Macro-EMG in mitochondriopathy

Clinical Neurophysiology 110 (1999) 1466±1470

Macro-EMG in mitochondriopathy Josef Finsterer a,*, Anders Fuglsang-Frederiksen b a

b

Ludwig Boltzmann Institute for Epilepsy and Neuromuscular Disorders, Vienna, Austria Department of Clinical Neurophysiology, Gentofte Hospital/University of Copenhagen, Copenhagen, Denmark Accepted 16 March 1999

Abstract Objectives: In a previous macro-EMG study on patients with mitochondriopathy, macro-MUAP amplitude has been shown to be the electromyographic parameter most often abnormal. We wanted to investigate the role of the macro-MUAP area and if macro-EMG is more helpful than conventional needle-EMG in detecting involvement of the skeletal muscle in patients with mitochondriopathy. Methods: From the right brachial biceps muscles of 38 healthy subjects and 20 patients with primary mitochondriopathy, aged 23±72 y, conventional needle EMGs and macro-EMGs were recorded one after the other. Results: Macro-MUAP amplitude and macro-MUAP area were not signi®cantly different between patients and controls. The sensitivity of the macro-EMG was 35%, that of conventional needle EMG 40%. Both methods supplemented each other. Conclusions: The sensitivity of the macro-EMG to detect involvement of the skeletal muscle in patients with mitochondriopathy is similar to that of conventional needle EMG. Macro-MUAP area was not more helpful than macro-MUAP amplitude in this respect. q 1999 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Electromyography; Concentric needle EMG; Macro-EMG; Mitochondriopathy; Fibre density; Diagnosis

1. Introduction

2. Materials and methods

Primary mitochondriopathies are a heterogeneous group of disorders which are due to mutations in the mitochondrial and/or nuclear DNA or due to an impaired transport of proteins between nucleus and mitochondrion (MorganHughes, 1994; Schapira and DiMauro, 1994; Finsterer, 1997; Servidei, 1998). In the majority of these patients the skeletal muscle is involved (primary mitochondrial myopathies (PMMP)). Skeletal muscle involvement is often mild and hardly detectable with conventional needle-EMG (Hirano et al., 1994) or single-®bre EMG (Torbergsen et al., 1991; Bertorini et al., 1994; Ukachoke et al., 1994). In the only macro-EMG study on patients with PMMP so far, macro-MUAP amplitude has been shown to be the electromyographic parameter most often abnormal (Torbergsen et al., 1991). The following study was carried out, (1) to evaluate if macro-EMG or conventional EMG is more sensitive to detect involvement of the skeletal muscle in patients with mitochondriopathy, and (2) to investigate if macro-MUAP area is more helpful than macro-MUAP amplitude in this respect.

Included were all patients who consecutively attended the 2nd Department of the Neurological Hospital RosenhuÈgel, Vienna, between February and August 1998 and who were previously or newly diagnosed as having PMMP. The diagnosis of PMMP was based on clinical features (involvement of the PNS (weakness, wasting, fatigability, muscle cramps, soreness, reduced deep tendon re¯exes, myokymia, tenderness), CNS, eyes, ears, heart, intestines, liver, kidney, endocrinium) and morphological clues like ragged red ®bres, subsarcolemmal accumulation of mitochondria, reduced oxidative enzyme staining, abnormally shaped mitochondria and mitochondrial cristae, paracristalline inclusions and sarcoplasmic glycogen and lipid storage (Table 2). Additionally, most of the included patients underwent lactate stress testing, electroneurography and electromyographic investigations (from muscles other than the brachial biceps) (Table 2). In 3 patients (patients 6, 9 and 14) the diagnosis was con®rmed by mtDNA analysis. Students, staff members and patients without any PNS disorder served as healthy controls. Informed consent was provided by all subjects and the investigation complied with all policies established by the local institutional review board for human experimentation. The muscle under investigation was the right brachial

* Corresponding author. Postfach 348, 1180 Vienna, Austria. Tel.: 1 43-1-88000-260; fax: 1 43-1-4781711. E-mail address: ®[email protected] (J. Finsterer)

1388-2457/99/$ - see front matter q 1999 Elsevier Science Ireland Ltd. All rights reserved. PII: S13 88-2457(99)0008 5-1

CLINPH 98764

J. Finsterer, A. Fuglsang-Frederiksen / Clinical Neurophysiology 110 (1999) 1466±1470

1467

Table 2 Patients' characteristics and concentric needle EMG and macro-EMG ®ndings a Pat

Sex

Age (years)

DD (months)

Cp

Eng

Lst

Histo

Mt

Md

Ma

Ppr

Mam

Mar

Fd

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20

M M M F M M F F F M F F F M M F F F M M

50 51 71 49 50 34 46 70 23 47 72 49 44 31 43 43 70 62 51 59

24 180 120 120 72 264 36 12 100 16 360 132 120 300 444 156 144 18 552 432

Mp Ms Mp, Dm, Epi Mp Mp, Unp Ms Mp,Unp Mp Kss Mp, Cmp Mp, Cpeo Mp Mp Ms Melas Ep, Cmp Mp, Cmp, Dm Mp Ms Melas

No * * No * * Nd * * No No No No * No No * No No Nd

* * * No * * * No * * No No * * * * * No * No

4,6,7 1,3,6,7 2,3,4,5,7 2,3,4,6,7 2,4,5,7 1,2,3,4,5,7 1,2,6,7 1,2,4,5,7 3,4,6,7 1,2,4,6,7 2,6,7 2,3,4,6,7 2,4,6,7 2,4,6,7 1,2,6,7 1,4,5,7 2,3,4,6 2,4,5,7 1,4,5,7 4,5,7

14.1 12.9 14.1 14.4 10.4 13.3 17.8 10.6 8.2 19.3 13.4 9.7 8.4 8.6 14.7 13.8 6.6 9.1 15.8 17.0

14.9 10.2* 17.6 9.7* 9.9* 14.2 10.1* 15.8 12.7 14.6 12.7 12.8 10.4* 13.0 13.0 14.0 15.6 15.8 13.4 15.6

215 156 320 Nd 166 244 147 274 96* 281 195 148 208 167 249 289 376* 224 254 221

10 5 15 5 5 0 5 5 20 5 0 0 5 0 5 25* 35* 15 0 5

226* 43 80 95 95 116 67 93 55 144 105 81 92 51 108 51 190 136 104 153

305 122* 183 275 229 427 153 381 137 458 458 214 214 107* 381 92* 427 458 270 519

1.2 1.6* 1.2 1.3 1.1 1.3 1.4 1.3 1.5 1.7* 1.0 1.3 1.5 1.3 1.2 1.5 1.2 1.0 1.7* 1.6*

a

Pat, patient; DD, disease duration; Cp, clinical presentation (Mp, myopathy; Ms, multi-system involvement (including myopathy); Dm, diabetes mellitus; Epi, epilepsy; Unp, unspeci®c neuropathy; Kss, Kearns±Sayre syndrome; Cmp, cardiomyopathy; Cpeo, chronic progressive external ophthalmoplegia; Melas, mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes; Ep, encephalopathy); Eng, electroneurography (no, normal; *abnormal; Nd, not done); Lst, lactate stress testing (no, normal, *abnormal), Histo, muscle biopsy (1: ragged red ®bres, 2: clustering of mitochondria, 3: paracrystalline and other intramitochondrial inclusions, 4: abnormally structured mitochondria on electron microscopy, 5: generally reduced oxidative enzyme activity, 6: partially reduced oxidative enzyme activity, 7: sarcoplasmic lipid or glycogen droplets); Mt, maximal elbow ¯exion; Md, MUAP-duration; Ma, MUAP-amplitude; Ppr, rate of polyphasia; Mam, macro-MUAP amplitude; Mar, macro-MUAP area; Fd, ®bre density; *abnormal.

biceps muscle. Before the EMGs, the maximal elbow ¯exion was measured with a hand-held strain-gauge dynamometer in a supine position. Conventional (concentric) needle-EMG and macro-EMG were applied one after the other. During each EMG, 20 different MUAPs and 20 different macroMUAPs were recorded via standard concentric and standard macro-needle electrodes respectively. Between 2 sites the needles were withdrawn for at least 5 mm. The EMG-recorder was a commercially available Counterpoint (Dantec, Skovlunde, Denmark). To record MUAPs the sensitivity was set at 100 mV/division, the ®lters between 10 Hz and 20 kHz and the sweep speed at 8 ms/ division. Macro-EMG recordings were made via 2 channels. Channel 1 recorded the potential difference between the recording surface of the wire inside the canula and the shaft of the standard macro-electrode. Channel 2 recorded the potential difference between the shaft and the remote, subcutaneous needle electrode. For channel 1 (2) the input sensitivity was set at 200 (200) mV/division, the ®lters between 500 (5) Hz and 20 (10) kHz, the time window at 20 (80) ms and the delay at 10 (40) ms. Macro-MUAPs were recorded as previously described and were averaged 200 times. (Stalberg, 1980; Stalberg and Fawcett, 1982). Macro-MUAP duration was determined manually between the potential's initial deviation from base line and the ultimate return to base line. Macro-MUAP amplitude and macro-MUAP area were then determined automatically.

Macro-MUAP area was de®ned as sum of areas under all phases of a macro-MUAP. Individual macro-MUAP amplitude and area were expressed as median of 20 values, since their distribution within a subject is not normal. Data distribution was established with the Kolmogorov± Smirnov test. Differences between group means were calculated with Student's t-test for independent samples (normal distribution) and with the Man±Whitney U test (non-normal distribution). Correlations between any of the variables were expressed as Pearson's correlation coef®cients. Individual values were compared to control values using group mean (^2SD). An individual result of the conventional EMG was interpreted as myopathic (neuropathic) if the MUAP-duration and/or the MUAP-amplitude were decreased (increased) below (above) its mean-2SD (mean 1 2SD). An individual result of the macro-EMG was interpreted as myopathic (neuropathic) if the macro-MUAP amplitude and/or the macro-MUAP area were decreased (increased) below (above) its mean-2SD (mean 1 2SD). Conventional EMG (macro-EMG) was unspeci®cally abnormal if the rate of polyphasia (®bre density) was increased exclusively. 3. Results The control group comprised 38 healthy subjects (21 women, 17 men). Mean (SD) age, maximal muscle torque,

1468

J. Finsterer, A. Fuglsang-Frederiksen / Clinical Neurophysiology 110 (1999) 1466±1470

Table 1 Mean (SD) age, muscle force and EMG variables in 38 controls and 20 patients with primary mitochondrial myopathy Variable

Controls

Patients

P-value

Number Age (years) Disease duration (months) Maximal torque (Nm) MUAP-duration (ms) MUAP-amplitude (mV) Rate of polyphasia (%) a Macro-MUAP amplitude (mV) Macro-MUAP area (ms*mV) Fibre density a

38 47 (19.2) Na 16.5 (5.0) 14.3 (1.8) 215.7 (55.4) 0±20 110.8 (42.0) 328.5 (103.0) 1.0±1.5

20 50.8 (13.5) 167.6 12.6 (3.5) 13.3 (2.3) 222.6 (68.6) 0±35 104.3 (47.1) 290.0 (137.2) 1.0±1.7

Na 0.440 Na 0.003 0.080 0.681 0.101 0.591 0.233 0.051

a

Missing normal distribution: P-values of the Man±Whitney U test are given; Na, not applicable.

MUAP-duration, MUAP-amplitude, macro-MUAP amplitude, macro-MUAP area and ®bre density are given in Table 1, (also see Fig. 1). Maximal muscle torque was signi®cantly (P ˆ 0:0001) lower in women than in men. MUAP-duration, MUAP-amplitude and ®bre density increased signi®cantly with age (r ˆ 0:406, r ˆ 0:393, r ˆ 0:407). None of the electromyographic variables was signi®cantly different between the genders. None of the electromyographic variables was dependent on the maximal muscle torque. The patient group comprised 20 individuals (10 women, 10 men). Two patients had classical MELAS-syndrome and one patient Kearns±Sayre syndrome. All other patients had myopathy exclusively or multisystem involvement including the skeletal muscle (Table 2). In patient No. 16 skeletal muscle involvement comprised soreness, muscle cramps and fatigability. Mean (SD) age, disease duration, maximal muscle torque, MUAP-duration, MUAP-amplitude, macroMUAP amplitude, macro-MUAP area and ®bre density are given in Table 1 (also see Fig. 1). Maximal muscle torque was signi®cantly (P ˆ 0:003) decreased compared to controls (Table 1). None of the electromyographic variables

Fig. 1. Macro-MUAP amplitude (MAM) and macro-MUAP area (MAR) in 38 healthy controls and 20 patients with primary mitochondrial myopathy. Additionally, mean (^2SD) values are indicated.

was dependent on the maximal muscle torque. Conventional EMG was myopathic in 6, neuropathic in one and unspeci®cally abnormal in one patient(s). Macro-EMG was myopathic in 3, neuropathic in one and unspeci®cally abnormal in 3 patient(s). The sensitivity to detect skeletal muscle involvement in patients with mitochondriopathy was 40% (conventional EMG) and 35% (macro-EMG) respectively. Combining the results of both methods, muscle abnormalities could be detected in 65% of the patients (Table 2). 4. Discussion This study has shown, that the sensitivity of macro-EMG to detect skeletal muscle involvement in patients with PMMP was low and similar to that of conventional needle EMG. Macro-MUAP area was not more helpful than macroMUAP amplitude in this respect. The contributions of electromyographic investigations to the diagnosis of PMMP are controversially discussed. In the few investigations with conventional needle EMG that have been carried out so far, the sensitivity to detect a myopathic pattern in patients with PMMP ranged from 15 to 100% (Table 3). Except for Torbergsen's study, myopathic changes were the major abnormality. Mixed or unspeci®c alterations on conventional EMG were found in up to half of the cases. Rarely, conventional EMG was neurogenic (Table 3). The low sensitivity of conventional EMG in our study compared to these studies can be explained as follows: (1) possibly the skeletal muscle was so mildly affected that no electromyographic alterations could be seen, (2) since only one muscle was studied, the affection of muscles other than the brachial biceps could have been easily overlooked, (3) the fairly large control group may predispose for wider reference limits, giving rise to false negative results, and (4) the morphological changes are often not associated with early and conspicuous electrophysiological abnormalities. Furthermore, electromyographic investigations in mitochondriopathy can be misleading if they show a neuropathic, mixed or unspeci®c pattern. Such patterns occur

J. Finsterer, A. Fuglsang-Frederiksen / Clinical Neurophysiology 110 (1999) 1466±1470

1469

Table 3 Results of previous conventional EMG studies in patients with mitochondriopathy a Study

No.

Muscle(s)

A

B

C

D

Kamieniecka, 1977 Fawcett et al., 1982 Torbergsen et al., 1991 Emeryk et al., 1992 Arpa et al., 1994 Bertorini et al., 1994 Hirano et al., 1994 Melberg et al., 1996 Lindner et al., 1997

17 5 13 9 15 7 8 11 19

Na Bb, Qf Bb, Ta Bb, Qf, Ta, 1Di Na Bb, Vl Na Oo, Fr, Tb, De, Bb, 1Di, Qf, Ta Na

16 5 2 7 5 6 2 6 14

Na 0 0 1 2 Na Na 0 0

Na 0 7 0 4 Na Na 3 3

Na 0 4 1 4 Na Na 2 2

a No., number of patients; A, myopathic; B, neuropathic; C, mixed (neuropathic and myopathic) or unspeci®c; D, normal; Bb, biceps brachii; Qf, quadriceps femoris; Ta, anterior tibial, 1Di, ®rst dorsal interosseus; Vl, vastus lateralis; Oo, orbicularis oculi; Fr, frontalis; Tb, triceps brachii; De, deltoid; Na, not available.

fairly frequently (Table 3) and may be due to diabetes or renal insuf®ciency, often associated with PMMP, or due to the primary affection of peripheral nerves. Even in the absence of any electromyographic changes, mitochondriopathy can not be excluded, particularly if tissues other than the muscle are preferentially or exclusively affected (Morgan-Hughes, 1994; Finsterer, 1997). Macro-EMG has been rarely applied to patients with mitochondriopathy so far (Torbergsen et al., 1991). In Torbergsen's study, the brachial biceps and the anterior tibial muscles were investigated in a series of 12 patients. Macro-MUAP amplitude was increased in 7, decreased in one and normal in 4 patients. For the most intriguing ®nding, the combination of an increased macro-MUAP amplitude with a normal ®bre density, the following explanations were proposed: (1) early sign of neuropathy, (2) early recruitment of high threshold motor units, (3) artefact, (4) abnormal volume conduction, (5) increased ®bre size, (6) prolonged membrane depolarisation (Torbergsen et al., 1991). Contrary to Torbergsen's results, we found the constellation of a normal ®bre density with an increased macro-MUAP amplitude in only one patient (patient 1). In this patient there was neither a clinical nor electroneurographic indication for neuropathy, why the high macroMUAP amplitude was interpreted due to ®bre hypertrophy and an increased number of muscle ®bres in a motor unit due to ®bre splitting and ®bre regeneration, also occurring in the early stages of myopathy (Nandedkar and Stalberg, 1983). Our normal values for the macro-MUAP amplitude were in agreement with previous reports (Stalberg, 1980). Normal values for the macro-MUAP area were lower in our study than previously reported, probably due to the number of investigated subjects and the selection bias (Roeleveld et al., 1997). The variable most often increased in our patients was the ®bre density. This ®nding is supported by previous reports on single-®bre EMG studies in patients with mitochondriopathy, which showed increased ®bre density in 43±100% of the cases (Fawcett et al., 1982; Torbergsen et al., 1991; Bertorini et al., 1994; Ukachoke et al., 1994). In our

patients the increased ®bre density was associated with normal macro-MUAP amplitude in 3 patients and with decreased macro-MUAP area in one patient. Both ®ndings are compatible with myopathy (Torbergsen et al., 1991). Increased ®bre density indicates regeneration (collateral sprouting) with ®bre-type grouping, muscle atrophy and ®bre splitting (Stalberg and Trontelj, 1994). Normal macro-MUAP amplitude and area may indicate a balance between degeneration and regeneration phenomena (Torbergsen et al., 1991). Macro-MUAP area was decreased in 3 of our patients. One of them showed also decreased mean MUAP-duration and one an increased rate of polyphasia. Reduced macroMUAP area is a typical myopathic feature. Since macroMUAP amplitude was normal in all patients with reduced macro-MUAP area, it was most probable due to a decreased macro-MUAP duration. The decreased macro-MUAP duration may be due to muscle ®bre atrophy, but not necessarily due to a decreased diameter of the motor unit territory (Nandedkar et al., 1988). The low sensitivity of macroEMG in our compared with Torbergsen's study might be due to the selection bias (he studied a relatively homogenous group compared to our heterogeneous group of patients), different reference limits, different number of muscles studied and the possibility that organs and tissues other than the brachial biceps muscle were more severely affected by the impaired oxidative phosphorylation. The poor relation between conventional EMG and macroEMG might be due to the different uptake-areas of conventional and macro-EMG electrodes (each electrode type samples a different portion of the motor unit area) and the fact that most abnormal ®ndings on conventional EMG were just beyond the cut-off level. Borderline pathologies found with one method may become normal with another method. Because of the absence of pathologic ®ndings on conventional and macro-EMG in the majority of the patients, it is important to note that normal EMG in mitochondriopathy may rather con®rm than exclude the diagnosis. The missing dependency of conventional EMG and macro-EMG variables on maximal muscle torque is an unexpected ®nding

1470

J. Finsterer, A. Fuglsang-Frederiksen / Clinical Neurophysiology 110 (1999) 1466±1470

and might be also due to the selection bias. Limitations of the study were that only a single muscle was investigated, that unequivocal diagnostic criteria for PMMP were lacking and that PMMP was not con®rmed by mtDNA analysis in all patients. In conclusion, the sensitivity of the macro-EMG to detect involvement of the skeletal muscle in patients with mitochondriopathy is similar to that of conventional needle EMG. Macro-MUAP area was not more helpful than macro-MUAP amplitude in this respect. A normal, neurogenic or unspeci®cally abnormal EMG does not exclude mitochondriopathy. Acknowledgements We are grateful to Professor H. Budka and Dr. R. Bittner for performing the histopathological investigations.

References Arpa J, Campos Y, Cruz-Martinez A, Gutierrez-Molina M, Arenas J, Alonso M, Plaza I, Morales C, Palomo F, Barreiro P. Clinical and investigative approaches in mitochondrial diseases. A review of 15 cases, Neurologia 1994;9:324±336. Bertorini TE, Stalberg E, Yuson CP, Engel WK. Single-®bre electromyography in neuromuscular disorders: correlation of muscle histochemistry, single-®bre electromyography, and clinical ®ndings. Muscle Nerve 1994;17:345±353. Emeryk B, Rowinska-Marcinska K, Nowak-Michalska T, Sawicka E. Muscular fatigability in mitochondrial myopathies. An electrophysiological study. Electromyogr Clin Neurophysiol 1992;32:235±245. Fawcett PR, Mastagliam FL, Mechler F. Electrophysiological ®ndings including single ®bre EMG in a family with mitochondrial myopathy. J Neurol Sci 1982;53:397±410. Finsterer J. Mitochondriopathies. Akt Neurol 1997;24:231±241. Hirano M, Silvestri G, Blake DM, Lombes A, Minetti C, Bonilla E, Hays

AP, Lovelace RE, Butler I, Bertorini TE, Threlkeld AB, Mitsumoto H, Salberg LM, Rowland LP, DiMauro S. Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE): clinical, biochemical, and genetic features of an autosomal recessive mitochondrial disorder. Neurology 1994;44:721±727. Kamieniecka Z. Myopathies with abnormal mitochondria. A clinical, histological, and electrophysiological study. Acta Neurol Scand 1977;55: 57±75. Lindner A, Hofmann E, Naumann M, Becker G, Reichmann H. Clinical, morphological, biochemical, and neuroradiological features of mitochondrial encephalomyopathies. Presentation of 19 patients. Mol Cell Biochem 1997;174:297±303. Melberg A, Lundberg PO, Henriksson KG, Olsson Y, Stalberg E. Musclenerve involvement in autosomal dominant progressive external ophthalmoplegia with hypogonadism. Muscle Nerve 1996;19:751±757. Morgan-Hughes JA. The mitochondrial myopathies. In: Engel AG, Franzini-Armstrong C, editors. Myology. Basic and clinical, New York: McGraw-Hill, 1994. pp. 1610±1651. Nandedkar S, Stalberg E. Simulation of macro EMG motor unit potentials. Electroenceph clin Neurophysiol 1983;56:52±62. Nandedkar SD, Sanders DB, Stalberg EV. EMG of reinnervated motor units: a simulation study. Electroencephalogr Clin Neurophysiol 1988;70:177±184. Roeleveld K, Stegeman DF, Falck B, Stalberg EV. Motor unit size estimation: confrontation of surface EMG with macro EMG. Electroencephalogr clin Neurophysiol 1997;105:181±188. Schapira AHV, DiMauro S. Mitochondrial disorders in neurology. Butterworth-Heinemann: Boston and London, 1994. Servidei S. Mitochondrial encephalomyopathies: gene mutation. Neuromusc Disord 1998;8:VIII±XI. Stalberg E. Macro EMG, new recording technique. J Neurol Neurosurg Psychiatry 1980;43:475±482. Stalberg E, Fawcett P. Macro EMG in healthy subjects of different ages. J Neurol Neurosurg Psychiatry 1982;45:870±878. Stalberg E, Trontelj JV. Single ®bre electromyography. Studies in healthy and diseased muscle. New York: Raven Press, 1994. pp. 83±94. Torbergsen T, Stalberg E, Bless JK. Nerve-muscle involvement in a large family with mitochondrial cytopathy: electrophysiological studies. Muscle Nerve 1991;14:35±41. Ukachoke C, Ashby P, Basinski A, Sharpe JA. Usefulness of single ®bre EMG for distinguishing neuromuscular from other causes of ocular muscle weakness. Can J Neurol Sci 1994;21:125±128.