Muscle cramp in Machado-Joseph disease - Altered motor axonal excitability properties and mexiletine treatment

Kazuaki Kanai, Satoshi Kuwabara, Kimihito Arai, Jia Ying Sung, Kazue Ogawara, Takamichi Hattori

Research output: Contribution to journalArticle

83 Citations (Scopus)

Abstract

Machado-Joseph disease is one of the most common hereditary spinocerebellar degenerative disorders with a wide range of clinical manifestations. Pathology studies have shown mild to moderate loss of anterior horn cells and, in terms of spinal pathology, Machado-Joseph disease is regarded as a type of lower motoneuron disease. Muscle cramps are often associated with lower motoneuron disorders, but features of cramps in Machado-Joseph disease patients have never been studied. We investigated the incidence and nature of muscle cramps in Machado-Joseph disease patients, the excitability properties of motor axons [strength-duration time constant (τSD), threshold electrotonus, refractoriness and supernormality] using threshold tracking and the effects of mexiletine hydrochloride on those cramps. Of 20 consecutive patients, 16 (80%) had frequent, severe muscle cramps in the legs, trunk or arms that disturbed their daily activities. The frequency of pathological muscle cramps was similar to that for patients with amyotrophic lateral sclerosis (68%) and higher than those for patients with spinal muscular atrophy (33%) or peripheral axonal neurophathy (24%). Threshold-tracking studies showed that τSD, which in part reflects Na+ conductance at the resting membrane potential, was significantly greater in the Machado-Joseph disease patients than in normal subjects; severe muscle cramps were associated with a longer τSD. Threshold electrotonus, refractoriness and supernormality were not significantly different between Machado-Joseph disease patients and normal subjects. Eight Machado-Joseph disease patients with severe cramps, who received mexiletine treatment, experienced nearly complete relief with a partial normalization of τSD (P = 0.08). Muscle cramps are a very frequent and disabling factor in Machado-Joseph disease. Pathological muscle cramps responded well to mexiletine treatment, and this is consistent with the hypothesis that they are caused by an increase in persistent Na+ conductance, possibly associated with axonal regeneration or collateral sprouting.

Original languageEnglish
Pages (from-to)965-973
Number of pages9
JournalBrain
Volume126
Issue number4
DOIs
Publication statusPublished - Apr 1 2003
Externally publishedYes

Fingerprint

Machado-Joseph Disease
Mexiletine
Muscle Cramp
Therapeutics
Motor Neurons
Anterior Horn Cells
Pathology
Spinal Muscular Atrophy
Amyotrophic Lateral Sclerosis
Membrane Potentials
Axons
Regeneration
Leg
Arm

Keywords

  • Axonal excitability
  • Machado-Joseph disease
  • Muscle cramps
  • Na conductance
  • Strength-duration time constant

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Muscle cramp in Machado-Joseph disease - Altered motor axonal excitability properties and mexiletine treatment. / Kanai, Kazuaki; Kuwabara, Satoshi; Arai, Kimihito; Sung, Jia Ying; Ogawara, Kazue; Hattori, Takamichi.

In: Brain, Vol. 126, No. 4, 01.04.2003, p. 965-973.

Research output: Contribution to journalArticle

Kanai, Kazuaki ; Kuwabara, Satoshi ; Arai, Kimihito ; Sung, Jia Ying ; Ogawara, Kazue ; Hattori, Takamichi. / Muscle cramp in Machado-Joseph disease - Altered motor axonal excitability properties and mexiletine treatment. In: Brain. 2003 ; Vol. 126, No. 4. pp. 965-973.
@article{c7a655625e954ae0bf64f71cdeb1dfb7,
title = "Muscle cramp in Machado-Joseph disease - Altered motor axonal excitability properties and mexiletine treatment",
abstract = "Machado-Joseph disease is one of the most common hereditary spinocerebellar degenerative disorders with a wide range of clinical manifestations. Pathology studies have shown mild to moderate loss of anterior horn cells and, in terms of spinal pathology, Machado-Joseph disease is regarded as a type of lower motoneuron disease. Muscle cramps are often associated with lower motoneuron disorders, but features of cramps in Machado-Joseph disease patients have never been studied. We investigated the incidence and nature of muscle cramps in Machado-Joseph disease patients, the excitability properties of motor axons [strength-duration time constant (τSD), threshold electrotonus, refractoriness and supernormality] using threshold tracking and the effects of mexiletine hydrochloride on those cramps. Of 20 consecutive patients, 16 (80{\%}) had frequent, severe muscle cramps in the legs, trunk or arms that disturbed their daily activities. The frequency of pathological muscle cramps was similar to that for patients with amyotrophic lateral sclerosis (68{\%}) and higher than those for patients with spinal muscular atrophy (33{\%}) or peripheral axonal neurophathy (24{\%}). Threshold-tracking studies showed that τSD, which in part reflects Na+ conductance at the resting membrane potential, was significantly greater in the Machado-Joseph disease patients than in normal subjects; severe muscle cramps were associated with a longer τSD. Threshold electrotonus, refractoriness and supernormality were not significantly different between Machado-Joseph disease patients and normal subjects. Eight Machado-Joseph disease patients with severe cramps, who received mexiletine treatment, experienced nearly complete relief with a partial normalization of τSD (P = 0.08). Muscle cramps are a very frequent and disabling factor in Machado-Joseph disease. Pathological muscle cramps responded well to mexiletine treatment, and this is consistent with the hypothesis that they are caused by an increase in persistent Na+ conductance, possibly associated with axonal regeneration or collateral sprouting.",
keywords = "Axonal excitability, Machado-Joseph disease, Muscle cramps, Na conductance, Strength-duration time constant",
author = "Kazuaki Kanai and Satoshi Kuwabara and Kimihito Arai and Sung, {Jia Ying} and Kazue Ogawara and Takamichi Hattori",
year = "2003",
month = "4",
day = "1",
doi = "10.1093/brain/awg073",
language = "English",
volume = "126",
pages = "965--973",
journal = "Brain",
issn = "0006-8950",
publisher = "Oxford University Press",
number = "4",

}

TY - JOUR

T1 - Muscle cramp in Machado-Joseph disease - Altered motor axonal excitability properties and mexiletine treatment

AU - Kanai, Kazuaki

AU - Kuwabara, Satoshi

AU - Arai, Kimihito

AU - Sung, Jia Ying

AU - Ogawara, Kazue

AU - Hattori, Takamichi

PY - 2003/4/1

Y1 - 2003/4/1

N2 - Machado-Joseph disease is one of the most common hereditary spinocerebellar degenerative disorders with a wide range of clinical manifestations. Pathology studies have shown mild to moderate loss of anterior horn cells and, in terms of spinal pathology, Machado-Joseph disease is regarded as a type of lower motoneuron disease. Muscle cramps are often associated with lower motoneuron disorders, but features of cramps in Machado-Joseph disease patients have never been studied. We investigated the incidence and nature of muscle cramps in Machado-Joseph disease patients, the excitability properties of motor axons [strength-duration time constant (τSD), threshold electrotonus, refractoriness and supernormality] using threshold tracking and the effects of mexiletine hydrochloride on those cramps. Of 20 consecutive patients, 16 (80%) had frequent, severe muscle cramps in the legs, trunk or arms that disturbed their daily activities. The frequency of pathological muscle cramps was similar to that for patients with amyotrophic lateral sclerosis (68%) and higher than those for patients with spinal muscular atrophy (33%) or peripheral axonal neurophathy (24%). Threshold-tracking studies showed that τSD, which in part reflects Na+ conductance at the resting membrane potential, was significantly greater in the Machado-Joseph disease patients than in normal subjects; severe muscle cramps were associated with a longer τSD. Threshold electrotonus, refractoriness and supernormality were not significantly different between Machado-Joseph disease patients and normal subjects. Eight Machado-Joseph disease patients with severe cramps, who received mexiletine treatment, experienced nearly complete relief with a partial normalization of τSD (P = 0.08). Muscle cramps are a very frequent and disabling factor in Machado-Joseph disease. Pathological muscle cramps responded well to mexiletine treatment, and this is consistent with the hypothesis that they are caused by an increase in persistent Na+ conductance, possibly associated with axonal regeneration or collateral sprouting.

AB - Machado-Joseph disease is one of the most common hereditary spinocerebellar degenerative disorders with a wide range of clinical manifestations. Pathology studies have shown mild to moderate loss of anterior horn cells and, in terms of spinal pathology, Machado-Joseph disease is regarded as a type of lower motoneuron disease. Muscle cramps are often associated with lower motoneuron disorders, but features of cramps in Machado-Joseph disease patients have never been studied. We investigated the incidence and nature of muscle cramps in Machado-Joseph disease patients, the excitability properties of motor axons [strength-duration time constant (τSD), threshold electrotonus, refractoriness and supernormality] using threshold tracking and the effects of mexiletine hydrochloride on those cramps. Of 20 consecutive patients, 16 (80%) had frequent, severe muscle cramps in the legs, trunk or arms that disturbed their daily activities. The frequency of pathological muscle cramps was similar to that for patients with amyotrophic lateral sclerosis (68%) and higher than those for patients with spinal muscular atrophy (33%) or peripheral axonal neurophathy (24%). Threshold-tracking studies showed that τSD, which in part reflects Na+ conductance at the resting membrane potential, was significantly greater in the Machado-Joseph disease patients than in normal subjects; severe muscle cramps were associated with a longer τSD. Threshold electrotonus, refractoriness and supernormality were not significantly different between Machado-Joseph disease patients and normal subjects. Eight Machado-Joseph disease patients with severe cramps, who received mexiletine treatment, experienced nearly complete relief with a partial normalization of τSD (P = 0.08). Muscle cramps are a very frequent and disabling factor in Machado-Joseph disease. Pathological muscle cramps responded well to mexiletine treatment, and this is consistent with the hypothesis that they are caused by an increase in persistent Na+ conductance, possibly associated with axonal regeneration or collateral sprouting.

KW - Axonal excitability

KW - Machado-Joseph disease

KW - Muscle cramps

KW - Na conductance

KW - Strength-duration time constant

UR - http://www.scopus.com/inward/record.url?scp=0037379363&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0037379363&partnerID=8YFLogxK

U2 - 10.1093/brain/awg073

DO - 10.1093/brain/awg073

M3 - Article

VL - 126

SP - 965

EP - 973

JO - Brain

JF - Brain

SN - 0006-8950

IS - 4

ER -