ORIGINAL CONTRIBUTION Muscle Excitability Abnormalities in Machado-Joseph Disease Marcondes C. Franc¸a Jr, MD; Anelyssa D’Abreu, MD; Anamarli Nucci, MD, PhD; Iscia Lopes-Cendes, MD, PhD Objectives: To estimate the frequency of and to char- their mean age at onset of the disease was 35 years, and acterize muscle excitability abnormalities in Machado- the mean duration of disease was 11.2 years. Abnormal Joseph disease (MJD). CAGn varied from 59 to 75 repeats. Forty-one patients presented with muscle cramps; in 10, this was their first Design: Machado-Joseph disease is a common autoso- symptom. The frequency of cramps varied between 1 and mal dominant cerebellar ataxia caused by an unstable CAG 90 episodes a week. For 15 patients, cramps were the chief trinucleotide repeat expansion. Muscle cramps and fas- complaint, frequently disturbing sleep or work (Cramps ciculations are frequent and sometimes disabling mani- Disability Scale score, 2 or 3). Lower limbs were af- festations. However, their frequency and pathophysi- fected in 37 individuals, but unusual regions, such as the ological mechanisms remain largely unknown. face and abdominal muscles, were also involved. Fas- Symptomatic patients with MJD (hereinafter MJD pa- ciculations were found in 25 individuals; in 8 patients, tients) with molecular confirmation were assessed pro- they included facial muscles. However, fasciculations were spectively. A standard questionnaire addressing clinical not a significant complaint for any of these patients. The features of muscle cramps and fasciculations was used. The Cramps Disability Scale was used to quantify cramps- clinical and neurophysiological profile of MJD patients related disability. Patients underwent neurophysiologi- with and without cramps was not significantly differ- cal testing with routine techniques. F waves of the right ent. However, MJD patients with fasciculations had more median nerves were obtained, and persistence indexes severe damage to their peripheral nerves. were calculated. Four muscles (deltoid, first dorsal in- terossei, tibialis anterior, and vastus lateralis) were ex- Conclusions: Muscle excitability abnormalities were amined by needle electromyography. A semiquantita- found in 41 MJD patients (82%), and they were the pre- tive scale (from 0 [no activity] to 4 [continuous activity]) senting complaint in 10 (20%). They are related to al- was used to determine the frequency of rest fascicula- tered excitability of peripheral motor axons, but mecha- tions in each muscle. nisms underlying cramps and fasciculations are possibly distinct in MJD patients. Results: Fifty MJD patients (29 men) were included in the study. Their mean age at examination was 46.3 years, Arch Neurol. 2008;65(4):525-529 ACHADO-JOSEPH DIS- cerebellar ataxia; and type 3, with late- ease (MJD) is the most onset, more frequent, peripheral neuropa- common autosomal thy (PN) and a more benign course. Pe- dominant cerebellar ripheral neuropathy is, thus, frequent in ataxia worldwide and MJD and may be an important source of Mis caused by an unstable CAG trinucleo- disability.3,4 In some patients, motor axons tide repeat expansion in the coding re- are specifically damaged in a pattern re- gion of the MJD1 gene (OMIM 60704).1 sembling motor neuron disease.5 It is characterized by remarkable pheno- Muscle excitability abnormalities typic heterogeneity with a wide range of (namely, muscle cramps and fascicula- Author Affiliations: cerebellar, ocular, pyramidal, and extra- tions) are typical findings in patients Departments of Neurology 2 (Drs Franc¸a, D’Abreu, and pyramidal manifestations. On clinical with motor neuron disease, such as Nucci) and Medical Genetics grounds, 3 classic types of MJD are rec- amyotrophic lateral sclerosis (ALS) and 2 6,7 (Dr Lopes-Cendes), University ognized : type 1, with marked pyramidal spinal muscular atrophy. This is attrib- of Campinas, Campinas, and dystonic signs and early onset; type uted to the collateral reinnervation that Sa˜o Paulo, Brazil. 2, characterized by pure or predominant develops in these conditions to compen- (REPRINTED) ARCH NEUROL / VOL 65 (NO. 4), APR 2008 WWW.ARCHNEUROL.COM 525 ©2008 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/25/2021 sate for axonal loss.6 Although such manifestations monopolar needle EMG. Rest activity was analyzed for 5 min- have long been recognized in MJD,8,9 systematic analy- utes at 4 different points in each muscle. The morphological sis of these features is still lacking and the few reports features of motor unit action potentials and interference pat- devoted to this issue relied on small series of patients or tern on voluntary muscle activation were recorded. case reports.10 A semiquantitative scale was used to determine the fre- quency of fasciculations in each muscle (0 indicates no activ- We, therefore, aimed to identify the frequency, sever- ity; 1, fasciculations Ͻ25% of the period; 2, fasciculations be- ity, clinical profile, and causative factors of muscle cramps tween 25% and 49% of the period; 3, fasciculations between and fasciculations in a large cohort of patients with MJD 50% and 75% of the period; and 4, fasciculations Ͼ75% of the (hereinafter MJD patients) through clinical and neuro- period), and a total fasciculation score represented the sum of physiological evaluations. individual scores (range, 0-16). METHODS STATISTICAL ANALYSIS SUBJECT SELECTION We compared the prevalence and characteristics of muscle cramps among MJD patients, patients with ALS, and healthy A group of symptomatic patients prospectively followed up in controls using analysis of variance and ␹2. We then compared our neurogenetics outpatient clinic with molecular confirma- the clinical, genetic, and neurophysiological profile of MJD pa- tion of MJD were included in the study. Clinical (sex, height, tients with and without muscle excitability abnormalities age at disease onset, duration of disease, and clinical subtype) through Mann-Whitney and ␹2 tests. Statistical significance was and genetic (length of expanded CAG repeat) data were re- considered at an ␣ of 5%. Statistical analysis was performed using corded. The severity of ataxia was quantified with the Interna- computer software (SYSTAT 10.2; Systat Software, Inc, San Jose, tional Cooperative Ataxia Rating Scale.11 A standardized ques- California). tionnaire specifically addressing the presence and features of muscle cramps was used. The age at onset of cramps, the fre- RESULTS quency and duration of the episodes, anatomical sites in- volved, and relief factors were identified. The Cramps Disabil- ity Scale (CDS) score was used to quantify its severity.10 We Fifty MJD patients, 20 patients with ALS, and 50 age- and looked for spontaneous fasciculations on upper limb, lower limb, sex-matched controls were included in the study. Among thoracic, abdominal, and facial muscles during the neurologi- MJD patients, the mean age at onset and the duration of cal examination. disease were 35.0 and 11.2 years, respectively. The mean Families with autosomal dominant cerebellar ataxia but no length of expanded CAGn was 66 (range, 59-75). Ac- molecular confirmation of MJD were excluded. Individuals with cording to nerve conduction studies, there were 20 pa- medical conditions or those taking drugs known to predis- tients in group 1, 12 in group 2, 13 in group 3, and 5 in pose to muscle cramps were not included in the final analysis. group 4. A group of age- and sex-matched individuals with no neu- The main clinical data are shown in Table 1. Cramps rological abnormalities and a group of patients with ALS were used for comparison. Most individuals in the healthy control began with a mean delay of 9.2 years after the onset of group were spouses or unrelated caregivers of MJD patients. MJD. However, in a group of 10 patients, they preceded Patients with ALS met the El Escorial World Federation of Neu- or began concomitantly with ataxia. The CDS scores in rology criteria for defined disease.12 those patients were slightly higher than in the remain- This study was approved by our institution’s ethics com- ing MJD patients (1.45 vs 1.38; P=.08). In contrast to mittee, and written informed consent was obtained from all par- the whole group with MJD, in these patients, upper limbs ticipants. were the major site of painful episodes (n=5), followed by abdominal muscles (n=3) and lower limbs (n=3). NEUROPHYSIOLOGICAL STUDIES There was a trend toward significant differences be- tween MJD patients with and without cramps regarding Patients with MJD underwent nerve conduction studies and age (46.9 vs 43.2 years; P=.39), duration of disease (11.9 needle electromyography (EMG) using an electromyograph vs 8.0 years; P=.06), and expanded CAGn (66.1 vs 68.0; (Neuropack 2 Electromyographer; Nihon Kohden, Tokyo, Ja- P=.10). Although the proportion of MJD clinical sub- pan). The protocol of the nerve conduction studies included sensory (median, ulnar, radial, and sural) and motor (median, types was not different among individuals with and with- ulnar, common peroneal, and tibial) nerves on both sides. Ac- out cramps (P=.81), 8 of the 11 patients with type 1 in cording to nerve conduction study findings, patients were clas- the entire group had muscle cramps. The frequency of PN sified into 4 groups: 1, healthy; 2, exclusively sensory PN; 3, was not different between MJD patients with and with- sensory motor PN; and 4, exclusively motor PN. out cramps (26 of 41 vs 4 of 9; P=.45). We analyzed The H-reflex of the right tibial nerve was searched for ac- whether cramps in those with MJD might be related to al- cording to routine techniques.13 H-reflex latency is expressed tered muscle excitability by studying F responses and the in milliseconds, and amplitude is expressed as the ratio of the H-reflex of tibial nerves. Ulnar nerve F-wave persistence amplitude of the maximum H-reflex to that of the maximum 13 and minimal latency were not significantly different (P=.3 compound muscle action potential of the soleus muscle.