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Single-fiber electromyography in sporadic inclusion body myopathy
Clinical Neurophysiology 118 (2007) 1563–1568 www.elsevier.com/locate/clinph
Single-fiber electromyography in sporadic inclusion body myopathy Yuki Hatanaka, Shin J. Oh
*
Department of Neurology, The University of Alabama at Birmingham, The Veterans Affair Medical Center, UAB Station, Birmingham, AL 35294, USA Accepted 21 March 2007 Available online 15 May 2007
Abstract Objective: To report the SFEMG findings in sporadic inclusion body myopathy (S-IBM). Methods: We have analyzed the SFEMG data in 25 patients (mean age: 63; 16 males) with S-IBM which was diagnosed by the presence of classical rimmed vacuoles in the muscle biopsy together with clinical, laboratory, and electrophysiological findings. Results: All patients had fibrillations, positive sharp waves, and small-amplitude short-duration motor unit potentials (MUPs) in the needle EMG. High-amplitude MUPs were observed in eight (32%) patients, two of whom had long-duration MUPs. SFEMG was abnormal in 17 (68%) cases: mean ‘‘mean consecutive difference (MCD)’’ was increased beyond the age-adjusted normal limit in 16 cases, and more than 10% of potential pairs (PP) had MCD longer than the upper normal limit of an individual MCD in one case. Mean fiber density (FD) was 2.16, with maximum FD being 4.15. Increased FD was noted in 11 (44%) cases. In four cases, more than 10% of PP had blocking, but there was no neurogenic blocking in any PP. As expected, MCD increased linearly (r = 0.85) with the percentage of PP beyond the normal upper limit. Conclusions: The SFEMG findings in S-IBM are typical of the classical pattern of myopathy. Significance: Our findings support the consensus that S-IBM is a myopathy. 2007 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved. Keywords: Inclusion body myositis; Jitter; Needle EMG; SFEMG; EMG; Fiber density
1. Introduction Single-fiber electromyography (SFEMG), an electrophysiological technique for evaluation of end-plate microphysiology, has been studied mainly in patients with neuromuscular transmission disorders. There are a few reports of SFEMG in inclusion body myopathy (IBM) (Eisen et al., 1983; Joy et al., 1990). We report here the SFEMG findings in 25 patients with sporadic IBM (S-IBM).
2. Materials and methods This study was based on a retrospective analysis of clinical, histological, and electrophysiological findings in 25 *
Corresponding author. Tel.: +1 205 934 2120; fax: +1 205 975 6758. E-mail address: [email protected] (S.J. Oh).
cases of S-IBM in the Neuromuscular Disease Clinic at the University of Alabama at Birmingham. These cases include 12 patients whose data were reported previously (Joy et al., 1990). Diagnosis of S-IBM was made on the basis of combined clinical, laboratory, electrophysiological and pathological criteria, as recommended by the European consensus group (Vershuuren et al., 1997). If the patient’s family history was positive, the case was excluded. Clinical findings included slowly progressive proximal and/or distal weakness, with either weakness or wasting of forearm or quadriceps muscles. Laboratory findings included a normal or mild to moderately increased CK. Electrophysiological findings included small-amplitude short-duration (SASD) motor unit potentials (MUPs). Pathological findings included rimmed vacuoles, with at least two muscle fibers showing rimmed vacuoles in the lower power field (40·). Nerve conduction study was performed using the conventional method in all cases. Needle EMG study was done
1388-2457/$32.00 2007 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.clinph.2007.03.023
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using a monopolar needle. SFEMG was performed with the help of a Counterpoint EMG machine with automatic analyzer. SFEMG was performed in the extensor digitorum communis (EDC) muscle in 17 patients, in the vastus lateralis muscle in four patients, in the anterior tibialis muscle in three patients, and in the biceps muscle in one patient, using conventional methods with a single-fiber needle and filter range of 500–10 kHz. All tested muscles were clinically weak except for normal EDC muscle strength in nine patients. In these cases, the needle EMG was abnormal in the EDC muscle. When the EDC muscle was normal in strength as well as on the needle EMG findings, another clinically weak muscle was selected for the SFEMG. Skin temperature was controlled at or above 32 C. The values of mean consecutive difference (MCD) in patients were compared with the normal values obtained in the University of Alabama at Birmingham EMG laboratory for the EDC muscle (Oh, 1988) and with normal values published by the Ad Hoc Committee of American Association of Electrodiagnostic Medicine (1992) for the other muscles. For the determination of abnormality of the jitter, we used the following guidelines (Sanders et al., 1979). (1) When more than 10 potential pairs were obtained, any one of three criteria was used to judge jitter abnormality: (a) mean MCD value exceeded the age-adjusted normal limit for the tested muscle (Ad Hoc Committee of AAEM. Muscle Nerve, 1992); (b) more than 10% of potential pairs showed blocking or jitter greater than the age-adjusted upper normal limit of an individual MCD for the tested muscle; or (c) blocking was frequently seen in the majority of fiber pairs in a muscle, so that it was perhaps impossible to calculate the MCD. (2) When fewer than 10 potential pairs were obtained, the jitter was considered abnormal when one of the following two criteria was met: (a) at least two potential pairs had blocking or jitter greater than the upper limit of an individual MCD for the tested muscle, or (b) blocking was frequently seen in the majority of fiber pairs in a muscle, so that it was perhaps impossible to calculate the MCD. The FD was measured from 20 different sites using the conventional methods and was considered abnormal when it was higher than the age-adjusted upper limit of normal for the tested muscle (Ad Hoc Committee of AAEM. Muscle Nerve, 1992). 3. Results 3.1. Clinical features There were 16 male and 9 female patients, with an age range of 23–86 years; the duration of disease at the time of testing ranged from 12 months to 20 years (mean duration, 7.0 years) (Table 1). All had, S-IBM. Two patients had onset of S-IBM before 50 years of age: onset at 30 years in one and at 40 in the other. The pattern of muscle weakness was proximal in 17 cases, distal in four cases, diffuse in three, and scapulo-peroneal in one case. All patients had either forearm or quadriceps weakness or
wasting. Respiratory failure was noted in one case, dysphagia in three cases, and ophthalmoplegia in one case at the initial evaluation. This patient had tubulofilaments demonstrated by electron-microscopic study typical of IBM in muscle biopsy. Deep-tendon reflexes were decreased or absent in all except three cases. CK was elevated in 18 (72%) cases. Mean CK level was 529 U (normal, <250 U), with a range of from 64 to 1910 U. 3.2. Muscle biopsy All patients had more than two muscle fibers with rimmed vacuoles in the low-power field. Rimmed vacuoles were numerous in six, moderate in three, and minimally present in the others. There was usually an increased proliferation of endomysial and perimysial connective tissue. We measured fiber diameter of the most atrophied and hypertrophied fibers in 23 cases. Atrophic fibers (<30 lm in fiber diameter) were observed in 22 (96%) cases: severe atrophy in nine, moderate in five, and mild in eight cases. Hypertrophic fibers (>130 lm in fiber diameter) were observed in 14 (61%) cases: nine out of 16 cases with SASD MUPs and five of seven cases with SASD and HA MUPs. Mean diameter of hypertrophied muscles was 137.5 lm in the SASD MUP group and 181.6 lm in the SASD and HA MUP group. Super-hypertrophied fibers (>200 lm) were observed in one case in the SASD MUP group and three cases in the SASD and HA MUP group. This difference was significant at P value (0.033). Grouping of atrophic fibers was noted in six cases. However, in eight (32%) patients, an additional diagnosis of denervation was made on the basis of the following findings: fascicular atrophy in two, target fibers in one, fiber type grouping in three, and angular fibers intensely stained with nicotinamide adenine dehydrogenase tetrazolium reductase in two cases. Inflammatory cells were observed in 17 (68%) cases. In three of these eight cases of denervation, high-amplitude (HA) motor unit potentials (MUPs) could be explained by chronic denervation in the muscle biopsy. 3.3. Nerve conduction study One patient had bilateral carpal tunnel syndrome and five (20%) had mild diffuse neuropathy: a mild demyelinating neuropathy pattern in three cases and axonal neuropathy in two (Table 1). HA MUPs were explained by diffuse neuropathy in one case. 3.4. Conventional needle EMG All 25 patients showed fibrillation and positive sharp waves and SASD MUPs with increased polyphasic MUPs. High-amplitude (>5 mV) MUPs were present in eight cases (32%) (Table 1). Duration of MUPs was normal in six cases and prolonged in two. HA and SASD MUPs were recorded from the same muscles in five cases, whereas
Table 1 Clinical, laboratory, and electrophysiological data No.
Age/sex (years)
Duration (years)
Clinical type
Group with weak muscle strength 10 70/M 3 11 68/F 4 12 60/M 5 13 78/M 5 14 63/F 7 15 71/M 12 16 70/F 15 17 78/M 20 18 70/M 15 19 62/F 1 20 55/M 1 21 68/M 1 22 54/M 3 23 66/F 2 24 63/F 6 25 66/M 15
Scapulo-peroneal Diffuse, dysphagia Diffuse Distal Proximal Proximal Distal Diffuse, oculo-bulbar Proximal Proximal Proximal, dyspnea Proximal Proximal Proximal Distal Proximal
EMG
SFEMG
Fib (+)
MUP
307 926 586 423 407 693 99 800 1910
2 3 3 3 2 1 4 2 3
SS SS SS/H SS/H SS SS SS SS SS
64 67 141 700 50 882 241 150 364 863 975 169 1601 666 527 326
2 2 2 2 3 1 2 2 1 3 3 2 3 2 3 2
SS SS/H SS SS/H SS SS SS SS SS/HL SS/HL SS SS SS SS/H SS/H SS
NCS Muscle
FD
mMCD (ls)
PP:UNL/B (%)
Na Ab Ab N Ab N Ab N N
EDC EDC EDC EDC EDC EDC EDC EDC EDC
2.30b 2.25 1.90 1.94 2.50 2.42 4.15a 1.80 2.20
17.0 67.0 51.0 22.0 65.0 29.0 62.0 18.0 34.0
0 89 33 0 41/5 0 59 0 13
Ab Ab Ab Ab N N Ab Ab N Ab Ab Ab Ab N Ab Ab
EDC EDC EDC EDC EDC EDC EDC EDC Biceps VL VL VL VL AT AT AT
2.90 2.35 1.81 3.50 1.85 1.61 2.55 2.36 1.60 1.75 1.50 2.15 1.70 1.60 1.55 1.76
53.0 45.0 76.0 50.0 22.5 31.0 68.0 50.0 31.0 88.5 49.0 68.0 59.0 32.0 65.0 88.0
33 25 80 17 0 0 37/11 22/22 9 77/31 20 41/10 43/14 0 50 92
Ab
Ab CTS
Ab
Ab Ab
Y. Hatanaka, S.J. Oh / Clinical Neurophysiology 118 (2007) 1563–1568
Group with normal muscle strength but with abnormal needle EMG 1 42/M 2 Distal 2 67/M 3 Proximal, leg 3 62/M 3 Proximal, leg 4 68/M 4 Proximal 5 61/M 5 Proximal, dysphagia 6 81/F 6 Proximal 7 66/F 8 Proximal 8 43/F 10 Proximal 9 64/M 20 Proximal
CK (U)
Abbreviations: M, male; F, female; CK, creatine kinase; Fib, fibrillations; MUP, motor unit potential; FD, fiber density; mMCD, mean ‘‘mean consecutive difference’’; PP:UNL/B, potential pair > upper normal limit of an individual MCD/blocking; NCS, nerve conduction study; SS, small-amplitude short-duration; H, high amplitude; L, long duration; Ab, abnormal; N, normal; EDC, extensor digitorum communis; VL, vastus lateralis; AT, anterior tibialis; CTS, carpal tunnel syndrome. a Jitter abnormality. b Abnormal values in SFEMG are bold lettered.
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HA MUPs were recorded in other muscles in three cases. HA MUPs were explained by diffuse neuropathy in one case and by denervation process in muscle biopsy in three cases. Intensity of fibrillations as well as MUP parameters were independent of disease duration, CK level, or presence of weakness. 3.5. SFEMG Fiber density (FD) was increased in 11 (44%) cases compared with the age-related normal upper limit, and mean FD was modestly increased (mean 2.18, range 1.50–4.15) (Table 1). In two cases, a high FD could be explained by neuropathy. However, there was no significant difference in FD between five cases of neuropathy (2.41) and twenty cases without neuropathy (2.10). Ten or more SF potential pairs (PP) were obtained in all but three cases, in which fewer than 10 SFPPs were obtained. SFEMG was abnormal in 17 (68%) cases: mean MCD was increased beyond the age-adjusted upper normal limit in 16 cases, and in one case more than 10% of potential pairs (PP) had MCD longer than the upper normal limit of an individual MCD (Table 1). In four cases, more than 10% of PP had blocking, but there was no neurogenic blocking (concomitant blocking of two or more SF potentials) in any PP. As expected, MCD increased linearly (r = 0.85) with the percentage of PP beyond the normal upper limit of an individual MCD. In FD and MCD, there was no apparent association with duration of disease, muscle strength, or CK level (Fig. 1). There was no correlation between MCD and FD, MCD and PP > 54ls%, or MCD and blocking. There was no difference in MCD between the neuropathy and non-neuropathy groups: 52.2 ls in neuropathy and 49.1 ls in non-neuropathy cases. 4. Discussion In this study, we made the diagnosis of S-IBM following the European Consensus Criteria which are based on the typical pattern of weakness in combination with rimmed vacuoles in muscle biopsy, but in which the presence of tubulofilaments or amyloid has not been demonstrated (Vershuuren et al., 1997). We found that the pathological diagnostic criteria recommended by Griggs et al. (1995) were too restrictive and impractical. We believe that the above diagnostic criteria are reasonable on the basis of our previous study: in all 10 randomly selected S-IBM cases diagnosed on the basis of the above criteria, we found amyloid precursor protein (Vilalanova et al., 1993). Instead of inclusion body myositis, we adopted the term, inclusion body myopathy, because inflammatory cells were not present in all cases. We made the histological diagnosis of S-IBM on the basis of two or more muscle fibers with rimmed vacuoles in the lower power field (40·). This corresponds roughly to 0.5–1%, depending on the size of fibers. We required 5–10· more than the number of muscle fibers with rimmed
Fig. 1. (a) Correlation of fiber density vs duration of disease. (b) Correlation of MCD vs duration of disease.
vacuoles recommended by the European consensus group: two rimmed vacuoles per 1000 fibers (Vershuuren et al., 1997). Lotz et al. (1989) recommended at least one rimmed vacuole in the low-power field as one of their pathological diagnostic features. Thus, our diagnostic requirement is much stricter than that previously proposed. Clinical features and laboratory findings were comparable to those previously reported (Lotz et al., 1989). All our patients had either forearm muscle or quadriceps weakness or wasting characteristic of S-IBM (Sekul et al., 1994; Engel and Askanas, 2006). Needle EMG studies in our patients showed fibrillation, PSW, and SASD MUPs in all cases, as reported in two previous studies (Joy et al., 1990; Lotz et al., 1989), indicating that these findings are typical of S-IBM. This illlustrates that fibrillation and PSW are not necessarily due to denervation process but are frequent features of active myopathy. The quantitative MUP analysis also showed a myopathy pattern in 17 cases (Barkhaus et al., 1999). In one-third of cases, SASD MUPs were present together with HA MUPs, as previously reported by us (Joy et al., 1990).
Y. Hatanaka, S.J. Oh / Clinical Neurophysiology 118 (2007) 1563–1568
In Barkhaus’s series (1999), 29% of cases had this mixed pattern of needle EMG findings. In the present study, long-duration MUPs were present in only three (11%) of cases, indicating that most HA MUPs have a normal or short duration. Joy et al. (1990) concluded that this mixed pattern of SASD and HA MUP was highly suggestive of SIBM. Our study showed that HA MUPs can be explained by denervation process in half the cases in which it was observed. In the remaining half of cases, hypertrophy of muscle fibers was suggested as a possible explanation in view of the normal or short duration of MUPs (Barkhaus et al., 1999). Our study showed that super-hypertrophied fibers were significantly common in SASD and HA MUP group than SASD group. Thus, our study supports the hypothesis that the hypertrophy of muscle fibers is responsible for HA MUP. Though the consensus has been that S-IBM is a myopathy, the possibility of a neurogenic pathogenesis has been raised in view of the prominent fibrillation potentials and PSW, HA MUPs in one of three cases, grouping of atrophic, often angular fibers in the muscle biopsy, and distal weakness together with areflexia. S-IBM has often been misdiagnosed as motor neuron disease (Ryan et al., 2000; Dabby et al., 2001). To resolve this issue, Eisen et al. (1983) studied seven S-IBM patients with SFEMG, and Luciano and Dalakas (1997) and Barkhaus et al. (1999) each analyzed 11 S-IBM patients and 17 sporadic S-IBM cases with the macro-EMG technique. Eisen et al. (1983) reported a strikingly high FD (mean = 6.3) and a moderately abnormal jitter (mean MCD = 83 ls). These findings led them to conclude that S-IBM had a substantial neurogenic component. In an earlier paper, we reported a mildly abnormal jitter in 58.3% of cases and a modestly increased FD (mean = 2.6) in 12 cases and concluded that SFEMG findings were typical of chronic myopathy (Joy et al., 1990). Luciano and Dalakas (1997) chose a macro-EMG technique, the best electrophysiological technique of the MUP territory in this endeavor, and found a smaller macroMUP amplitude and area in S-IBM than in normal controls. Barkhaus et al. (1999) found a smaller macro-MUP amplitude in only three of 17 cases. Both studies concluded that their findings did not support the co-existence of neurogenic components in S-IBM but were consistent with a primary muscle disorder. Because Eisen et al. (1983) studied only seven IBM patients, it is possible that their data might be biased because of the small number of patients. To avoid this possible bias, we studied the SFEMG in a larger number of patients. In contrast to Eisen’s cases, we had more younger patients and more with proximal muscle involvement. Only one patient was under 61 years of age in Eisen’s series, whereas we had four patients in this age group in our series. In Eisen’s series, there was distal muscle involvement in all cases and none had predominant proximal involvement. In our series, distal muscle involvement was seen in nine and predominant proximal involvement in 18 cases. Other-
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wise, there is no major difference between Eisen’s patients and ours with regard to areflexia, CK and conventional needle EMG findings. The major differences between the SFEMG findings in Eisen’s series (Eisen et al., 1983) and ours are the lower FD and lower mean MCD in our series: 2.18 vs 6.3 in FD and 49 vs 83 ls in mean MCD. No neurogenic blocking was found in any of our cases or Eisen’s cases. The minimal increase in FD in S-IBM can be explained by the presence of many small atrophic fibers, a common finding on the muscle biopsy in S-IBM, and the minimal increase in MCD by the end-plate dysfunction by the presence of a myopathic process. In SFEMG, FD and MCD values are helpful in differentiating among neuromuscular transmission defect, myopathy, and denervation (Oh, 1988). In classical neuromuscular transmission defect, FD is relatively normal and MCD is markedly abnormal. In denervation, FD is markedly increased but MCD is only minimally increased, whereas in myopathy FD and MCD are minimally increased. In 34 patients with polymyositis or dermatomyositis, Jian et al. (2005) found an increased FD (mean value, 2.34; range 1–6) and a mildly increased jitter (mean 41 ls; range 5–78 ls). Our findings are almost identical to those found in polymyositis or dermatomyositis and typical of the classical pattern of myopathy. Thus, our findings, though non-specific, support the consensus that S-IBM is a myopathy. References Ad Hoc Committee of AAEM. Single fiber EMG reference values: a collaborative effort. Muscle Nerve 1992; 15:151–161. Barkhaus PE, Periquet MS, Nandedkar SD. Quantitative electrophysiologic studies in sporadic inclusion body myositis. Muscle Nerve 1999;22:480–7. Dabby R, Lange DJ, Trojaborg W, Hays AP, Lovelace RE, Brannagan TH, et al. Inclusion body myositis mimicking motor neuron disease. Arch Neurol 2001;589:1253–6. Eisen A, Berry K, Gibson G. Inclusion body myositis: myopathy or neuropathy? Neurology 1983;33:1109–14. Engel WK, Askanas V. Inclusion-body myositis. Clinical, diagnostic, and pathologic aspects. Neurology 2006;66:S20–9. Griggs RC, Askanas V, DiMauro S, Engel A, Karpati G, Mendell JR, et al. Inclusion body myositis and myopathies. Ann Neurol 1995;38:705–16. Jian F, Cui LY, Li BH, Du H. Changes of single fiber electromyography in patients with inflammatory myopathies. Chin Med Sci J 2005;20:1–4. Joy JL, Oh SJ, Baysal AL. Electrophysiologic spectrum of inclusion body myositis. Muscle Nerve 1990;13:949–51. Lotz BP, Engel AG, Nishino H, Stevens JC, Litchy WJ. Inclusion body myositis; observations in 40 patients. Brain 1989;112:727–47. Luciano CA, Dalakas MC. Inclusion body myositis. Neurology 1997;48:29–33. Oh SJ. Electromyography. Neuromuscular transmission defect. Baltimore, MD: Williams & Wilkins; 1988. Ryan HF, Claussen GC, Oh SJ. A case review. Initial misdiagnosis of amyotrophic lateral sclerosis and spinal muscular atrophy in the presentation of inclusion body myositis. Muscle Nerve 2000;13:1639. Sanders DB, Howard Jr JF, Johns TS. Single-fiber electromyography in myasthenia gravis. Neurology 1979;29:68–76.
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Sekul E, Chow C, Dalakas MC. Magnectic resonance imaging (MRI) of the forearm as a diagnostic aid in patients with inclusion body myositis (IBM). Neurology 1994;44:A310. Vershuuren JJ, Baldrising UA, Wintzen AR, van Engelen BGM, van der Hoeven H, Hoogendijk J. Inclusion body myositis. In: Emery AEH, editor. Diagnostic criteria for neuromuscular disease. 2nd ed.
European neuromuscular center. The Royal Society of Medicine; 1997. p. 81–4. Vilalanova M, Kawai M, Lu¨bke U, Oh SJ, Perry G, Six J, et al. Rimmed vacuoles of inclusion body myositis and oculopharyngeal muscular dystrophy contain amyloid precursor protein and lysosomal markers. Brain Res 1993;603:343–7.
Single-fiber electromyography in sporadic inclusion body myopathy Yuki Hatanaka, Shin J. Oh
*
Department of Neurology, The University of Alabama at Birmingham, The Veterans Affair Medical Center, UAB Station, Birmingham, AL 35294, USA Accepted 21 March 2007 Available online 15 May 2007
Abstract Objective: To report the SFEMG findings in sporadic inclusion body myopathy (S-IBM). Methods: We have analyzed the SFEMG data in 25 patients (mean age: 63; 16 males) with S-IBM which was diagnosed by the presence of classical rimmed vacuoles in the muscle biopsy together with clinical, laboratory, and electrophysiological findings. Results: All patients had fibrillations, positive sharp waves, and small-amplitude short-duration motor unit potentials (MUPs) in the needle EMG. High-amplitude MUPs were observed in eight (32%) patients, two of whom had long-duration MUPs. SFEMG was abnormal in 17 (68%) cases: mean ‘‘mean consecutive difference (MCD)’’ was increased beyond the age-adjusted normal limit in 16 cases, and more than 10% of potential pairs (PP) had MCD longer than the upper normal limit of an individual MCD in one case. Mean fiber density (FD) was 2.16, with maximum FD being 4.15. Increased FD was noted in 11 (44%) cases. In four cases, more than 10% of PP had blocking, but there was no neurogenic blocking in any PP. As expected, MCD increased linearly (r = 0.85) with the percentage of PP beyond the normal upper limit. Conclusions: The SFEMG findings in S-IBM are typical of the classical pattern of myopathy. Significance: Our findings support the consensus that S-IBM is a myopathy. 2007 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved. Keywords: Inclusion body myositis; Jitter; Needle EMG; SFEMG; EMG; Fiber density
1. Introduction Single-fiber electromyography (SFEMG), an electrophysiological technique for evaluation of end-plate microphysiology, has been studied mainly in patients with neuromuscular transmission disorders. There are a few reports of SFEMG in inclusion body myopathy (IBM) (Eisen et al., 1983; Joy et al., 1990). We report here the SFEMG findings in 25 patients with sporadic IBM (S-IBM).
2. Materials and methods This study was based on a retrospective analysis of clinical, histological, and electrophysiological findings in 25 *
Corresponding author. Tel.: +1 205 934 2120; fax: +1 205 975 6758. E-mail address: [email protected] (S.J. Oh).
cases of S-IBM in the Neuromuscular Disease Clinic at the University of Alabama at Birmingham. These cases include 12 patients whose data were reported previously (Joy et al., 1990). Diagnosis of S-IBM was made on the basis of combined clinical, laboratory, electrophysiological and pathological criteria, as recommended by the European consensus group (Vershuuren et al., 1997). If the patient’s family history was positive, the case was excluded. Clinical findings included slowly progressive proximal and/or distal weakness, with either weakness or wasting of forearm or quadriceps muscles. Laboratory findings included a normal or mild to moderately increased CK. Electrophysiological findings included small-amplitude short-duration (SASD) motor unit potentials (MUPs). Pathological findings included rimmed vacuoles, with at least two muscle fibers showing rimmed vacuoles in the lower power field (40·). Nerve conduction study was performed using the conventional method in all cases. Needle EMG study was done
1388-2457/$32.00 2007 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.clinph.2007.03.023
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using a monopolar needle. SFEMG was performed with the help of a Counterpoint EMG machine with automatic analyzer. SFEMG was performed in the extensor digitorum communis (EDC) muscle in 17 patients, in the vastus lateralis muscle in four patients, in the anterior tibialis muscle in three patients, and in the biceps muscle in one patient, using conventional methods with a single-fiber needle and filter range of 500–10 kHz. All tested muscles were clinically weak except for normal EDC muscle strength in nine patients. In these cases, the needle EMG was abnormal in the EDC muscle. When the EDC muscle was normal in strength as well as on the needle EMG findings, another clinically weak muscle was selected for the SFEMG. Skin temperature was controlled at or above 32 C. The values of mean consecutive difference (MCD) in patients were compared with the normal values obtained in the University of Alabama at Birmingham EMG laboratory for the EDC muscle (Oh, 1988) and with normal values published by the Ad Hoc Committee of American Association of Electrodiagnostic Medicine (1992) for the other muscles. For the determination of abnormality of the jitter, we used the following guidelines (Sanders et al., 1979). (1) When more than 10 potential pairs were obtained, any one of three criteria was used to judge jitter abnormality: (a) mean MCD value exceeded the age-adjusted normal limit for the tested muscle (Ad Hoc Committee of AAEM. Muscle Nerve, 1992); (b) more than 10% of potential pairs showed blocking or jitter greater than the age-adjusted upper normal limit of an individual MCD for the tested muscle; or (c) blocking was frequently seen in the majority of fiber pairs in a muscle, so that it was perhaps impossible to calculate the MCD. (2) When fewer than 10 potential pairs were obtained, the jitter was considered abnormal when one of the following two criteria was met: (a) at least two potential pairs had blocking or jitter greater than the upper limit of an individual MCD for the tested muscle, or (b) blocking was frequently seen in the majority of fiber pairs in a muscle, so that it was perhaps impossible to calculate the MCD. The FD was measured from 20 different sites using the conventional methods and was considered abnormal when it was higher than the age-adjusted upper limit of normal for the tested muscle (Ad Hoc Committee of AAEM. Muscle Nerve, 1992). 3. Results 3.1. Clinical features There were 16 male and 9 female patients, with an age range of 23–86 years; the duration of disease at the time of testing ranged from 12 months to 20 years (mean duration, 7.0 years) (Table 1). All had, S-IBM. Two patients had onset of S-IBM before 50 years of age: onset at 30 years in one and at 40 in the other. The pattern of muscle weakness was proximal in 17 cases, distal in four cases, diffuse in three, and scapulo-peroneal in one case. All patients had either forearm or quadriceps weakness or
wasting. Respiratory failure was noted in one case, dysphagia in three cases, and ophthalmoplegia in one case at the initial evaluation. This patient had tubulofilaments demonstrated by electron-microscopic study typical of IBM in muscle biopsy. Deep-tendon reflexes were decreased or absent in all except three cases. CK was elevated in 18 (72%) cases. Mean CK level was 529 U (normal, <250 U), with a range of from 64 to 1910 U. 3.2. Muscle biopsy All patients had more than two muscle fibers with rimmed vacuoles in the low-power field. Rimmed vacuoles were numerous in six, moderate in three, and minimally present in the others. There was usually an increased proliferation of endomysial and perimysial connective tissue. We measured fiber diameter of the most atrophied and hypertrophied fibers in 23 cases. Atrophic fibers (<30 lm in fiber diameter) were observed in 22 (96%) cases: severe atrophy in nine, moderate in five, and mild in eight cases. Hypertrophic fibers (>130 lm in fiber diameter) were observed in 14 (61%) cases: nine out of 16 cases with SASD MUPs and five of seven cases with SASD and HA MUPs. Mean diameter of hypertrophied muscles was 137.5 lm in the SASD MUP group and 181.6 lm in the SASD and HA MUP group. Super-hypertrophied fibers (>200 lm) were observed in one case in the SASD MUP group and three cases in the SASD and HA MUP group. This difference was significant at P value (0.033). Grouping of atrophic fibers was noted in six cases. However, in eight (32%) patients, an additional diagnosis of denervation was made on the basis of the following findings: fascicular atrophy in two, target fibers in one, fiber type grouping in three, and angular fibers intensely stained with nicotinamide adenine dehydrogenase tetrazolium reductase in two cases. Inflammatory cells were observed in 17 (68%) cases. In three of these eight cases of denervation, high-amplitude (HA) motor unit potentials (MUPs) could be explained by chronic denervation in the muscle biopsy. 3.3. Nerve conduction study One patient had bilateral carpal tunnel syndrome and five (20%) had mild diffuse neuropathy: a mild demyelinating neuropathy pattern in three cases and axonal neuropathy in two (Table 1). HA MUPs were explained by diffuse neuropathy in one case. 3.4. Conventional needle EMG All 25 patients showed fibrillation and positive sharp waves and SASD MUPs with increased polyphasic MUPs. High-amplitude (>5 mV) MUPs were present in eight cases (32%) (Table 1). Duration of MUPs was normal in six cases and prolonged in two. HA and SASD MUPs were recorded from the same muscles in five cases, whereas
Table 1 Clinical, laboratory, and electrophysiological data No.
Age/sex (years)
Duration (years)
Clinical type
Group with weak muscle strength 10 70/M 3 11 68/F 4 12 60/M 5 13 78/M 5 14 63/F 7 15 71/M 12 16 70/F 15 17 78/M 20 18 70/M 15 19 62/F 1 20 55/M 1 21 68/M 1 22 54/M 3 23 66/F 2 24 63/F 6 25 66/M 15
Scapulo-peroneal Diffuse, dysphagia Diffuse Distal Proximal Proximal Distal Diffuse, oculo-bulbar Proximal Proximal Proximal, dyspnea Proximal Proximal Proximal Distal Proximal
EMG
SFEMG
Fib (+)
MUP
307 926 586 423 407 693 99 800 1910
2 3 3 3 2 1 4 2 3
SS SS SS/H SS/H SS SS SS SS SS
64 67 141 700 50 882 241 150 364 863 975 169 1601 666 527 326
2 2 2 2 3 1 2 2 1 3 3 2 3 2 3 2
SS SS/H SS SS/H SS SS SS SS SS/HL SS/HL SS SS SS SS/H SS/H SS
NCS Muscle
FD
mMCD (ls)
PP:UNL/B (%)
Na Ab Ab N Ab N Ab N N
EDC EDC EDC EDC EDC EDC EDC EDC EDC
2.30b 2.25 1.90 1.94 2.50 2.42 4.15a 1.80 2.20
17.0 67.0 51.0 22.0 65.0 29.0 62.0 18.0 34.0
0 89 33 0 41/5 0 59 0 13
Ab Ab Ab Ab N N Ab Ab N Ab Ab Ab Ab N Ab Ab
EDC EDC EDC EDC EDC EDC EDC EDC Biceps VL VL VL VL AT AT AT
2.90 2.35 1.81 3.50 1.85 1.61 2.55 2.36 1.60 1.75 1.50 2.15 1.70 1.60 1.55 1.76
53.0 45.0 76.0 50.0 22.5 31.0 68.0 50.0 31.0 88.5 49.0 68.0 59.0 32.0 65.0 88.0
33 25 80 17 0 0 37/11 22/22 9 77/31 20 41/10 43/14 0 50 92
Ab
Ab CTS
Ab
Ab Ab
Y. Hatanaka, S.J. Oh / Clinical Neurophysiology 118 (2007) 1563–1568
Group with normal muscle strength but with abnormal needle EMG 1 42/M 2 Distal 2 67/M 3 Proximal, leg 3 62/M 3 Proximal, leg 4 68/M 4 Proximal 5 61/M 5 Proximal, dysphagia 6 81/F 6 Proximal 7 66/F 8 Proximal 8 43/F 10 Proximal 9 64/M 20 Proximal
CK (U)
Abbreviations: M, male; F, female; CK, creatine kinase; Fib, fibrillations; MUP, motor unit potential; FD, fiber density; mMCD, mean ‘‘mean consecutive difference’’; PP:UNL/B, potential pair > upper normal limit of an individual MCD/blocking; NCS, nerve conduction study; SS, small-amplitude short-duration; H, high amplitude; L, long duration; Ab, abnormal; N, normal; EDC, extensor digitorum communis; VL, vastus lateralis; AT, anterior tibialis; CTS, carpal tunnel syndrome. a Jitter abnormality. b Abnormal values in SFEMG are bold lettered.
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HA MUPs were recorded in other muscles in three cases. HA MUPs were explained by diffuse neuropathy in one case and by denervation process in muscle biopsy in three cases. Intensity of fibrillations as well as MUP parameters were independent of disease duration, CK level, or presence of weakness. 3.5. SFEMG Fiber density (FD) was increased in 11 (44%) cases compared with the age-related normal upper limit, and mean FD was modestly increased (mean 2.18, range 1.50–4.15) (Table 1). In two cases, a high FD could be explained by neuropathy. However, there was no significant difference in FD between five cases of neuropathy (2.41) and twenty cases without neuropathy (2.10). Ten or more SF potential pairs (PP) were obtained in all but three cases, in which fewer than 10 SFPPs were obtained. SFEMG was abnormal in 17 (68%) cases: mean MCD was increased beyond the age-adjusted upper normal limit in 16 cases, and in one case more than 10% of potential pairs (PP) had MCD longer than the upper normal limit of an individual MCD (Table 1). In four cases, more than 10% of PP had blocking, but there was no neurogenic blocking (concomitant blocking of two or more SF potentials) in any PP. As expected, MCD increased linearly (r = 0.85) with the percentage of PP beyond the normal upper limit of an individual MCD. In FD and MCD, there was no apparent association with duration of disease, muscle strength, or CK level (Fig. 1). There was no correlation between MCD and FD, MCD and PP > 54ls%, or MCD and blocking. There was no difference in MCD between the neuropathy and non-neuropathy groups: 52.2 ls in neuropathy and 49.1 ls in non-neuropathy cases. 4. Discussion In this study, we made the diagnosis of S-IBM following the European Consensus Criteria which are based on the typical pattern of weakness in combination with rimmed vacuoles in muscle biopsy, but in which the presence of tubulofilaments or amyloid has not been demonstrated (Vershuuren et al., 1997). We found that the pathological diagnostic criteria recommended by Griggs et al. (1995) were too restrictive and impractical. We believe that the above diagnostic criteria are reasonable on the basis of our previous study: in all 10 randomly selected S-IBM cases diagnosed on the basis of the above criteria, we found amyloid precursor protein (Vilalanova et al., 1993). Instead of inclusion body myositis, we adopted the term, inclusion body myopathy, because inflammatory cells were not present in all cases. We made the histological diagnosis of S-IBM on the basis of two or more muscle fibers with rimmed vacuoles in the lower power field (40·). This corresponds roughly to 0.5–1%, depending on the size of fibers. We required 5–10· more than the number of muscle fibers with rimmed
Fig. 1. (a) Correlation of fiber density vs duration of disease. (b) Correlation of MCD vs duration of disease.
vacuoles recommended by the European consensus group: two rimmed vacuoles per 1000 fibers (Vershuuren et al., 1997). Lotz et al. (1989) recommended at least one rimmed vacuole in the low-power field as one of their pathological diagnostic features. Thus, our diagnostic requirement is much stricter than that previously proposed. Clinical features and laboratory findings were comparable to those previously reported (Lotz et al., 1989). All our patients had either forearm muscle or quadriceps weakness or wasting characteristic of S-IBM (Sekul et al., 1994; Engel and Askanas, 2006). Needle EMG studies in our patients showed fibrillation, PSW, and SASD MUPs in all cases, as reported in two previous studies (Joy et al., 1990; Lotz et al., 1989), indicating that these findings are typical of S-IBM. This illlustrates that fibrillation and PSW are not necessarily due to denervation process but are frequent features of active myopathy. The quantitative MUP analysis also showed a myopathy pattern in 17 cases (Barkhaus et al., 1999). In one-third of cases, SASD MUPs were present together with HA MUPs, as previously reported by us (Joy et al., 1990).
Y. Hatanaka, S.J. Oh / Clinical Neurophysiology 118 (2007) 1563–1568
In Barkhaus’s series (1999), 29% of cases had this mixed pattern of needle EMG findings. In the present study, long-duration MUPs were present in only three (11%) of cases, indicating that most HA MUPs have a normal or short duration. Joy et al. (1990) concluded that this mixed pattern of SASD and HA MUP was highly suggestive of SIBM. Our study showed that HA MUPs can be explained by denervation process in half the cases in which it was observed. In the remaining half of cases, hypertrophy of muscle fibers was suggested as a possible explanation in view of the normal or short duration of MUPs (Barkhaus et al., 1999). Our study showed that super-hypertrophied fibers were significantly common in SASD and HA MUP group than SASD group. Thus, our study supports the hypothesis that the hypertrophy of muscle fibers is responsible for HA MUP. Though the consensus has been that S-IBM is a myopathy, the possibility of a neurogenic pathogenesis has been raised in view of the prominent fibrillation potentials and PSW, HA MUPs in one of three cases, grouping of atrophic, often angular fibers in the muscle biopsy, and distal weakness together with areflexia. S-IBM has often been misdiagnosed as motor neuron disease (Ryan et al., 2000; Dabby et al., 2001). To resolve this issue, Eisen et al. (1983) studied seven S-IBM patients with SFEMG, and Luciano and Dalakas (1997) and Barkhaus et al. (1999) each analyzed 11 S-IBM patients and 17 sporadic S-IBM cases with the macro-EMG technique. Eisen et al. (1983) reported a strikingly high FD (mean = 6.3) and a moderately abnormal jitter (mean MCD = 83 ls). These findings led them to conclude that S-IBM had a substantial neurogenic component. In an earlier paper, we reported a mildly abnormal jitter in 58.3% of cases and a modestly increased FD (mean = 2.6) in 12 cases and concluded that SFEMG findings were typical of chronic myopathy (Joy et al., 1990). Luciano and Dalakas (1997) chose a macro-EMG technique, the best electrophysiological technique of the MUP territory in this endeavor, and found a smaller macroMUP amplitude and area in S-IBM than in normal controls. Barkhaus et al. (1999) found a smaller macro-MUP amplitude in only three of 17 cases. Both studies concluded that their findings did not support the co-existence of neurogenic components in S-IBM but were consistent with a primary muscle disorder. Because Eisen et al. (1983) studied only seven IBM patients, it is possible that their data might be biased because of the small number of patients. To avoid this possible bias, we studied the SFEMG in a larger number of patients. In contrast to Eisen’s cases, we had more younger patients and more with proximal muscle involvement. Only one patient was under 61 years of age in Eisen’s series, whereas we had four patients in this age group in our series. In Eisen’s series, there was distal muscle involvement in all cases and none had predominant proximal involvement. In our series, distal muscle involvement was seen in nine and predominant proximal involvement in 18 cases. Other-
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wise, there is no major difference between Eisen’s patients and ours with regard to areflexia, CK and conventional needle EMG findings. The major differences between the SFEMG findings in Eisen’s series (Eisen et al., 1983) and ours are the lower FD and lower mean MCD in our series: 2.18 vs 6.3 in FD and 49 vs 83 ls in mean MCD. No neurogenic blocking was found in any of our cases or Eisen’s cases. The minimal increase in FD in S-IBM can be explained by the presence of many small atrophic fibers, a common finding on the muscle biopsy in S-IBM, and the minimal increase in MCD by the end-plate dysfunction by the presence of a myopathic process. In SFEMG, FD and MCD values are helpful in differentiating among neuromuscular transmission defect, myopathy, and denervation (Oh, 1988). In classical neuromuscular transmission defect, FD is relatively normal and MCD is markedly abnormal. In denervation, FD is markedly increased but MCD is only minimally increased, whereas in myopathy FD and MCD are minimally increased. In 34 patients with polymyositis or dermatomyositis, Jian et al. (2005) found an increased FD (mean value, 2.34; range 1–6) and a mildly increased jitter (mean 41 ls; range 5–78 ls). Our findings are almost identical to those found in polymyositis or dermatomyositis and typical of the classical pattern of myopathy. Thus, our findings, though non-specific, support the consensus that S-IBM is a myopathy. References Ad Hoc Committee of AAEM. Single fiber EMG reference values: a collaborative effort. Muscle Nerve 1992; 15:151–161. Barkhaus PE, Periquet MS, Nandedkar SD. Quantitative electrophysiologic studies in sporadic inclusion body myositis. Muscle Nerve 1999;22:480–7. Dabby R, Lange DJ, Trojaborg W, Hays AP, Lovelace RE, Brannagan TH, et al. Inclusion body myositis mimicking motor neuron disease. Arch Neurol 2001;589:1253–6. Eisen A, Berry K, Gibson G. Inclusion body myositis: myopathy or neuropathy? Neurology 1983;33:1109–14. Engel WK, Askanas V. Inclusion-body myositis. Clinical, diagnostic, and pathologic aspects. Neurology 2006;66:S20–9. Griggs RC, Askanas V, DiMauro S, Engel A, Karpati G, Mendell JR, et al. Inclusion body myositis and myopathies. Ann Neurol 1995;38:705–16. Jian F, Cui LY, Li BH, Du H. Changes of single fiber electromyography in patients with inflammatory myopathies. Chin Med Sci J 2005;20:1–4. Joy JL, Oh SJ, Baysal AL. Electrophysiologic spectrum of inclusion body myositis. Muscle Nerve 1990;13:949–51. Lotz BP, Engel AG, Nishino H, Stevens JC, Litchy WJ. Inclusion body myositis; observations in 40 patients. Brain 1989;112:727–47. Luciano CA, Dalakas MC. Inclusion body myositis. Neurology 1997;48:29–33. Oh SJ. Electromyography. Neuromuscular transmission defect. Baltimore, MD: Williams & Wilkins; 1988. Ryan HF, Claussen GC, Oh SJ. A case review. Initial misdiagnosis of amyotrophic lateral sclerosis and spinal muscular atrophy in the presentation of inclusion body myositis. Muscle Nerve 2000;13:1639. Sanders DB, Howard Jr JF, Johns TS. Single-fiber electromyography in myasthenia gravis. Neurology 1979;29:68–76.
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Sekul E, Chow C, Dalakas MC. Magnectic resonance imaging (MRI) of the forearm as a diagnostic aid in patients with inclusion body myositis (IBM). Neurology 1994;44:A310. Vershuuren JJ, Baldrising UA, Wintzen AR, van Engelen BGM, van der Hoeven H, Hoogendijk J. Inclusion body myositis. In: Emery AEH, editor. Diagnostic criteria for neuromuscular disease. 2nd ed.
European neuromuscular center. The Royal Society of Medicine; 1997. p. 81–4. Vilalanova M, Kawai M, Lu¨bke U, Oh SJ, Perry G, Six J, et al. Rimmed vacuoles of inclusion body myositis and oculopharyngeal muscular dystrophy contain amyloid precursor protein and lysosomal markers. Brain Res 1993;603:343–7.