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Investigative strategies for muscle pain
Journal of the Neurological Sciences, 1983, 58:73 88
73
Elsevier Biomedical Press
INVESTIGATIVE STRATEGIES FOR MUSCLE PAIN
K.R. MILLS and R.H.T. EDWARDS
Department (~["Medicine. The Rayne Institute, Universit)' College London School ~[' Medicine, Universi O' Street, London WCIE 6JJ (Great Britain) (Received 8 July, 1982) (Accepted 13 July, 1982)
SUMMARY
Muscle pain is the presenting symptom in patients with a wide variety of conditions. Such patients often pose problems in diagnosis and management and a rational scheme for their investigation is needed. The results of muscle biopsy, electromyography, exercise and strength testing and blood measurements in 109 consecutive patients presenting with myalgia are reported. By determining the sensitivity and specificity of the tests in identifying patients with specific muscle abnormalities, a rational investigative protocol has been constructed. Creatine kinase and erythrocyte sedimentation rate are the most useful screening tests and if either is abnormal, muscle biopsy, electromyography, muscle strength and exercise testing are then performed. Despite exhaustive investigation, specific muscle abnormalities were found in only one-third of the patients; whilst many of the remaining patients undoubtedly had a psychogenic component to their pain, it is likely that a number of unidentified specific metabolic defects remain as causes of myalgia.
Key words: Muscle investigations
Muscle pain
INTRODUCTION
Pain in muscles, often related to exercise, is a common feature of a variety of conditions, and indeed, may be the presenting symptom in many. The diagnosis may be clear, such as in rheumatoid disease or severe depressive illness, but there This work was supported financially by The Wellcome Trust and The Muscular Dystrophy Group of Great Britain. Correspondence to Professor R. H. T. Edwards al above address. 0022-510X/82/0000-0000/$02.75 © 1982 Elsevier Biomedical Press
74 are a number of patients, in whom myalgia is a consistent and clearly genuine symptom, who pose a problem in diagnosis and management. The volume of secondary and tertiary referral of such patients to a specialised muscle clinic prompted this study of muscle pain as a presenting symptom, with the aim of providing a rational scheme for diagnosis and treatment. The finding by McArdle (1951) of a defect in glycolysis in a patient with muscle pain started a long and exciting search for enzyme defects in muscle. It is now recognised that phosphofructokinase deficiency can cause a similar syndrome (Tarui et al. 1965). With the development of biochemical techniques applicable to small tissue samples, such as needle muscle biopsies (Gohil et al. 1981; Edwards et al. 1980), the search for as yet undefined metabolic defects in muscle cells has intensified. At least 8 specific mitochondrial enzyme defects have now been described (Land and Clarke 1979: Morgan-Hughes 1982); many of these patients present with muscle pain related to exercise. Management of muscle pain can be difficult; often a specific diagnosis cannot be made and patients with chronic pain may be unresponsive to analgesics. Simple treatments such as mechanical vibration, the application of heat or cold, a trial of anti-depressants or the use of transcutaneous nerve stimulation may then be tried. Even when the diagnosis is clear, it is often by no means settled what the treatment should be. In polymyositis, for instance, steroid therapy, though conventional, is not without risk and may in fact be unnecessary (Edwards et al. 1980). Serratrice et al. (1978) have reviewed 210 cases of muscle pain and found two groups of about equal numbers; one group contained mainly cases of polymyositis and polymyalgia rheumatica, and the other group were classified as "functional myalgia," but no attempt was made to identify enzyme defects or metabolic causes of muscle pain within this group. An overview of painful myopathy has also been given by Morgan-Hughes (1979). This paper summarises the results of investigations of 109 patients with muscle pain and seeks to propose a rational strategy for investigating patients with muscle pain in future. PATIENTS A N D METHODS
A total of 109 consecutive patients, referred to a specialised Muscle Clinic on account of muscle pain were studied over a two-year period. A comprehensive history was taken from all patients and details such as pain type, onset, duration, location and relationship to exercise noted, and physical examination carried out. In all patients blood was taken for creatine kinase (CK) and erythrocyte sedimentation rate (ESR) and where indicated, other tests including plasma calcium, rheumatoid factor, anti-nuclear factor, thyroxine and fasting lipids.
Strength testing Because weakness is often associated with pain, quadriceps muscle strength was measured with a strain gauge method (Edwards et al. 1977). The patient sits
75 in a muscle testing chair with the pelvis stabilised by a lap strap. An inextensible loop around the ankle is connected to a strain gauge. Forces developed during maximal voluntary isometric contractions of the knee extensors are measured by amplifying the strain gauge signal and displaying it on an ultraviolet oscillograph. If weakness is present [defined as a maximum strength more than two standard deviations below the mean for a normal population of the same weight (Edwards et al. 1977)], then this was further analysed to determine whether the weakness was central or peripheral in origin. Force generation with the volition of the patient eliminated could be measured by applying two large pad electrodes to the anterior surface of the thigh and using stimuli up to 100 s ~. If more force could be generated by stimulated contractions than by voluntary efforts, then the weakness was classified as central, implying a defect proximal to the fine intramuscular nerves which were stimulated. Poor force generation in both situations would imply a peripheral lesion (Bigland-Ritchie et al. 1978: Edwards 1981).
Exercise testing Many patients related their symptoms to exercise, and, therefore, exercise testing was useful not only in defining maximum power output, but also in provoking symptoms which could then be analysed further. In other cases, exercise testing had a therapeutic role in that it could be used to reassure patients of their ability to exercise without provoking undue pain. A progressive exercise test was used in which work rate was increased by 25 W every 90 s from a starting value of 50 W. Patients were encouraged to produce their maximum output and to report any abnormal sensations. Heart rate and blood pressure were monitored before, during and for i0 min after the test. Blood for lactate determination was taken before and 5 min alter exercise.
t:Tectromyography Painful muscles were sampled with a concentric needle electrode (Disa, Type 13150). Motor unit duration, amplitude and phase count were noted as was the presence of spontaneous or insertion activity. In patients where pain was not present at rest, electromyography of the quadriceps muscle was performed.
Needle muscle biopsy Samples, usually of the quadriceps muscle, were obtained by the percutaneous needle muscle biopsy technique (Edwards et al. 1980). Samples were orientated by direct inspection under a dissecting microscope, frozen in liquid isopentane cooled in liquid nitrogen and cut on a cryostat for subsequent histochemical staining. A small piece was fixed in glutaraldehyde for electron microscopy. All samples were stained with haemotoxylin and eosin, a modified trichome stain, Miller's Van Giesen, NADH-tetrazolium reductase, ATPase (pH 9.4) and acid phosphatase, and additionally screened for adenylate deaminase activity. If indicated histochemical stains for myophosphorylase and phosphofructokinase were also used. The fibre type distribution and the mean fibre areas of type 1 and II
76 fibres were measured using a computer automated planimetric device (Round et al. 1982). In addition, 35 samples were subjected to tests of mitochondrial function (Gohil et al. 1981) in which components of the electron transport chain or the ability of mitochondria to take up and oxidise fatty acids were tested. Because of the possibility that the procedure of muscle biopsy itself may provoke different symptoms or signs in patients with different disease processes, a group of 50 consecutive patients with muscle pain were asked to complete a questionnaire about symptoms of pain or stiffness during or for one week alter the procedure. RESULTS Abnormalities consistent with a specific diagnosis were found in 37 of the 109 patients (Table 1). The wide variety of pathological conditions is evident. It should be pointed out that this cannot reflect the incidence of diseases presenting as muscle pain since the group were highly selected and were "difficult" cases. The large number of cases with enzyme defects probably reflects the interests of the department. Polymyositis and cervical spondylosis which are only sparsely represented are diseases in which the presentation and findings may m a k e diagnosis relatively simple and secondary referral unnecessary. TABLE 1 MUSCLE PAIN SERIES MUSCLE PAIN
DIAGNOSIS IN 109 PATIENTS PRESENTING WITH
16
(A) Enzyme de/ects
Mitochondrial myopathy Myophosphorylase deficiency Phosphofructokinase deficiency
8 6 2
(B) Inflammatory myopathy
Polymyositis Dermatomyositis Temporal arteritis Rheumatoid disease Polyarteritis nodosa
8
2 2 2 1 1
(C) Neurogenie disorders
Motor neurone disease Cervical spondylosis Spinal dysraphism Parkinson's disease Dissection of vertebral artery Stiff man syndrome
7
2 l l 1 l l
(D) Endocrine and metabolic disorders
Hypothyroidism Adult onset hypophosphataemic rickets Alcoholic myopathy (E; Miscellaneous (no tissue diagnosis)
6
3 1 2 72
77
Clinical Jeatures Most of the patients fell into the age group 31 50 years: males and females were about equally represented (Fig. 1). The features of interest in the patients" histories are summarised in Figs. 2, 3 and 4. Pain onset was classified as acute (single event or over hours or days), subacute (over days or weeks) or insidious (over months). It can be seen (Fig. 2) that most patients had an insidious onset to their problem especially those patients in whom no abnormalities were found. The duration of the s y m p t o m at the time of referral (Fig. 3) varied from 2 weeks to 53 years. Most patients had either had pain for 3 months to 1 year when first seen, or had had the pain for more than 10 years; this latter group contained many patients in whom no abnormality was found. The location of pain is summarised in Fig. 4. Pain in the legs was the commonest presenting complaint and in about half of these patients a specific tissue abnormality was found. Pain described as "'widespread" or "in arms and legs" provided only few cases with a specific abnormality; on the other hand, patients in whom pain was limited to the arms or
Males 0
Females
..
lO
f
I
r
3O A G 4O 5O
I [
I I
I
70
I
80
I I L [ I 14 12 10 8
I 6
I 4
2
0
2
I 4
t 6
I 8
I I I I 10 12 14 16
Number
Fig. I. Age distribution of 109 patients presenting with muscle pain.
Males
Onset
Females
[]
Acutet
No cause found Subacute
11
t
I
Insidious.J[
I 30
I 20
10
0
I 10
I I
I
I 20
[ 30
Number
Fig. 2. Mode of onset of pain in 109 patients presenting with muscle pain.
78 Males
Females
<3m 3m -1 1-2 2-3 c
.o
3-4
" 1= E
4-5
O
5-6
@
6-7
~
7-G
No cause found
8-9 9-10 >10
12 10
8
6
4
2
0
2
4
6
8
10 12 14 16
Number
Fig. 3. Duration of pain at the time of initial referral in 109 patients presenting with muscle pain,
Males
Females
Location Widespread Limbs Legs
Armsl Thighs
@
Calves Active muscle
20 18 16 14 12 10 8
No cause found
6
4
2 0 2 Number
4
6
8
10 12 14 16 18 20
Fig. 4. Location of pain in 109 patients presenting with muscle pain.
who had pain only when a single muscle or muscle group was exercised provided a high yield of muscle abnormalities. Patients most commonly described their pain as "aching;" only a few patients described cramp-like pains. In the group of patients in whom no specific abnormality was found, elaborate or histrionic descriptions of the pain such as "like many needles sticking into the muscle" were common, as were descriptions of pain relating solely to specified activities, e.g. "when I try to produce a vibrato on the trumpet". Also in this group of patients, the associated complaint of swelling of
79 the painful muscle was c o m m o n ; in no patient with a specific muscle abnormality was this ever documented. Most patients reported that exercise exacerbated or brought on the pain, and this feature was not found to be a useful predictor of specific muscle abnormality. Even when the patient said that exercise made no difference to the pain, or that pain was relieved by exercise was a specific abnormality more likely. Patients, even those in whom abnormalities were found, infrequently had physical signs, either in the musculature, or indeed, in any other system. This lack of physical signs, therefore, cannot be taken as an indicator that further investigation is not warranted. A number of patients (12) gave a clear history of pain following a viral infection~ most of these patients had no abnormality on investigation apart from reduced exercise tolerance. Two patients gave a history of muscle pain starting in the last trimester of pregnancy and persisting for months or years after this. Plasma creatine kinase (CK) All patients had creatine kinase measured on at least one occasion. 72% had values within the normal range (10-120 I.U./1); of these, specific muscle abnormalities were found in 34%, and no clear cause for the pain was found in 66'~0. A marginally raised C K (120 200 I.U./I) was found in 7 patients, in two of whom a diagnosis was reached. An unequivocal C K rise (200 500 l.U./1) was found in 9 patients in 6 of whom specific abnormality was found. High CK values ( >500 I.U./I) were seen in 10 patients all of whom had specific enzyme defects. Levels of CK up to 300 I.U./1 can easily occur in normal subjects after moderate exercise (Thompson et al. 1975; Brooke et al. 1979), and it is known that CK is higher in outpatients than in inpatients (Griffiths 1966). In situations where C K is marginally raised, it is prudent to ask about habitual level of exercise, and to repeat the C K after a period of rest or less vigorous activity. Other blood tests Erythrocyte sedimentation rate (ESR) was measured in 103 patients of whom 85 had results in the normal range (0 30 m m in 1st h). Of those with a normal ESR, 31 had some abnormality of muscle. An ESR between 30 and 50 m m in 1st h was found in 8 patients of whom 5 had a muscle abnormality. Ten patients had an ESR greater than 50 m m in 1st h of whom a clear diagnosis could be made in 9. This confirms the time honoured practice of using the ESR as a screening test for active disease. A number of other blood abnormalities were found in patients with muscle pain. Two patients had hypercalcaemia; in one the finding was transient, but in the other, a diagnosis of hyperparathyroidism was made but neck exploration for a parathyroid adenoma was negative. One woman with muscle pain also had sideroblastic anaemia and had been treated with considerable amounts of oral iron. A man presenting with pain in the calves also had secondary polycythaemia, and one man with pain in the legs on exercise was found to have hypertriglyceridaemia.
80 It is seen in Table 1 that three patients with hypothyroidism presented as muscle pain and it is worthwhile emphasising that a high level of suspicion should be maintained for this slowly progressive but treatable condition.
Exercise testing Progressive exercise tests were carried out in 54 patients. The test was classified as abnormal if one or more of the following criteria were satisfied : (i) Inability to exercise to the expected maximum work rate as indicated by age, sex, heart rate and physical fitness. (ii) Provocation of pain, cramp or contracture with submaximal exercise. (ii) Plasma lactate 5 min after the completion o f submaximal exercise of greater than 10 mmol/l. Abnormal tests were found in 26 patients; 10 of these were finally diagnosed. Three patients with mitochondrial myopathy had raised resting plasma lactate levels ( > 1.0 mmol/1) with levels after exercise rising to 15 mmol/1 or more. Four patients had abnormal tests because of the provocation of symptoms : 1 had mitochondrial myopathy, 2 had McArdle's disease and 1 phosphofructokinase deficiency. Of the 16 patients with no final diagnosis, 13 were classified as abnormal because of failure to achieve the predicted work rate, and 3 stopped exercise because of pain in the thighs.
Muscle strength Quadriceps maximal strength was measured in 102 patients; of these 46 had normal strength as defined above. A specific muscle abnormality was found in 18 of these patients but in 28 no firm diagnosis was reached. The remaining 56 patients had weakness of the quadriceps. These were further investigated to determine whether the weakness was of central or peripheral origin (Edwards et al. 1977, Bigland-Ritchie et al. 1978). In 34 patients, electrical stimulation of the muscle was not able to produce more force than with a maximal voluntary contraction and thus they were considered to have peripheral weakness: 22 of these patients had specific muscle abnormalities but in 12 a firm diagnosis could not be made. The remaining 20 patients had central weakness, i.e. electrical stimulation of the muscle produced a greater force than that generated by maximal volition. Of these 20, only 3 had a specific muscle abnormality.
Electromyography Conventional concentric needle electromyography was carried out in the painful muscles of 75 patients. Abnormalities were found in 28 patients: the most common abnormality was an excess of polyphasic motor unit potentials, although in several cases a frankly myopathic picture was seen. In the patients with motor neurone disease, evidence of denervation was obtained. Electromyographic abnormalities were found in 8 patients with no firm diagnosis. In the 47 patients with no abnormality on electromyography, 14 had a final specific diagnosis and 33 did not.
81
Needle muscle biopsy Of the 103 patients having muscle biopsy, abnormalities of histology or histochemistry were found in 49; 34 of these had a firm tissue diagnosis, but in 15 only non-specific changes were found. Normal muscle structure was found in 54 patients of whom eight had a final diagnosis and 46 did not. In addition, samples from 34 patients were screened for possible defects in the mitochondrial cytochrome system, or in fatty acid uptake or utilisation by mitochondria (Fig. 5). This allowed more precise diagnosis in the 4 cases of mitochondrial myopathy and identification of a further 4 patients who demonstrated abnormality in fatty acid uptake or utilisation by mitochondria (Table 2). A number of patients in whom no final diagnosis was made had low levels of all enzymes measured, although the ratios of enzyme activities were normal. This may reflect the fibre type distribution in these patients or the relatively poor state of training of the muscle. Estimations of proportions of Type I and II fibres and of mean fibre areas were made on 56 biopsies. The results are seen in Fig. 6. For type I fibre areas, all but 2 females with specific muscle abnormalities, and 4 males and 2 females with no specific abnormality fell within 2 standard deviations of the normal mean fibre area. The values for men, however, tended to be grouped in the lower part of the distribution. In contrast, the mean fibre area of type I1 fibres in patients with no specific diagnosis were below 2 standard deviations from the normal mean in 9 cases, whereas those of patients with a firm diagnosis were within the normal range. The results of patients' replies to the questionnaire concerning the pain of biopsy and its sequelae are seen in Fig. 7. The finding of specific abnormalities in the histology of histochemistry of the muscle appeared to bear no relation to the duration or severity of any pain, discomfort or stiffness of the muscle in the 7 days following biopsy. DISCUSSION
The variety of conditions which can present as painful muscles is seen in Table 1, but more important is to be noted the large number of cases in which no firm diagnosis could be made despite exhaustive investigation. Many of these undoubtedly had depressive states of which myalgia was the most prominent symptom, but it is seen in Table 2 that a significant number had abnormalities of muscle structure or function which may represent a covert disease process. In particular a small group of 5 patients can be discerned with myalgia, abnormal muscle biopsy and raised creatine kinase; they were young (age range 15 32) and 4 of the 5 were female. It may be that these patients have muscles which are unusually sensitive to damage, or have an undiscovered enzyme defect. On the other hand, it should be pointed out that the biopsy changes are on the whole non-specific and the raised creatine kinase may merely be a reflection of unaccustomed exercise in the days before the test.
82 ,~YRUVATE
PALMITYL CARNIIINE (PC)
/
I
~'~
I I
PYRUVATE
I
II
IIIIHI
PALCoA
L OXALOACETATE
I
CARNITINE
ACEIYL CoA 4
i
t 1
/ CITRATE
FADIi
ADDED CYI.C
Components of the various enzyme activities measured Enzyme activity
Components
Pyruvate + malate cytochrome c_ reductase (P + M) CR
Palmitoylcarnitine + malate cytochrome c_ reductase
Pyruvate dehydrogenase complex, malate dehydrogenase (MDH), citrate synthase (CS), complexes I and III.
Carnitine palmitoyl transferase(ll) B-oxidation pathway, MDH, CS, iPC + M) CR and complexes I and III.
Succinate cytochrome c reductase
SCR
Succinate dehydrogenase, complexesI I and I II.
Cytochrome c oxidase
CoX
Complex IV
Fig. 5. Study of mitochondrial function in needle biopsy samples. Above is shown a schematic figure of the pathways involved in translocation and metabolism of substrates in mitochondria engaged in oxidative phosphorylation. These functions are studied in detail by observing the state of oxidation or reduction of added eytochrome-c when combinations of substrates are added to homogenates of the needle biopsy sample. The enzyme pathways studied by this means are listed below. (For more detail see Gohil et al. 1981.)
7.16
4.3
2.82
N.D.
105.0
6.26
0.96
6.8
1
2
3
4
5
6
7
8
5.44
2.85
31.18
16.4
N.D.
0.77
1.32
1.8
1.25 4.7
Succinate cytochrome-c reductase
0.57
1.{)2
6.39
<0.05
N.D.
0.28
0.11
0.31
0.5 2.2
Pyruvate + malate cytochrome-c reductase
N.D. = not determined. ~' Data based on samples from 9 untrained normal controls.
6 25
Normal
Cytochrome c-oxidase
0.19
0.56
4.52
N.D.
0.63
Absent
2.06
<0.02
0.2 1.5
Palmityl carnitine + malate cytochrome-c reductase
N.D.
N.D.
N.D.
N.D.
Absent
N.D.
0.028
0.067
0.04 0.14
Myalgia and weakness related to exercise. Electron transport chain defect
Myalgia related to exercise. Cytochrome oxidase deficiency
Myalgia related to exercise. Abnormal EEG. Defect in Complex IV of electron transport chain
Myalgia related to exercise. Electron transport chain defect
Myoglobinuria related to exercise. Carnitine pahnityltransferase deficiency
Myalgia related to cxcrcise. Possible defect in palmityl carnitine oxidation
Myoglobinuria following viral infection. Possible defect in palmityl carnitine oxidation
Paroxysmal myoglobinuria and muscle pain unrelated to exercise. Possible defect in carnitine oxidation
Comments
MYOPATHY
Carnitine palmityl transferase
M I T O C H O N D R I A L ENZYME STUI)IES IN 8 P A T I E N T S WITH M I T O C H O N D R I A L Enz}mc activities are expressed as ,umol . g 1 .mm I at 37 ':C.
IABI.I 2
Specific abnormality found on biopsy
Mean fibre area ~m z x 10-3 9
Type I
U
No specific abnormality found on biopsy Type II
F
Type
M
Type II
M
,
M
!9 J
8
1s
7
~z J W
6 5
•
t°
01 I
•1
4
!
01
3
:1 •
I
III
N
2
,l
•
•
I
1
Fig. 6. Mean fibre area (/lm 2 x 10-3) of type I and II fibres in patients with muscle pain. The norma range is indicated as mean + SD.
Severity of pain in 7 days after biopsy Number ~
2O
Abnormality on biopsy Muscle normal on biopsy
15-
]0-
"....... [Ill]Ill ,,,...,
5 -
!!if!i!!
o [1I Nil
Mild
Mod
Sev
Duration of pain after biopsy 15 ' " ' - " "
0
<24h
24"-48h
>48h
Fig. 7. Severity and duration of pain after muscle biopsy reported by 50 consecutive patients.
85 Pain may arise in muscle by a number of mechanisms, but ultimately all mechanisms must function by activating pain receptors in the muscle or in its attachments. The evidence for such receptors in man is scanty, although nociceptors in cat muscle responsive to tension, lactate, potassium ions, bradykinin, histamine and serotonin have been described (Mense 1977a,b). It is likely that the pain of inflammatory muscle disease is mediated by stimulation of such nociceptors by the kinins, etc., released from inflammatory cells. The pain of ischaemic muscle or muscle deprived of energy substrates may be related to the accumulation of lactate, potassium or phosphate in muscle, although lactate is clearly not responsible in myophosphorylase deficiency. Many patients report that pain is exacerbated if the muscle is made to contract; the role of tension in the production of muscle pain may be related to the presence of mechanonociceptors in muscle and central interaction between these afferents and other fibres signalling the metabolic state of the muscle may account for the symptom described (Mills et al. 1982). Pain due to unaccustomed exercise is a familiar phenomenon and a mechanism akin to this may have been responsible for the pain in some of the cases described here. It is known that such pain is mainly associated with eccentric muscle contraction (contraction with simultaneous lengthening of the muscle) (Asmussen 1956: Abraham 1977). Repeated eccentric contractions in normal subjects leads to fatigue (Edwards et al. 1981a), a rise in creatine kinase (Newham et al. 1982) and damage to Z-lines and disruption of sarcomeres on electron microscopy (Newham et al. 1982). It is possible that some of the patients in the series may have been at one end of a normal spectrum of response to eccentric contraction. The practical value of the investigations used in this study in identifying cases with a pathological or metabolic defect is summarised in Table 3. The sensitivity of an investigation represents its ability to detect abnormalities in all cases where a firm final diagnosis could be made. The specificity of an investigation represents its ability to report a negative result in all cases where no specific diagnosis was reached (Feinstein 1977). It is not intended that these parameters should indicate the true discriminability of investigations; they are merely used to compare the usefulness of tests in the diagnosis of myalgia in this study. Muscle biopsy was the most sensitive indicator of organic disease and also had a high specificity. The least sensitive test was the ESR yet it was the most specific (see Table 3). Since a large proportion of the total number of patients had no specific muscle abnormality (Table 1), investigations with a high specificity should be used as screening tests in the first place since these will tend to pick out the patients in whom no tissue diagnosis will be made. If these initial tests a r e abnormal, then the most sensitive tests should then be chosen. A scheme for the investigation of myalgia based on the specificity and the sensitivity of tests in this study is presented in Fig. 8. In practical terms, ESR and CK estimations are made at the time of initial referral. If either investigation is abnormal, then muscle biopsy, electromyography, muscle strength and exercise testing are then performed. If the initial investigations are normal, then the discovery of a specific muscle abnormality is
103 105 I01 103 75 54
Muscle biopsy Creatine kinase Muscle strength ESR Electromyograpby Exercise test
49 26 54 18 28 26
Number which were abnormal
__L
34 18 23 14 20 l0 __
15 8 31 4 8 16
8 27 18 31 14 9
Firm (c) diagnosis
Firm (a) diagnosis
No (b) diagnosis
Normal results
A b n o r m a l results
* Sensitivity calculated by a/(a + c). Specificity calculated by d/(b + d). IFeinstein 1977).
Total number
Investigation
SENSITIVITY A N D SPECIFICITY O F I N V E S T I G A T I O N S IN M Y A L G I A
TABLE 3
46 52 29 54 33 19
No (d) diagnosis 0.81 0.59 0.56 0.31 0.59 0.53
Sensitivity*
0.75 0.81 0.48 0.93 0.81 0.54
Specificity*
O Q
87
Either investigation abnormal
]es
CK
J Specific muscle abnormality less likely
Review J" h
No[I
Specificabnormality still suspected
Muscle biopsy EMG Muscle strength Exercise Test
I Yes
Fig. 8. Scheme for investigation of myalgia.
less likely, but if some abnormality is still suspected, then muscle biopsy and electromyography are likely to be the most productive investigations. Muscle pain is the most prominent feature in the symptomatology of a wide variety of conditions: a rational scheme for the investigation of these patients is needed, and our experience in the management of 109 consecutive cases has allowed us to evolve such a scheme. The number of patients for whom no definite cause is found remains high and although a number may present with myalgia as part of a psychiatric problem, the consistency and credibility of many patient's complaints make it likely that a number of specific metabolic muscle disorders remain to be identified. REFERENCES Abraham, W. M. (1977) Factors in delayed muscle soreness, Medicine & Science in Sports, 9 : 1 1 26. A smussen, E. (1956) Observations on experimental muscle soreness, Acta rheum, seam/., 2 : 1 0 9 116. Bigland-Ritchie, B., D . A . Jones, G.P. Hosking and R . H . T . Edwards (1978) Central and peripheral fatigue ill sustained m a x i m u m voluntary contractions of h u m a n quadriceps muscle, Clin. Sci. mrd. Med., 54:609 614. Brooke, M. H., J. E. Carrol, J. E. Davis and J. M. Hagberg (1979) The prolonged exercise test, Neurolo~,,y ( Minne~qJ. ), 29 : 636 643. Edwards, R. H. T. (1981) H u m a n muscle function and fatigue. In: Human Muscle Fatigue Phvsioloeical Mechanisms (Ciba Foundations Symposium No. 82), Pitman Medical, London, pp. 1 18. Edwards. R. H. T., A. Young, G. P. Hosking and D. A. Jones (1977) H u m a n skeletal muscle function Description of tests and normal values, Clin Sci. tool. Med., 52:283 29(I. Edwards, R. H. T., A. Young and C. M. Wiles (1980) Needle biopsy of skeletal muscle in the diagnosis of myopathy and the clinical study of muscle function and repair, N. Engl. J. Med., 302:261 271. Edwards, R. It.T., R.C. Harris and D.A. Jones (1981a) ] h e biochemis|ry o1 muscle biopsy m man Clinical applications. In: K . G . M . M . Alberti and C'.P, Price (Eds.), Recent ..tdvam~'~ m (Tinical Biochcmi~trl'. London. Ed,sards, R. tt. I . , K. R. Mills and D.J. Newham (I 981 b/ Greater low frequency fatigue produced by eccentric than concentric muscle contractions, J. Physiol. (Lond.), 317 : 17P. Edwards, R . H . T . , D.A. lsenberg, C. M. Wiles. A. Young and M . L . Snaith (1981c) The investigation of inflammatory myopathy, J. roy. Coll. Phys., 15:19 24.
ChurchillLivingstone,
88 Feinstein, A. R. (1977) ('linical Bmsmtlstics, C. V. Mosby Co., SI. Louis, MO. Gohil, K., D. A. Jones, R. H.T. Edwards (1981)Analysis of muscle mitochondrial l\mction with techniques applicable to needle biopsy samples, Clin. Physiol., 1 : 195 207. Griffiths. P.D. (1966) Serum levels of ATP and creatine phosphotransferase (creatine kinase) -. The normal range and effect of muscular activity, Clin. chim. Acta, 13: 413-420. Land, J. M. and J. B. Clark (1979) Mitochondrial myopathies, Biochem. Trans., 7:231 245. McArdle, B. (1951) Myopathy due to a defect in muscle glycogen breakdown, Clin. Sci., 10: 13-33. Mense, S. S. (1977a) Nervons outflow from skeletal muscle following chemical noxious stimuli, J. Physiol. (Lond.), 267 : 75-88. Mense, S.S. (1977b) Muscle nociceptors, J. Physiol. (Paris'), 73:233 240. Mills, K.R., D.J. Newham and R.H.T. Edwards (1982) Force, contraction frequency and energy metabolism as interactive determinants of ischaemic muscle pain, Pain, 14:149-154. Morgan-Hughes, J.A. (1979) Painful disorders of muscle, Brit. J. Hosp. Med., 22: 360-365. Morgan-Hughes, J.A. (1982) Defects of the energy pathways of skeletal muscle. In: W.B. Matthews and G.H. Glaser (Eds.) Recent Advances in Clinical Neurology, Churchill Livingstone, London, pp. 1 46. Newham, D.J., K. R. Mills, G. McPhail and R.H.T. Edwards (1982) Muscle damage in response to exercise, Europ. J. clin. Invest., 12 (2): 29 (Abstr. 171). Round, J.M., D.A. Jones and R.H.T. Edwards (1982) A flexible microprocessor system for the estimation of cell size, J. olin. Path., 35 : 620 624. Serratrice, G., J.L. Gastaut, A. Schiano, J. F. Pellisier and P. Carrelet (1980) A p r o p o s de 210 cas de myalgies diffuses, Sere. H6p. (Paris), 56: 1241-1244. Tarui, S., G. Okuno, Y. Ikura, T. Tanaka, M. Suda and M. Nishikawa (1965) Phosphofructokinase deficiency in skeletal muscle A new type of glycogenosis, Biochem. biophys. Res. Comm., 19: 517-523. Thomson, W. H. S., J.C. Sweetin and I.J.D. Hamilton (1975) ATP and muscle enzyme efflux alter physical exertion, Clin. chim. Acta, 59:241 245.
73
Elsevier Biomedical Press
INVESTIGATIVE STRATEGIES FOR MUSCLE PAIN
K.R. MILLS and R.H.T. EDWARDS
Department (~["Medicine. The Rayne Institute, Universit)' College London School ~[' Medicine, Universi O' Street, London WCIE 6JJ (Great Britain) (Received 8 July, 1982) (Accepted 13 July, 1982)
SUMMARY
Muscle pain is the presenting symptom in patients with a wide variety of conditions. Such patients often pose problems in diagnosis and management and a rational scheme for their investigation is needed. The results of muscle biopsy, electromyography, exercise and strength testing and blood measurements in 109 consecutive patients presenting with myalgia are reported. By determining the sensitivity and specificity of the tests in identifying patients with specific muscle abnormalities, a rational investigative protocol has been constructed. Creatine kinase and erythrocyte sedimentation rate are the most useful screening tests and if either is abnormal, muscle biopsy, electromyography, muscle strength and exercise testing are then performed. Despite exhaustive investigation, specific muscle abnormalities were found in only one-third of the patients; whilst many of the remaining patients undoubtedly had a psychogenic component to their pain, it is likely that a number of unidentified specific metabolic defects remain as causes of myalgia.
Key words: Muscle investigations
Muscle pain
INTRODUCTION
Pain in muscles, often related to exercise, is a common feature of a variety of conditions, and indeed, may be the presenting symptom in many. The diagnosis may be clear, such as in rheumatoid disease or severe depressive illness, but there This work was supported financially by The Wellcome Trust and The Muscular Dystrophy Group of Great Britain. Correspondence to Professor R. H. T. Edwards al above address. 0022-510X/82/0000-0000/$02.75 © 1982 Elsevier Biomedical Press
74 are a number of patients, in whom myalgia is a consistent and clearly genuine symptom, who pose a problem in diagnosis and management. The volume of secondary and tertiary referral of such patients to a specialised muscle clinic prompted this study of muscle pain as a presenting symptom, with the aim of providing a rational scheme for diagnosis and treatment. The finding by McArdle (1951) of a defect in glycolysis in a patient with muscle pain started a long and exciting search for enzyme defects in muscle. It is now recognised that phosphofructokinase deficiency can cause a similar syndrome (Tarui et al. 1965). With the development of biochemical techniques applicable to small tissue samples, such as needle muscle biopsies (Gohil et al. 1981; Edwards et al. 1980), the search for as yet undefined metabolic defects in muscle cells has intensified. At least 8 specific mitochondrial enzyme defects have now been described (Land and Clarke 1979: Morgan-Hughes 1982); many of these patients present with muscle pain related to exercise. Management of muscle pain can be difficult; often a specific diagnosis cannot be made and patients with chronic pain may be unresponsive to analgesics. Simple treatments such as mechanical vibration, the application of heat or cold, a trial of anti-depressants or the use of transcutaneous nerve stimulation may then be tried. Even when the diagnosis is clear, it is often by no means settled what the treatment should be. In polymyositis, for instance, steroid therapy, though conventional, is not without risk and may in fact be unnecessary (Edwards et al. 1980). Serratrice et al. (1978) have reviewed 210 cases of muscle pain and found two groups of about equal numbers; one group contained mainly cases of polymyositis and polymyalgia rheumatica, and the other group were classified as "functional myalgia," but no attempt was made to identify enzyme defects or metabolic causes of muscle pain within this group. An overview of painful myopathy has also been given by Morgan-Hughes (1979). This paper summarises the results of investigations of 109 patients with muscle pain and seeks to propose a rational strategy for investigating patients with muscle pain in future. PATIENTS A N D METHODS
A total of 109 consecutive patients, referred to a specialised Muscle Clinic on account of muscle pain were studied over a two-year period. A comprehensive history was taken from all patients and details such as pain type, onset, duration, location and relationship to exercise noted, and physical examination carried out. In all patients blood was taken for creatine kinase (CK) and erythrocyte sedimentation rate (ESR) and where indicated, other tests including plasma calcium, rheumatoid factor, anti-nuclear factor, thyroxine and fasting lipids.
Strength testing Because weakness is often associated with pain, quadriceps muscle strength was measured with a strain gauge method (Edwards et al. 1977). The patient sits
75 in a muscle testing chair with the pelvis stabilised by a lap strap. An inextensible loop around the ankle is connected to a strain gauge. Forces developed during maximal voluntary isometric contractions of the knee extensors are measured by amplifying the strain gauge signal and displaying it on an ultraviolet oscillograph. If weakness is present [defined as a maximum strength more than two standard deviations below the mean for a normal population of the same weight (Edwards et al. 1977)], then this was further analysed to determine whether the weakness was central or peripheral in origin. Force generation with the volition of the patient eliminated could be measured by applying two large pad electrodes to the anterior surface of the thigh and using stimuli up to 100 s ~. If more force could be generated by stimulated contractions than by voluntary efforts, then the weakness was classified as central, implying a defect proximal to the fine intramuscular nerves which were stimulated. Poor force generation in both situations would imply a peripheral lesion (Bigland-Ritchie et al. 1978: Edwards 1981).
Exercise testing Many patients related their symptoms to exercise, and, therefore, exercise testing was useful not only in defining maximum power output, but also in provoking symptoms which could then be analysed further. In other cases, exercise testing had a therapeutic role in that it could be used to reassure patients of their ability to exercise without provoking undue pain. A progressive exercise test was used in which work rate was increased by 25 W every 90 s from a starting value of 50 W. Patients were encouraged to produce their maximum output and to report any abnormal sensations. Heart rate and blood pressure were monitored before, during and for i0 min after the test. Blood for lactate determination was taken before and 5 min alter exercise.
t:Tectromyography Painful muscles were sampled with a concentric needle electrode (Disa, Type 13150). Motor unit duration, amplitude and phase count were noted as was the presence of spontaneous or insertion activity. In patients where pain was not present at rest, electromyography of the quadriceps muscle was performed.
Needle muscle biopsy Samples, usually of the quadriceps muscle, were obtained by the percutaneous needle muscle biopsy technique (Edwards et al. 1980). Samples were orientated by direct inspection under a dissecting microscope, frozen in liquid isopentane cooled in liquid nitrogen and cut on a cryostat for subsequent histochemical staining. A small piece was fixed in glutaraldehyde for electron microscopy. All samples were stained with haemotoxylin and eosin, a modified trichome stain, Miller's Van Giesen, NADH-tetrazolium reductase, ATPase (pH 9.4) and acid phosphatase, and additionally screened for adenylate deaminase activity. If indicated histochemical stains for myophosphorylase and phosphofructokinase were also used. The fibre type distribution and the mean fibre areas of type 1 and II
76 fibres were measured using a computer automated planimetric device (Round et al. 1982). In addition, 35 samples were subjected to tests of mitochondrial function (Gohil et al. 1981) in which components of the electron transport chain or the ability of mitochondria to take up and oxidise fatty acids were tested. Because of the possibility that the procedure of muscle biopsy itself may provoke different symptoms or signs in patients with different disease processes, a group of 50 consecutive patients with muscle pain were asked to complete a questionnaire about symptoms of pain or stiffness during or for one week alter the procedure. RESULTS Abnormalities consistent with a specific diagnosis were found in 37 of the 109 patients (Table 1). The wide variety of pathological conditions is evident. It should be pointed out that this cannot reflect the incidence of diseases presenting as muscle pain since the group were highly selected and were "difficult" cases. The large number of cases with enzyme defects probably reflects the interests of the department. Polymyositis and cervical spondylosis which are only sparsely represented are diseases in which the presentation and findings may m a k e diagnosis relatively simple and secondary referral unnecessary. TABLE 1 MUSCLE PAIN SERIES MUSCLE PAIN
DIAGNOSIS IN 109 PATIENTS PRESENTING WITH
16
(A) Enzyme de/ects
Mitochondrial myopathy Myophosphorylase deficiency Phosphofructokinase deficiency
8 6 2
(B) Inflammatory myopathy
Polymyositis Dermatomyositis Temporal arteritis Rheumatoid disease Polyarteritis nodosa
8
2 2 2 1 1
(C) Neurogenie disorders
Motor neurone disease Cervical spondylosis Spinal dysraphism Parkinson's disease Dissection of vertebral artery Stiff man syndrome
7
2 l l 1 l l
(D) Endocrine and metabolic disorders
Hypothyroidism Adult onset hypophosphataemic rickets Alcoholic myopathy (E; Miscellaneous (no tissue diagnosis)
6
3 1 2 72
77
Clinical Jeatures Most of the patients fell into the age group 31 50 years: males and females were about equally represented (Fig. 1). The features of interest in the patients" histories are summarised in Figs. 2, 3 and 4. Pain onset was classified as acute (single event or over hours or days), subacute (over days or weeks) or insidious (over months). It can be seen (Fig. 2) that most patients had an insidious onset to their problem especially those patients in whom no abnormalities were found. The duration of the s y m p t o m at the time of referral (Fig. 3) varied from 2 weeks to 53 years. Most patients had either had pain for 3 months to 1 year when first seen, or had had the pain for more than 10 years; this latter group contained many patients in whom no abnormality was found. The location of pain is summarised in Fig. 4. Pain in the legs was the commonest presenting complaint and in about half of these patients a specific tissue abnormality was found. Pain described as "'widespread" or "in arms and legs" provided only few cases with a specific abnormality; on the other hand, patients in whom pain was limited to the arms or
Males 0
Females
..
lO
f
I
r
3O A G 4O 5O
I [
I I
I
70
I
80
I I L [ I 14 12 10 8
I 6
I 4
2
0
2
I 4
t 6
I 8
I I I I 10 12 14 16
Number
Fig. I. Age distribution of 109 patients presenting with muscle pain.
Males
Onset
Females
[]
Acutet
No cause found Subacute
11
t
I
Insidious.J[
I 30
I 20
10
0
I 10
I I
I
I 20
[ 30
Number
Fig. 2. Mode of onset of pain in 109 patients presenting with muscle pain.
78 Males
Females
<3m 3m -1 1-2 2-3 c
.o
3-4
" 1= E
4-5
O
5-6
@
6-7
~
7-G
No cause found
8-9 9-10 >10
12 10
8
6
4
2
0
2
4
6
8
10 12 14 16
Number
Fig. 3. Duration of pain at the time of initial referral in 109 patients presenting with muscle pain,
Males
Females
Location Widespread Limbs Legs
Armsl Thighs
@
Calves Active muscle
20 18 16 14 12 10 8
No cause found
6
4
2 0 2 Number
4
6
8
10 12 14 16 18 20
Fig. 4. Location of pain in 109 patients presenting with muscle pain.
who had pain only when a single muscle or muscle group was exercised provided a high yield of muscle abnormalities. Patients most commonly described their pain as "aching;" only a few patients described cramp-like pains. In the group of patients in whom no specific abnormality was found, elaborate or histrionic descriptions of the pain such as "like many needles sticking into the muscle" were common, as were descriptions of pain relating solely to specified activities, e.g. "when I try to produce a vibrato on the trumpet". Also in this group of patients, the associated complaint of swelling of
79 the painful muscle was c o m m o n ; in no patient with a specific muscle abnormality was this ever documented. Most patients reported that exercise exacerbated or brought on the pain, and this feature was not found to be a useful predictor of specific muscle abnormality. Even when the patient said that exercise made no difference to the pain, or that pain was relieved by exercise was a specific abnormality more likely. Patients, even those in whom abnormalities were found, infrequently had physical signs, either in the musculature, or indeed, in any other system. This lack of physical signs, therefore, cannot be taken as an indicator that further investigation is not warranted. A number of patients (12) gave a clear history of pain following a viral infection~ most of these patients had no abnormality on investigation apart from reduced exercise tolerance. Two patients gave a history of muscle pain starting in the last trimester of pregnancy and persisting for months or years after this. Plasma creatine kinase (CK) All patients had creatine kinase measured on at least one occasion. 72% had values within the normal range (10-120 I.U./1); of these, specific muscle abnormalities were found in 34%, and no clear cause for the pain was found in 66'~0. A marginally raised C K (120 200 I.U./I) was found in 7 patients, in two of whom a diagnosis was reached. An unequivocal C K rise (200 500 l.U./1) was found in 9 patients in 6 of whom specific abnormality was found. High CK values ( >500 I.U./I) were seen in 10 patients all of whom had specific enzyme defects. Levels of CK up to 300 I.U./1 can easily occur in normal subjects after moderate exercise (Thompson et al. 1975; Brooke et al. 1979), and it is known that CK is higher in outpatients than in inpatients (Griffiths 1966). In situations where C K is marginally raised, it is prudent to ask about habitual level of exercise, and to repeat the C K after a period of rest or less vigorous activity. Other blood tests Erythrocyte sedimentation rate (ESR) was measured in 103 patients of whom 85 had results in the normal range (0 30 m m in 1st h). Of those with a normal ESR, 31 had some abnormality of muscle. An ESR between 30 and 50 m m in 1st h was found in 8 patients of whom 5 had a muscle abnormality. Ten patients had an ESR greater than 50 m m in 1st h of whom a clear diagnosis could be made in 9. This confirms the time honoured practice of using the ESR as a screening test for active disease. A number of other blood abnormalities were found in patients with muscle pain. Two patients had hypercalcaemia; in one the finding was transient, but in the other, a diagnosis of hyperparathyroidism was made but neck exploration for a parathyroid adenoma was negative. One woman with muscle pain also had sideroblastic anaemia and had been treated with considerable amounts of oral iron. A man presenting with pain in the calves also had secondary polycythaemia, and one man with pain in the legs on exercise was found to have hypertriglyceridaemia.
80 It is seen in Table 1 that three patients with hypothyroidism presented as muscle pain and it is worthwhile emphasising that a high level of suspicion should be maintained for this slowly progressive but treatable condition.
Exercise testing Progressive exercise tests were carried out in 54 patients. The test was classified as abnormal if one or more of the following criteria were satisfied : (i) Inability to exercise to the expected maximum work rate as indicated by age, sex, heart rate and physical fitness. (ii) Provocation of pain, cramp or contracture with submaximal exercise. (ii) Plasma lactate 5 min after the completion o f submaximal exercise of greater than 10 mmol/l. Abnormal tests were found in 26 patients; 10 of these were finally diagnosed. Three patients with mitochondrial myopathy had raised resting plasma lactate levels ( > 1.0 mmol/1) with levels after exercise rising to 15 mmol/1 or more. Four patients had abnormal tests because of the provocation of symptoms : 1 had mitochondrial myopathy, 2 had McArdle's disease and 1 phosphofructokinase deficiency. Of the 16 patients with no final diagnosis, 13 were classified as abnormal because of failure to achieve the predicted work rate, and 3 stopped exercise because of pain in the thighs.
Muscle strength Quadriceps maximal strength was measured in 102 patients; of these 46 had normal strength as defined above. A specific muscle abnormality was found in 18 of these patients but in 28 no firm diagnosis was reached. The remaining 56 patients had weakness of the quadriceps. These were further investigated to determine whether the weakness was of central or peripheral origin (Edwards et al. 1977, Bigland-Ritchie et al. 1978). In 34 patients, electrical stimulation of the muscle was not able to produce more force than with a maximal voluntary contraction and thus they were considered to have peripheral weakness: 22 of these patients had specific muscle abnormalities but in 12 a firm diagnosis could not be made. The remaining 20 patients had central weakness, i.e. electrical stimulation of the muscle produced a greater force than that generated by maximal volition. Of these 20, only 3 had a specific muscle abnormality.
Electromyography Conventional concentric needle electromyography was carried out in the painful muscles of 75 patients. Abnormalities were found in 28 patients: the most common abnormality was an excess of polyphasic motor unit potentials, although in several cases a frankly myopathic picture was seen. In the patients with motor neurone disease, evidence of denervation was obtained. Electromyographic abnormalities were found in 8 patients with no firm diagnosis. In the 47 patients with no abnormality on electromyography, 14 had a final specific diagnosis and 33 did not.
81
Needle muscle biopsy Of the 103 patients having muscle biopsy, abnormalities of histology or histochemistry were found in 49; 34 of these had a firm tissue diagnosis, but in 15 only non-specific changes were found. Normal muscle structure was found in 54 patients of whom eight had a final diagnosis and 46 did not. In addition, samples from 34 patients were screened for possible defects in the mitochondrial cytochrome system, or in fatty acid uptake or utilisation by mitochondria (Fig. 5). This allowed more precise diagnosis in the 4 cases of mitochondrial myopathy and identification of a further 4 patients who demonstrated abnormality in fatty acid uptake or utilisation by mitochondria (Table 2). A number of patients in whom no final diagnosis was made had low levels of all enzymes measured, although the ratios of enzyme activities were normal. This may reflect the fibre type distribution in these patients or the relatively poor state of training of the muscle. Estimations of proportions of Type I and II fibres and of mean fibre areas were made on 56 biopsies. The results are seen in Fig. 6. For type I fibre areas, all but 2 females with specific muscle abnormalities, and 4 males and 2 females with no specific abnormality fell within 2 standard deviations of the normal mean fibre area. The values for men, however, tended to be grouped in the lower part of the distribution. In contrast, the mean fibre area of type I1 fibres in patients with no specific diagnosis were below 2 standard deviations from the normal mean in 9 cases, whereas those of patients with a firm diagnosis were within the normal range. The results of patients' replies to the questionnaire concerning the pain of biopsy and its sequelae are seen in Fig. 7. The finding of specific abnormalities in the histology of histochemistry of the muscle appeared to bear no relation to the duration or severity of any pain, discomfort or stiffness of the muscle in the 7 days following biopsy. DISCUSSION
The variety of conditions which can present as painful muscles is seen in Table 1, but more important is to be noted the large number of cases in which no firm diagnosis could be made despite exhaustive investigation. Many of these undoubtedly had depressive states of which myalgia was the most prominent symptom, but it is seen in Table 2 that a significant number had abnormalities of muscle structure or function which may represent a covert disease process. In particular a small group of 5 patients can be discerned with myalgia, abnormal muscle biopsy and raised creatine kinase; they were young (age range 15 32) and 4 of the 5 were female. It may be that these patients have muscles which are unusually sensitive to damage, or have an undiscovered enzyme defect. On the other hand, it should be pointed out that the biopsy changes are on the whole non-specific and the raised creatine kinase may merely be a reflection of unaccustomed exercise in the days before the test.
82 ,~YRUVATE
PALMITYL CARNIIINE (PC)
/
I
~'~
I I
PYRUVATE
I
II
IIIIHI
PALCoA
L OXALOACETATE
I
CARNITINE
ACEIYL CoA 4
i
t 1
/ CITRATE
FADIi
ADDED CYI.C
Components of the various enzyme activities measured Enzyme activity
Components
Pyruvate + malate cytochrome c_ reductase (P + M) CR
Palmitoylcarnitine + malate cytochrome c_ reductase
Pyruvate dehydrogenase complex, malate dehydrogenase (MDH), citrate synthase (CS), complexes I and III.
Carnitine palmitoyl transferase(ll) B-oxidation pathway, MDH, CS, iPC + M) CR and complexes I and III.
Succinate cytochrome c reductase
SCR
Succinate dehydrogenase, complexesI I and I II.
Cytochrome c oxidase
CoX
Complex IV
Fig. 5. Study of mitochondrial function in needle biopsy samples. Above is shown a schematic figure of the pathways involved in translocation and metabolism of substrates in mitochondria engaged in oxidative phosphorylation. These functions are studied in detail by observing the state of oxidation or reduction of added eytochrome-c when combinations of substrates are added to homogenates of the needle biopsy sample. The enzyme pathways studied by this means are listed below. (For more detail see Gohil et al. 1981.)
7.16
4.3
2.82
N.D.
105.0
6.26
0.96
6.8
1
2
3
4
5
6
7
8
5.44
2.85
31.18
16.4
N.D.
0.77
1.32
1.8
1.25 4.7
Succinate cytochrome-c reductase
0.57
1.{)2
6.39
<0.05
N.D.
0.28
0.11
0.31
0.5 2.2
Pyruvate + malate cytochrome-c reductase
N.D. = not determined. ~' Data based on samples from 9 untrained normal controls.
6 25
Normal
Cytochrome c-oxidase
0.19
0.56
4.52
N.D.
0.63
Absent
2.06
<0.02
0.2 1.5
Palmityl carnitine + malate cytochrome-c reductase
N.D.
N.D.
N.D.
N.D.
Absent
N.D.
0.028
0.067
0.04 0.14
Myalgia and weakness related to exercise. Electron transport chain defect
Myalgia related to exercise. Cytochrome oxidase deficiency
Myalgia related to exercise. Abnormal EEG. Defect in Complex IV of electron transport chain
Myalgia related to exercise. Electron transport chain defect
Myoglobinuria related to exercise. Carnitine pahnityltransferase deficiency
Myalgia related to cxcrcise. Possible defect in palmityl carnitine oxidation
Myoglobinuria following viral infection. Possible defect in palmityl carnitine oxidation
Paroxysmal myoglobinuria and muscle pain unrelated to exercise. Possible defect in carnitine oxidation
Comments
MYOPATHY
Carnitine palmityl transferase
M I T O C H O N D R I A L ENZYME STUI)IES IN 8 P A T I E N T S WITH M I T O C H O N D R I A L Enz}mc activities are expressed as ,umol . g 1 .mm I at 37 ':C.
IABI.I 2
Specific abnormality found on biopsy
Mean fibre area ~m z x 10-3 9
Type I
U
No specific abnormality found on biopsy Type II
F
Type
M
Type II
M
,
M
!9 J
8
1s
7
~z J W
6 5
•
t°
01 I
•1
4
!
01
3
:1 •
I
III
N
2
,l
•
•
I
1
Fig. 6. Mean fibre area (/lm 2 x 10-3) of type I and II fibres in patients with muscle pain. The norma range is indicated as mean + SD.
Severity of pain in 7 days after biopsy Number ~
2O
Abnormality on biopsy Muscle normal on biopsy
15-
]0-
"....... [Ill]Ill ,,,...,
5 -
!!if!i!!
o [1I Nil
Mild
Mod
Sev
Duration of pain after biopsy 15 ' " ' - " "
0
<24h
24"-48h
>48h
Fig. 7. Severity and duration of pain after muscle biopsy reported by 50 consecutive patients.
85 Pain may arise in muscle by a number of mechanisms, but ultimately all mechanisms must function by activating pain receptors in the muscle or in its attachments. The evidence for such receptors in man is scanty, although nociceptors in cat muscle responsive to tension, lactate, potassium ions, bradykinin, histamine and serotonin have been described (Mense 1977a,b). It is likely that the pain of inflammatory muscle disease is mediated by stimulation of such nociceptors by the kinins, etc., released from inflammatory cells. The pain of ischaemic muscle or muscle deprived of energy substrates may be related to the accumulation of lactate, potassium or phosphate in muscle, although lactate is clearly not responsible in myophosphorylase deficiency. Many patients report that pain is exacerbated if the muscle is made to contract; the role of tension in the production of muscle pain may be related to the presence of mechanonociceptors in muscle and central interaction between these afferents and other fibres signalling the metabolic state of the muscle may account for the symptom described (Mills et al. 1982). Pain due to unaccustomed exercise is a familiar phenomenon and a mechanism akin to this may have been responsible for the pain in some of the cases described here. It is known that such pain is mainly associated with eccentric muscle contraction (contraction with simultaneous lengthening of the muscle) (Asmussen 1956: Abraham 1977). Repeated eccentric contractions in normal subjects leads to fatigue (Edwards et al. 1981a), a rise in creatine kinase (Newham et al. 1982) and damage to Z-lines and disruption of sarcomeres on electron microscopy (Newham et al. 1982). It is possible that some of the patients in the series may have been at one end of a normal spectrum of response to eccentric contraction. The practical value of the investigations used in this study in identifying cases with a pathological or metabolic defect is summarised in Table 3. The sensitivity of an investigation represents its ability to detect abnormalities in all cases where a firm final diagnosis could be made. The specificity of an investigation represents its ability to report a negative result in all cases where no specific diagnosis was reached (Feinstein 1977). It is not intended that these parameters should indicate the true discriminability of investigations; they are merely used to compare the usefulness of tests in the diagnosis of myalgia in this study. Muscle biopsy was the most sensitive indicator of organic disease and also had a high specificity. The least sensitive test was the ESR yet it was the most specific (see Table 3). Since a large proportion of the total number of patients had no specific muscle abnormality (Table 1), investigations with a high specificity should be used as screening tests in the first place since these will tend to pick out the patients in whom no tissue diagnosis will be made. If these initial tests a r e abnormal, then the most sensitive tests should then be chosen. A scheme for the investigation of myalgia based on the specificity and the sensitivity of tests in this study is presented in Fig. 8. In practical terms, ESR and CK estimations are made at the time of initial referral. If either investigation is abnormal, then muscle biopsy, electromyography, muscle strength and exercise testing are then performed. If the initial investigations are normal, then the discovery of a specific muscle abnormality is
103 105 I01 103 75 54
Muscle biopsy Creatine kinase Muscle strength ESR Electromyograpby Exercise test
49 26 54 18 28 26
Number which were abnormal
__L
34 18 23 14 20 l0 __
15 8 31 4 8 16
8 27 18 31 14 9
Firm (c) diagnosis
Firm (a) diagnosis
No (b) diagnosis
Normal results
A b n o r m a l results
* Sensitivity calculated by a/(a + c). Specificity calculated by d/(b + d). IFeinstein 1977).
Total number
Investigation
SENSITIVITY A N D SPECIFICITY O F I N V E S T I G A T I O N S IN M Y A L G I A
TABLE 3
46 52 29 54 33 19
No (d) diagnosis 0.81 0.59 0.56 0.31 0.59 0.53
Sensitivity*
0.75 0.81 0.48 0.93 0.81 0.54
Specificity*
O Q
87
Either investigation abnormal
]es
CK
J Specific muscle abnormality less likely
Review J" h
No[I
Specificabnormality still suspected
Muscle biopsy EMG Muscle strength Exercise Test
I Yes
Fig. 8. Scheme for investigation of myalgia.
less likely, but if some abnormality is still suspected, then muscle biopsy and electromyography are likely to be the most productive investigations. Muscle pain is the most prominent feature in the symptomatology of a wide variety of conditions: a rational scheme for the investigation of these patients is needed, and our experience in the management of 109 consecutive cases has allowed us to evolve such a scheme. The number of patients for whom no definite cause is found remains high and although a number may present with myalgia as part of a psychiatric problem, the consistency and credibility of many patient's complaints make it likely that a number of specific metabolic muscle disorders remain to be identified. REFERENCES Abraham, W. M. (1977) Factors in delayed muscle soreness, Medicine & Science in Sports, 9 : 1 1 26. A smussen, E. (1956) Observations on experimental muscle soreness, Acta rheum, seam/., 2 : 1 0 9 116. Bigland-Ritchie, B., D . A . Jones, G.P. Hosking and R . H . T . Edwards (1978) Central and peripheral fatigue ill sustained m a x i m u m voluntary contractions of h u m a n quadriceps muscle, Clin. Sci. mrd. Med., 54:609 614. Brooke, M. H., J. E. Carrol, J. E. Davis and J. M. Hagberg (1979) The prolonged exercise test, Neurolo~,,y ( Minne~qJ. ), 29 : 636 643. Edwards, R. H. T. (1981) H u m a n muscle function and fatigue. In: Human Muscle Fatigue Phvsioloeical Mechanisms (Ciba Foundations Symposium No. 82), Pitman Medical, London, pp. 1 18. Edwards. R. H. T., A. Young, G. P. Hosking and D. A. Jones (1977) H u m a n skeletal muscle function Description of tests and normal values, Clin Sci. tool. Med., 52:283 29(I. Edwards, R. H. T., A. Young and C. M. Wiles (1980) Needle biopsy of skeletal muscle in the diagnosis of myopathy and the clinical study of muscle function and repair, N. Engl. J. Med., 302:261 271. Edwards, R. It.T., R.C. Harris and D.A. Jones (1981a) ] h e biochemis|ry o1 muscle biopsy m man Clinical applications. In: K . G . M . M . Alberti and C'.P, Price (Eds.), Recent ..tdvam~'~ m (Tinical Biochcmi~trl'. London. Ed,sards, R. tt. I . , K. R. Mills and D.J. Newham (I 981 b/ Greater low frequency fatigue produced by eccentric than concentric muscle contractions, J. Physiol. (Lond.), 317 : 17P. Edwards, R . H . T . , D.A. lsenberg, C. M. Wiles. A. Young and M . L . Snaith (1981c) The investigation of inflammatory myopathy, J. roy. Coll. Phys., 15:19 24.
ChurchillLivingstone,
88 Feinstein, A. R. (1977) ('linical Bmsmtlstics, C. V. Mosby Co., SI. Louis, MO. Gohil, K., D. A. Jones, R. H.T. Edwards (1981)Analysis of muscle mitochondrial l\mction with techniques applicable to needle biopsy samples, Clin. Physiol., 1 : 195 207. Griffiths. P.D. (1966) Serum levels of ATP and creatine phosphotransferase (creatine kinase) -. The normal range and effect of muscular activity, Clin. chim. Acta, 13: 413-420. Land, J. M. and J. B. Clark (1979) Mitochondrial myopathies, Biochem. Trans., 7:231 245. McArdle, B. (1951) Myopathy due to a defect in muscle glycogen breakdown, Clin. Sci., 10: 13-33. Mense, S. S. (1977a) Nervons outflow from skeletal muscle following chemical noxious stimuli, J. Physiol. (Lond.), 267 : 75-88. Mense, S.S. (1977b) Muscle nociceptors, J. Physiol. (Paris'), 73:233 240. Mills, K.R., D.J. Newham and R.H.T. Edwards (1982) Force, contraction frequency and energy metabolism as interactive determinants of ischaemic muscle pain, Pain, 14:149-154. Morgan-Hughes, J.A. (1979) Painful disorders of muscle, Brit. J. Hosp. Med., 22: 360-365. Morgan-Hughes, J.A. (1982) Defects of the energy pathways of skeletal muscle. In: W.B. Matthews and G.H. Glaser (Eds.) Recent Advances in Clinical Neurology, Churchill Livingstone, London, pp. 1 46. Newham, D.J., K. R. Mills, G. McPhail and R.H.T. Edwards (1982) Muscle damage in response to exercise, Europ. J. clin. Invest., 12 (2): 29 (Abstr. 171). Round, J.M., D.A. Jones and R.H.T. Edwards (1982) A flexible microprocessor system for the estimation of cell size, J. olin. Path., 35 : 620 624. Serratrice, G., J.L. Gastaut, A. Schiano, J. F. Pellisier and P. Carrelet (1980) A p r o p o s de 210 cas de myalgies diffuses, Sere. H6p. (Paris), 56: 1241-1244. Tarui, S., G. Okuno, Y. Ikura, T. Tanaka, M. Suda and M. Nishikawa (1965) Phosphofructokinase deficiency in skeletal muscle A new type of glycogenosis, Biochem. biophys. Res. Comm., 19: 517-523. Thomson, W. H. S., J.C. Sweetin and I.J.D. Hamilton (1975) ATP and muscle enzyme efflux alter physical exertion, Clin. chim. Acta, 59:241 245.