L, Feltri ML, Kleopa KA, Scherer SS. Inherited neuropathies: clinical, genetic and biological features. Myelin biology and disorders. Lazzarini RA, editor. San Diego: Elsevier Academic; 2004. p. 908–952.


Woolf CJ, Salter MW. Neuronal plasticity: increasing the gain in pain. Science. 2000;288:1765–1769.
crossref pmid

Zuchner S, Vance JM. Emerging pathways for hereditary axonopathies. J Mol Med. 2005;83:935–943.
crossref pmid

TOOLS
PDF Links  PDF Links
PubReader  PubReader
XML Download  XML Download
Full text via DOI  Full text via DOI
Download Citation  Download Citation
  Print
Share:      
METRICS
5
Crossref
0
Scopus
7,803
View
69
Download
Related article
Editorial Office
E-mail: journal@kser.co.kr
Copyright © Korean Society of Exercise Rehabilitation.            Developed in M2PI