nifedipine in the treatment ofmyotonia in myotonic dystrophy
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Journal of Neurology, Neurosurgery, and Psychiatry 1987;50:199-206
Nifedipine in the treatment of myotonia in myotonicdystrophyR GRANT,* D L SUTTON,t P 0 BEHAN,* J P BALLANTYNE*
From the Department ofNeurology*, Institute ofNeurological Sciences, Southern General Hospital, and theDepartment of Clinical Physics and Bioengineering,t Glasgow, UK
SUMMARY Abnormal calcium transport may be implicated in the membrane defect in myotonicdystrophy. A single blind crossover trial of placebo (t.i.d.), nifedipine 10mg (t.i.d.) and nifedipine20mg (t.i.d.), was performed in 10 patients with myotonic dystrophy. The severity of myotonia wasassessed by measuring finger extension time after maximum voluntary finger flexion. A significantimprovement in myotonia, after nifedipine, was recorded by this technique and supported by asubjective improvement in 50% of patients and clinical improvement of greater than 20% in fivepatients. Initial grip strength and muscle fatiguability measured by grip strength ergometry were notsignificantly altered.
Myotonic dystrophy is an autosomal dominant disor-der characterised by myotonia and a predominantlydistal distribution of muscular wasting. Mytonia,manifest by slow relaxation of muscle after con-traction, is clinically most obvious in relaxation of thegrasp, and tends to improve with exercise. Abnormal-ities of the cardiac conduction system, eyes, testes andcentral nervous system are found in some patients.'
There is no satisfactory animal model for myotonicdystrophy. In patients with this disorder, chlorideconductance of muscle membrane is not significantlyaltered but resting muscle membrane potential isreduced.23 Abnormalities of erythrocyte and lym-phocyte membrane are also described suggesting awidespread cell membrane defect.4 5
Treatment of myotonia has been directed at "sta-bilising" the muscle membrane. In 1939, Harveyrecorded an improvement in myotonia in patientstreated with quinine.6 Since then procainamide,7corticosteroids8 and phenytoin,9 have also beenfound to be beneficial in some cases. A small trialrevealed that 56% of cases with myotonia improvedon phenytoin and a similar percentage on pro-cainamide; however, phenytoin produced fewer sideeffects.9 More recently tricyclic antidepressants,'0lithium" and verapamil'2 have been successful inimproving myotonia refractory to more established
Address for reprint requests: Dr R Grant, Magnetic ResonanceImaging Unit, Southern General Hospital, 1345 Govan Rd, GlasgowG51 4TF, UK.Received 3 April 1986 and in revised form 8 July 1986.Accepted 10 July 1986
treatment. In an uncontrolled trial, the calcium chan-nel blocker, verapamil lessened myotonia in five casesresistant to phenytoin. Verapamil may worsen car-diac conduction abnormalities and is not recommen-ded in patients with myotonic dystrophy of whom40% have first degree heart block, over 30% haveinterventricular conduction defects,'3 both of whichmay progress to complete heart block.'4The calcium channel blocker, nifedipine, does not
affect cardiac conduction in man, and side effects areminor and relatively infrequent.'5 A single blindcrossover trial of placebo, nifedipine 1Omg and nif-edipine 20mg was performed in patients with myo-tonic dystrophy to assess the effect on the myotonia,muscle power and muscle fatigue.
Finger Extension Dynamometer This consisted of a simplegoniometer with battery powered potentiometer, which wasmechanically coupled, via a miniature universal joint to alightweight copper tube 150mm long. A Velcro strap to fixthe finger was connected to the end of the copper tube viaanother miniature universal joint. The finger/tube arrange-ment therefore had freedom of movement in any plane. Thepotentiometer shaft was only rotated by finger extension andflexion but not by lateral movements. The displacementtrace of relaxation and contraction was measured by con-necting the potentiometer output to a modified chartrecorder. The mechanical rotation of the potentiometer waslimited to 290 + 100 (effective rotation 2650 15).Grip Strength Ergometer Grip strength was recorded by astrain gauge ergometer. This comprised of a handgrip,bonded strain gauge, a strain gauge amplifier and a single
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200chart recorder. The strain gauge was bonded on a 3 mmthick steel bar measuring 11Om x 15 mm. The bar wasmounted on a handgrip such that hand pressure on the gripcaused distortion of the steel bar and the strain gauge. Cali-bration of the grip strength dynamometer demonstrated that4-2 Kg of force at the midpoint of the steel bar produced1 cm deflection on the chart recorder. There was a linearrelationship between force and chart deflection in cm., overthe range used. The maximum distortion was adjustable bya screw/nut combination. The foil strain gauge (Showa) hada resting resistance of 119-7 ohm, which formed a variablearm of a conventional bridge circuit powered from a lowvoltage source. During muscle contraction therefore anunbalanced voltage, obtained across the bridge wasamplified by a low noise instrumentation amplifier circuit.The power for the amplifier was derived from the mainframe of the chart recorder via a DC/DC converter. Thisvoltage powered anbther circuit consisting of an oscillatordriving a piezo-electric sounder to give a I Hz metronome.The metronome prompted the subject to give regularmaximum voluntary contractions of the handgrip eachsecond.Chart recorder The chart recorder used was a single chan-nel ink jet ECG recorder (Mingo 14) modified to bypass itsinput stages (that is, ECG amplifier). The output from thestrain gauge amplifier was AC coupled to the driver stage ofthe ink jet galvonometer. The time constant was very high,approximately 100 seconds, to produce a DC response.Technique Before each procedure the chart recorder wascalibrated and the test demonstrated to the subject by theexaminer. After resting for 10-15 minutes at a room tem-perature of 22C + 1C subjects were comfortably seated at
Grant, Sutton, Behan, Ballantynea table and speed of finger flexion and extension was testedfirst using the finger extension dynamometer (fig 1). The sub-ject's hand was placed in a supine position and the Velcrofinger strap, with recorder arm attached, was tightly placedaround the distal phalanx of the index finger. A secondVelcro strap was placed across the palmar aspect of the handand forearm lightly restrained against the table to preventforearm pronation and wrist extension. It was emphasisedthat the important movements were speed of finger flexionand extension when requested and that the forearm shouldnot be pronated. The patient was asked to flex his fingersfully for 2 seconds and then to extend the fingers as quicklyas possible. After full extension for 2 seconds, a similar com-mand was repeated. Ten such cycles were recorded and chartrecorder speed maintained at 10mm/s. Both hands weretested. This active finger extension has been referred to byother authors as "Finger relaxation".9 16 17 Finger extensiontime ("Relaxation Time") after maximum voluntary con-traction was measured. This method provides a lowresistance method which produces an accurate recording ofclinical myotonia.
Grip strength was then assessed, using the ergometer, byasking the subject to squeeze the moulded handgrip astightly as possible every second (fig 2). The piezo-electricmetronome prompted the subject at second intervals and thehandgrip was fully released between auditory cues. Eachhand was tested for 60 maximal contractions and encour-agement given after each 10 second period.
In individual patients, recordings of myotonia and gripstrength were measured at the same time of day and at thesame time after drug administration.Subjects Control values were obtained from 20 age and sex
Fig 1 Finger extension dynamometer.
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Nifedipine in the treatment ofmyotonia in myotonic dystrophy
matched normal volunteers (10 males, 10 females) withoutclinical evidence of neurological or joint disease. Fingerextension time, initial grip strength and muscle fatigue afterexercise were measured. Ages ranged from 18-65 years. Themean age for males was 40 6 years and 35-2 years forfemales.Ten patients (six male, four female) with myotonic dys-
trophy were studied, aged from 28 to 64 years, mean 40 4years. Diagnosis was established by accepted clinicalcriteria2 and by electromyographic characteristics.'8 Therange of severity of clinical myotonia and dystrophy variedbut, in the past, all had taken phenytoin for myotonia with-out symptomatic relief. Prior to inclusion in the trial allpatients had full clinical neurological examination and elec-trocardiograph.Four patients had first degree heart block and two had
evidence of an interventricular conduction defect. Fingerextension time after maximum voluntary contraction, initialgrip strength and muscle fatigue after I minute of exercisewere measured, in each patient, at the onset of the trial andafter each treatment period of either placebo, one tabletthree times per day for 2 weeks; nifedipine 10mg threetimes per day for 2 weeks or nifedipine 20 mg three times perday for 2 weeks. As a precautionary measure, patients wererandomised to either placebo or nifedipine 10 mg. As no seri-ous side effects occurred at the lower dosage, the patientswere then given nifedipine 20mg. This was a single blindcrossover trial during which no drugs were taken. Erect andsupine blood pressures and ECGs were recorded after each 2
week period of medication. Drug compliance was assessedby counting t