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Overwork weakness in Charcot-Marie-Tooth disease1

      Abstract

      Vinci P, Esposito C, Perelli SL, Antenor JV, Thomas FP. Overwork weakness in Charcot-Marie-Tooth disease.

      Objective:

      To determine the incidence of overwork weakness in Charcot-Marie-Tooth disease (CMT).

      Design:

      Prospective survey.

      Setting:

      Rehabilitation department for CMT in an Italian tertiary care hospital.

      Participants:

      A total of 106 outpatients with CMT, selected for absence of other causes of weakness (age range, 11–69y), and 48 healthy volunteers (controls).

      Interventions:

      The strength of 2 intrinsic hand muscles (abductor pollicis brevis [APB], first dorsal interosseous) in the dominant and nondominant hands was graded by using manual muscle testing and a modified Medical Research Council (MRC) Scale.

      Main Outcome Measures:

      The side of the stronger muscle and the difference in strength between the nondominant and dominant muscles.

      Results:

      Muscles were stronger on the nondominant side in 65.57% of patients versus 1.04% of controls, and on the dominant side in .94% of patients versus 84.38% controls. The difference in strength for first dorsal interosseous was .51 in patients and −.32 in controls (P>.01). The difference in strength for APB was .65 in patients and −.35 in controls (P>.01).

      Conclusions:

      CMT muscles in the dominant hand are weaker than in the nondominant hand. This may be the result of overwork weakness.

      Keywords

      THE TERM OVERWORK WEAKNESS refers to a syndrome in which muscles are permanently weakened through exercise.
      • Fowler Jr, W.M.
      Importance of overwork weakness.
      Since its first description in postpoliomyelitis patients almost half a century ago,
      • Bennett R.L.
      • Knowlton G.C.
      Overwork weakness in partially denervated skeletal muscle.
      many studies have confirmed its existence.
      • Peach F.E.
      Overwork weakness with evidence of muscle damage in a patient with residual paralysis from polio.
      ,
      • Borg K.
      • Borg J.
      • Edstrom L.
      • Grimby L.
      Effects of excessive use of remaining muscle fibers in prior polio and LV lesion.
      Overwork weakness has been documented in other neuromuscular disorders, both neurogenic, such as amyotrophic lateral sclerosis,
      • Janiszewski D.W.
      • Caroscio J.T.
      • Wisham L.H.
      Amyotrophic lateral sclerosis a comprehensive rehabilitation approach.
      and myogenic, such as Duchenne’s muscular dystrophy.
      • Bonsett R.W.
      Pseudohypertrophic muscular dystrophy distribution of degenerative feature as revealed by anatomical study.
      In neuromuscular diseases, such as Charcot-Marie-Tooth disease (CMT), the pathologic process is slowly progressive. Therefore, it is not easy to show that weakening of muscles, which are chronically overactivated to compensate for loss of strength in other muscles,
      • Vinci P.
      results from overwork weakness rather than disease progression itself.
      A study of overwork weakness by using exercise against maximal resistance with CMT patients would likely be unethical, because patients could suffer permanent loss of muscle strength.
      • Vinci P.
      • Perelli S.L.
      Malattia di Charcot-Marie-Tooth aspetti clinico-riabilitativi.
      ,
      • Vinci P.
      • Perelli S.L.
      Trattamento riabilitativo della malattia di Charcot-Marie-Tooth (CMT).
      Because overwork weakness occurs in muscles that are used more frequently, and because muscles are used more in the dominant than in the nondominant upper limb, the asymmetrical weakness found in numerous members of a family with facioscapulohumeral muscular dystrophy has been interpreted as an example of overwork weakness because of daily living activities.
      • Johnson E.W.
      • Braddom R.
      Overwork weakness in facioscapulohumeral muscular dystrophy.
      In a previous study,
      • Carter G.T.
      • Abresch R.T.
      • Fowler Jr, W.M.
      • Johnson E.R.
      • Kilmer D.D.
      • McDonald C.M.
      Profiles of neuromuscular diseases. Hereditary motor and sensory neuropathy, types I and II.
      power was equal in both hands in 53 patients with CMT, whereas in normal individuals the dominant hand was stronger. However, that study measured pinch and grip strength generated in part by relatively unaffected forearm muscles; the most affected muscles in CMT are the more distal intrinsic hand muscles.
      The goal of this study was to compare the strength of 2 intrinsic hand muscles responsible for the pinch between the tips of thumb and forefinger, in the dominant and nondominant sides in 106 patients with CMT. Our findings may be relevant to health care professionals who design safe rehabilitative protocols for patients with CMT.

      Methods

      From 124 patients diagnosed with CMT based on clinical, electrodiagnostic, and genetic features according to the Dyck criteria,
      • Dyck P.J.
      • Chance P.F.
      • Lebo R.V.
      • Carney J.A.
      Hereditary motor and sensory neuropathies.
      who were referred to a rehabilitation hospital over 18 months, 106 subjects were selected. Causes of weakness other than CMT (including entrapment neuropathics) were excluded by history, examination, and, in 21 of these patients, also by neurophysiologic studies. Eighty patients had the demyelinating form of CMT whereas 26 had the axonal form of CMT, as determined by a median motor nerve conduction velocity below or above 38m/s.
      • Dyck P.J.
      • Chance P.F.
      • Lebo R.V.
      • Carney J.A.
      Hereditary motor and sensory neuropathies.
      The average age was 36.44 years (range, 11–69y). Controls (n=48, 8 for each decade from the second to the seventh) were selected from hospital workers, physiotherapy students, and relatives of inpatients. They were evaluated with the same criteria as the patients with CMT for possible causes of hand weakness.
      All human experimentation conformed to the Helsinki Declaration. In Italy, where the study was conducted, a formal institutional review board (IRB) process or subject consenting procedures are not required or in existence for noninvasive studies limited to standard methods of clinical examination. Approval was obtained from the IRB of Saint Louis University for the data analysis performed there.
      All patients and controls were examined in an identical fashion by the same registered physiotherapist, who was experienced in performing manual muscle testing and was blinded to the presence of disease and hand dominance. Two muscles in each hand were tested in each subject: the abductor pollicis brevis (APB), innervated by the median nerve, and the first dorsal interosseous, innervated by the ulnar nerve. Both muscles are used in the pinch between the tips of thumb and forefinger.
      • Kapandji I.A.
      If necessary, surface temperature of the hands was raised to 34°C before testing, because strength can diminish with low limb temperature and patients with CMT often have cool distal limbs.
      • Vinci P.
      • Perelli S.L.
      Trattamento riabilitativo della malattia di Charcot-Marie-Tooth (CMT).
      We determined whether muscles were stronger on the dominant (D) or nondominant (ND) side and computed the difference of strength (Δ) between the them as Δ=ND−D. A hand-held dynamometer was not used, because the strength of muscles grading 3+ or less could not be measured quantitatively.
      For muscle grading, we used a modified Medical Research Council (MRC) Scale, according to published methods for impairment profiles of several neuromuscular disorders including CMT.
      • Carter G.T.
      • Abresch R.T.
      • Fowler Jr, W.M.
      • Johnson E.R.
      • Kilmer D.D.
      • McDonald C.M.
      Profiles of neuromuscular diseases. Hereditary motor and sensory neuropathy, types I and II.
      ,
      • Kilmer D.D.
      • Abresch R.T.
      • Fowler Jr, W.M.
      Serial manual muscle testing in Duchenne muscular dystrophy.
      ,
      • Fowler Jr, W.M.
      • Abresch R.T.
      • Aitkens S.
      • et al.
      Profiles of neuromuscular diseases design of the protocol.
      To calculate the average power for statistical analysis, we used the system proposed by Kilmer et al
      • Kilmer D.D.
      • Abresch R.T.
      • Fowler Jr, W.M.
      Serial manual muscle testing in Duchenne muscular dystrophy.
      and Fowler et al
      • Fowler Jr, W.M.
      • Abresch R.T.
      • Aitkens S.
      • et al.
      Profiles of neuromuscular diseases design of the protocol.
      to convert the MRC intermediary power grades of, for example, 4−, 3+, 3−, into “study grade” numeric values of 3.67, 3.33, and 2.67 (table 1). Because intrinsic hand muscles are affected less by gravity
      • Hislop H.J.
      • Montgomery J.
      and to grade those muscles that move joints only through partial mechanical ranges with greater detail and objectivity, we adapted this scale further (table 1). Therefore, in accordance with Daniels and Worthingham,
      • Hislop H.J.
      • Montgomery J.
      MRC grade 3 (movement against gravity) was assigned to active movement through the entire range of motion (ROM), whereas grade 2 (movement with gravity eliminated) was used for movement through a partial range. For greater precision, grade 3− was used for an almost entire ROM (above 90%), grade 2 for a ROM between 10% and 90%, and grade 1+ for a ROM up to 10%. For strength rated as 5 bilaterally, as expected in normal people, the resistance generated by the examiner was increased further to identify the stronger side; in this case, the stronger side was rated as 5, the weaker as 5−. Similarly, for lesser strength side-to-side, differences were expressed as 4+/4− and 2+/2−.
      Table 1Strength Testing for Intrinsic Hand Muscles
      Modified from Kilmer et al.14 Reprinted with permission.
      MRC GradeStudy GradeDegree of Strength
      55.00Normal strength
      5−4.67Barely detectable weakness
      4+4.33Same as 4 but stronger than the reference side
      44.00Muscle is weak but moves the joint against some resistance
      4−3.67Same as 4 but weaker than the reference side
      3+3.33Muscle moves the joint fully and is capable of transient resistance but collapses abruptly
      33.00Muscle moves the joint through the full mechanical range
      3−2.67Muscle moves the joint through an incomplete mechanical range but greater than 90%
      2+2.33Same as 2 but greater than the reference side
      22.00Muscle moves the joint through a mechanical range between 10% and 90%
      2−1.67Same as 2 but weaker than the reference side
      1+1.33Muscle moves the joint through a mechanical range lower than 10%
      11.00A flicker of movement is seen or felt in the muscle
      00.00No movement
      Modified from Kilmer et al.
      • Kilmer D.D.
      • Abresch R.T.
      • Fowler Jr, W.M.
      Serial manual muscle testing in Duchenne muscular dystrophy.
      Reprinted with permission.

      Statistical analysis

      The mean and standard deviation (SD) of the differential strength in both sides were computed for patients and controls for the APB and first dorsal interosseous muscles, respectively. An independent samples t test was used to determine if the average differential strength in both sides differed statistically for patients and controls for each of the muscles tested. This compared the means for 2 different study groups (patients vs controls). Test reliability was evaluated with the Cronbach α, which characterizes the internal consistency of a test using average interitem correlations. Intratester reliability was computed with the intraclass correlation coefficient (ICC). SPSS
      SPSS Inc, 233 S Wacker Dr, 11th F1, Chicago, IL 60606.
      for Windows was used for statistical tests.

      Results

      The Cronbach α was .90, which is consistent with a high reliability of the scale in measuring strength difference. The ICC was .87, with a 95% confidence interval of .80 to .92; this is relatively high and indicates that subject strength was rated in each individual in a similar and comparable manner. Table 2 shows the frequency distribution of the side with the stronger muscle among CMT patients and controls. Table 3 shows the mean difference in strength between the 2 sides. By using the described formula for differential strength, we found that the nondominant hand was stronger than the dominant hand in the patients with CMT, whereas the opposite was true for controls for the first dorsal interosseous (P<.001) and APB muscles (P<.001). The control group had smaller SDs than the CMT group.
      Table 2Side of the Stronger Muscle
      Side of the Stronger MuscleCMTControls
      N (%)
      Number of subjects in that specific study category.
      1DIAPBN (%)
      Number of subjects in that specific study category.
      1DIAPB
      Dominant2 (0.94)1181 (84.38)3942
      Nondominant139 (65.57)66731 (1.04)01
      Equal71 (33.49)393214 (14.58)95
      No. of muscles tested212106106964848
      Abbreviation: 1DI, first dorsal interosseous.
      Number of subjects in that specific study category.
      Table 3Average Difference of Strength Between the 2 Sides
      MuscleCMTControlsP
      P value obtained using independent samples t test.
      Average Δ
      Δ= [(∑ND−∑D)/N], where ND is nondominant, D is dominant, and N is the number of subjects.
      SDAverage Δ
      Δ= [(∑ND−∑D)/N], where ND is nondominant, D is dominant, and N is the number of subjects.
      SD
      1DI.51.54−.32.24<.001
      ABP.65.69−.35.26<.001
      P value obtained using independent samples t test.
      Δ= [(∑ND−∑D)/N], where ND is nondominant, D is dominant, and N is the number of subjects.

      Discussion

      This study of intrinsic hand muscles in 106 patients with CMT revealed that fewer than 1% were stronger in the dominant than the nondominant hand and that in about 66% of cases the nondominant hand was stronger. In contrast, normal controls were stronger in the dominant side, as more often used muscles hypertrophy. This finding cannot be explained by asymmetrical muscle involvement due to CMT, because then we would have expected 50% of patients to have a weaker dominant hand and 50% to have a weaker nondominant hand.
      Because other diseases possibly responsible for more severe weakness in the dominant side (eg, focal median, ulnar entrapment) were excluded, our findings may be the result of overwork weakness.
      The high prevalence of overwork weakness in this study might be the consequence of independent effects on both nerve and muscle fibers. It is widely accepted that, in CMT muscle, weakness results from axonal degeneration, which is primary in axonal forms and secondary in demyelinating ones.
      • Bjartmar C.
      • Yin X.
      • Trapp B.D.
      Axonal pathology in myelin disorders.
      ,
      • Krajewski K.
      • Lewis R.A.
      • Fuerst D.R.
      • et al.
      Neurological dysfunction and axonal degeneration in Charcot-Marie-Tooth disease type 1A.
      Even though all nerve fibers are subject to the same genetic defect, they are not all affected to the same degree at the same time. It is conceivable that increased physiologic stimulation might hasten the axonal degeneration of nerve fibers that would otherwise survive for a longer time. The nerve fibers that survive engage in axonal sprouting, which in part compensates for the loss of other fibers. Enlarged motor units might be more susceptible to possible deleterious effects of intense physiologic stimulation. Furthermore, muscle fibers that have hypertrophied might split and degenerate in case of overuse, as happens in postpolio syndrome.

      Conclusions

      Although further studies are necessary to investigate the pathophysiologic basis of overwork weakness and its relation to disease duration, CMT subtype, and occupational activities, overwork weakness may deserve more consideration as a possible cause of disease progression. We suggest that health care professionals need to consider overwork weakness when they design rehabilitative programs for CMT patients with weakened distal muscles. Associated conditions that may result in further compensatory muscle overactivity should likely be corrected, and patients should be advised about excessive physical exertion at work.
      • Vinci P.
      ,
      • Vinci P.
      • Perelli S.L.
      Malattia di Charcot-Marie-Tooth aspetti clinico-riabilitativi.
      ,
      • Vinci P.
      • Perelli S.L.
      Trattamento riabilitativo della malattia di Charcot-Marie-Tooth (CMT).
      ,
      • Vinci P.
      Strengthening of the proximal muscles in Charcot-Marie-Tooth disease.
      Supplier

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