Myopathic Muscle Histopathology And The Origin Of Abnormal Electrical Activity Detected By

The Peripheral Neuropathy Solution

Peripheral Neuropathy Program By Dr. Randall Labrum

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3.1. Histopathology

Myopathic states result in a variety of structural alterations in the muscle. Muscle fiber atrophy is typically produced by denervation, although it can be observed in the late stages of severe myopathies (Fig. 8). Muscle fiber hypertrophy (Fig. 8) is observed in chronic muscle diseases, notably in the muscular dystrophies and in other longstanding disorders (e.g., hypothyroid myopathy). Muscle fiber necrosis results in disruption and fragmentation

Chronic Muscle Disease

Fig. 8. Chronic myopathic changes (Emery-Dreifuss muscular dystrophy). Cross-section demonstrating pronounced variation in muscle fiber size with enlarged (hypertrophic) and small (atrophic) fibers. Additionally, there are prominent internalized myonuclei, fiber splitting (arrows), and an excess of connective tissue. This increase in fiber size variation compared with healthy muscle contributes to the temporal dispersion of muscle fiber action potentials arriving at the recording electrode and, hence, to the polyphasic MUAP of myopathic disorders [see Fig. 7]. By creating two fibers from one, fiber splitting has the effect of increasing MUAP amplitude. H&E stain.

Fig. 8. Chronic myopathic changes (Emery-Dreifuss muscular dystrophy). Cross-section demonstrating pronounced variation in muscle fiber size with enlarged (hypertrophic) and small (atrophic) fibers. Additionally, there are prominent internalized myonuclei, fiber splitting (arrows), and an excess of connective tissue. This increase in fiber size variation compared with healthy muscle contributes to the temporal dispersion of muscle fiber action potentials arriving at the recording electrode and, hence, to the polyphasic MUAP of myopathic disorders [see Fig. 7]. By creating two fibers from one, fiber splitting has the effect of increasing MUAP amplitude. H&E stain.

of the sarcoplasm and loss of normal cross striations (Fig. 9). Regenerating fibers stain dark blue with hematoxylin stain because of their increased RNA content. Segmental necrosis may result in separation of a portion of a muscle fiber from the NMJ, resulting in denervation of the detached portion of the muscle fiber. Interstitial mononuclear cell infiltrates (Fig. 10) are important markers for inflammatory muscle disease, such as polymyositis. Vacuolar degeneration may be observed in a number of myopathies, including glycogen and lipid storage disorders, IBM (Fig. 11), and hypokalemic periodic paralysis. By electron microscopy, the vacuoles may contain normal or abnormal material and fluid. Various structural changes may be observed with congenital myopathies, such as nemaline rod myopathy, centronuclear myopathy (Fig. 12), and central core disease. Additionally, mitochondrial abnormalities (Fig. 13) are observed in a variety of myopathies, including the Kearns-Sayre syndrome.

3.2. EMG Correlates of Myopathic Muscle

3.2.1. Insertional Activity in Myopathic Muscle

A marked reduction of insertional activity occurs if muscle fibers are severely atrophied or replaced by fibrous tissue or fat, or if they become unexcitable, for example, during severe paralysis in familial periodic paralysis. An increase in insertional activity is the first EMG clue to the presence of abnormal spontaneous potentials in the muscle (Fig. 14).

3.2.2. Spontaneous Activity in Myopathic Muscle

The general rule of thumb is that any spontaneous potential with an initial positive deflection should be regarded as abnormal. It is also important to pause and allow sufficient time

Necrotic Muscle

Fig. 9. Muscle fiber necrosis. Longitudinal section showing a necrotic muscle fiber segment (arrows) with disruption/fragmentation of the sarcoplasm and loss of normal cross striations. Myonuclei (arrowheads), with prominent nucleoli of a regenerating muscle fiber (open arrowheads) are also noted. Such a pathological state may be associated with fibrillation potential activity because still healthy muscle fiber segments may have become separated from the muscle end-plate region by segmental fiber necrosis. H&E stain.

Fig. 9. Muscle fiber necrosis. Longitudinal section showing a necrotic muscle fiber segment (arrows) with disruption/fragmentation of the sarcoplasm and loss of normal cross striations. Myonuclei (arrowheads), with prominent nucleoli of a regenerating muscle fiber (open arrowheads) are also noted. Such a pathological state may be associated with fibrillation potential activity because still healthy muscle fiber segments may have become separated from the muscle end-plate region by segmental fiber necrosis. H&E stain.

(>1-2 s) between each needle electrode advancement to look for abnormal spontaneous potentials. The four abnormal spontaneous potentials to look for in a patient with myopathy comprise: fibrillation potentials, positive sharp waves (PSWs), myotonic potentials, and complex repetitive discharges (CRDs).

Fibrillation potentials are the most common abnormal insertional/spontaneous activity observed in myopathies. They seem to arise spontaneously from either a single muscle fiber or a few muscle fibers and are not associated with visible contractions. They are biphasic or triphasic waves with an initial positive deflection (Fig. 15). They are usually 1 to 2 ms in duration and less than 100 ^V in amplitude. They are identified by their regular frequency, with a typical sound on the loudspeaker that is likened to "raindrops on tin roof." PSW, as the name implies, are biphasic waves with an initial PSW followed by a long negative wave. They are usually 30 ms in duration, with amplitudes of 50 ^V to 1 mV. They are regular in frequency and are identified by their "dull thud" or "ticking of clock" sounds on the loudspeaker. Fibrillation potentials in myopathic disorders were described as early as 1949 by

Myopathy Histopathology
Fig. 10. Mononuclear cell infiltration and excessive muscle fiber size variation in inflammatory myopathy. The inflammation surrounds small vessels (*) and spills out into the endomysium to surround some muscle fibers. H&E stain.
Rimmed Vacuoles
Fig. 11. Vacuolated muscle fiber in the setting of inclusion body myositis. The vacuoles are lined or "rimmed" with granular material. H&E stain.

Kugelberg. They are thought to result from segmental necrosis of muscle fibers, in which the necrosis leaves a distal muscle fiber segment separated from the part carrying the motor plate. Both fibrillation potentials and PSWs have the same clinical significance and can be observed with both neurogenic and myopathic disorders. However, when observed in excess in a myopathic illness, the muscle biopsy almost always shows some necrotizing features.

Myotonic discharges are the second most common abnormal insertional/spontaneous activity observed in myopathies. They are the EMG hallmark of myotonia and are often associated with clinical myotonia. When observed diffusely on needle examination, the patient is considered to have a myotonic disorder unless proven otherwise. They are generated by single

Kearns Sayre
Fig. 12. Centronuclear myopathy. Instead of their normal peripheral location, muscle nuclei are located in the central regions of the muscle fibers. H&E stain.
Myopathic Discharges Emg
Fig. 13. Mitochondrial myopathy in the context of Kearns-Sayre syndrome. Note the accumulation of darkly staining material in the subsarcolemmal regions that prove by electron microscopy to be abnormal mitochondria. H&E stain.

muscle fibers and can occur either spontaneously, by stimulation of the nerves supplying the recorded muscle, by voluntary MUAP activation, or by mechanical stimulation. Cold is thought to enhance myotonic discharges in most conditions; the one exception to this rule is paramyotonia congenita, in which prolonged cooling will lead to complete electrical silence of the muscle. The frequency of their discharge ranges between 15 and 150 Hz, and their amplitude ranges between 10 ^V and 1 mV. Their waxing and waning amplitudes and the "dive-bomber sound" on the loudspeaker are characteristic (Fig. 16). Although the precise

Emg Dive Bomber
Fig. 14. Insertion activity. Top, normal insertion activity. Bottom, increased insertion activity. From Daube, 1991 with permission.
Emg Abnormal Waveforms Image

0.001"

Fig. 15. Fibrillation potentials. Top, spike form. Center, positive waveform. Bottom, development of a positive wave form (serial photographs taken after insertion of needle electrode). From Daube, 1991 with permission.

0.001"

Fig. 15. Fibrillation potentials. Top, spike form. Center, positive waveform. Bottom, development of a positive wave form (serial photographs taken after insertion of needle electrode). From Daube, 1991 with permission.

mechanism of myotonia is unclear, it is thought to be secondary to a defect in ion channels on the muscle membrane (the chloride channel in myotonia congenita, and the sodium channel in paramyotonia and hyperkalemic periodic paralysis).

CRDs are repetitive discharges of polyphasic or serrated action potentials characterized by their uniform frequency, shape, and amplitude, with abrupt onset, cessation, or change in configuration (Fig. 17). In contrast to myotonic discharges, CRDs do not wax and wane in amplitude or frequency. Formerly referred to as "bizarre high-frequency waves" or the confusing

Insertional Wave Emg
Fig. 16. Myotonic discharge. Note that the potentials wax and wane in amplitude and frequency. From Daube, 1991 with permission.
Complex Repetitive Discharges
Fig. 17. Complex repetitive discharges. These are the action potentials of groups of muscle fibers discharging in near synchrony at high rates. Note that they are characterized by abrupt onset and cessation. From Daube, 1991 with permission.

term "pseudomyotonic discharges," they are indicative of a hyperirritable muscle membrane with a group of muscle fibers firing in near synchrony. CRDs are observed in both neurogenic and myopathic disorders. Their presence is suggestive of a more chronic or longstanding process. They may be found in patients with muscular dystrophy, hyperkalemic periodic paralysis, glycogen storage disorders, and hypothyroid myopathy, but also in chronic dener-vating diseases.

Clinically, fasciculations are visible muscle twitches and they represent the spontaneous contractions of a group of muscle fibers belonging to a single motor unit. The electrical activity associated with the twitch is called a fasciculation potential, and it has the configuration of a MUAP. Although fasciculation potentials generally arise in the wake of an underlying neurogenic process, rarely, they are observed in myopathies, such as thyrotoxic myopathy and inclusion body myositis (IBM). Even in such rare instances, an underlying neurogenic component may be the cause of fasciculations. Likewise, myokymic potentials are not usually observed in diseases of the muscle in the absence of a coexisting or underlying neurogenic process. In fact, the presence of fasciculations or myokymia should prompt the clinician to rethink the diagnosis of a primary muscle disease.

3.2.3. MUAP Changes in Myopathic Muscle

In myopathy, there is a reduction in the average number of functional muscle fibers per motor unit. Some of the fibers within a motor unit may be nonfunctional because of muscle fiber necrosis and, hence, the electrode may be less likely to record activity from distant fibers. The initial and terminal portions of the MUP are not recorded, thereby producing short-duration MUAPs. The shortening does not depend on the type of myopathy but is greater in patients with weakness that is more advanced, and is more likely to be found in

Emg Pseudomyotonic

Fig. 18. Normal and abnormal motor unit action potential (MUAP) configurations. (A) Normal MUAPs. (B) Myopathic MUAPs. Short-duration, low-to-moderate amplitude, "spikey" and polypha-sic MUAPs. The reduced number of muscle fibers per motor unit leads to a MUAP that is shorter in duration and lower in amplitude than normal. Because of the increased variation in size of remaining muscle fibers, there is less synchronous firing of individual muscle fibers, leading to increased polyphasia. (C) Large-amplitude, long-duration (including satellite potentials), polyphasic MUAPs, as observed in neurogenic disorders. Time marker, 10 ms; voltage marker, 200 |V. From Bromberg and Albers, 1988 with permission.

Fig. 18. Normal and abnormal motor unit action potential (MUAP) configurations. (A) Normal MUAPs. (B) Myopathic MUAPs. Short-duration, low-to-moderate amplitude, "spikey" and polypha-sic MUAPs. The reduced number of muscle fibers per motor unit leads to a MUAP that is shorter in duration and lower in amplitude than normal. Because of the increased variation in size of remaining muscle fibers, there is less synchronous firing of individual muscle fibers, leading to increased polyphasia. (C) Large-amplitude, long-duration (including satellite potentials), polyphasic MUAPs, as observed in neurogenic disorders. Time marker, 10 ms; voltage marker, 200 |V. From Bromberg and Albers, 1988 with permission.

proximal than distal muscles. If the number of active fibers lying close to the electrode is also reduced, the mean amplitude of the potentials may also be diminished because of loss of contributions of fibers that have disappeared. In adult limb muscles, MUAPs of shorter than 6 ms are considered to be short in duration. Short-duration MUAPs are usually also low in amplitude (<500 |V) and recruited early (see below) (an inappropriately large number of MUAPs in the face of a weak voluntary muscle contraction). Thus, small-amplitude, short-duration (SASD) MUAPs are the EMG hallmarks of myopathy (Fig. 18). There are likened to "newspaper rubbing between two fingers" on the loudspeaker. These potentials (SASDs) are often referred to as "myopathic." As discussed below, it is important to remember that the so-called "myopathic" potentials are not diagnostic of myopathy and can be observed with a number of other conditions.

In chronic or end-stage myopathies, some MUAPs may be increased rather than decreased in amplitude and duration. These alterations in MUAP appearance, observed mostly in necrotizing myopathies (Fig. 9), probably result from reinnervation of previously denervated muscle fiber segments by secondary collateral sprouts, fiber splitting, and from the increase in numbers of hypertrophic fibers (Fig. 8). An additional point to keep in mind is that in severe,

Normal Muaps

Fig. 19. Pattern of motor unit action potential (MUAP) recruitment at low levels of muscle force. (A) Normal recruitment with 3 MUAPs recruited. (B) Myopathy (myositis). Early recruitment with many short duration polyphasic MUAPs despite low level of force. Because each motor unit contains fewer muscle fibers, it generates less force than normal. To develop a given level of force, an increased number of MUAPs is required compared with normal. (C) Decreased recruitment with only one high-amplitude MUAP firing rapidly, as observed in neurogenic disorders. Time marker, 10 ms; voltage marker, 200 |V. From Bromberg and Albers, 1988 with permission.

Fig. 19. Pattern of motor unit action potential (MUAP) recruitment at low levels of muscle force. (A) Normal recruitment with 3 MUAPs recruited. (B) Myopathy (myositis). Early recruitment with many short duration polyphasic MUAPs despite low level of force. Because each motor unit contains fewer muscle fibers, it generates less force than normal. To develop a given level of force, an increased number of MUAPs is required compared with normal. (C) Decreased recruitment with only one high-amplitude MUAP firing rapidly, as observed in neurogenic disorders. Time marker, 10 ms; voltage marker, 200 |V. From Bromberg and Albers, 1988 with permission.

end-stage disease, the process of recruitment (see next section) may actually be reduced (Fig. 19) rather than early or increased because the extensive loss of muscle fibers leads to the functional equivalent of a loss of motor units.

3.2.4. Recruitment Pattern in Myopathic Muscle

In myopathic disorders, individual muscle fibers drop out of the motor unit without affecting the integrity of the motor unit's connection with the central nervous system. Accordingly, the number of functional motor units remains unaltered until an advanced stage of the disease. Because each motor unit contains fewer functioning muscle fibers, it generates less force than normal. As a result, more motor units than normal are required to generate a certain level of force; this phenomenon is called early recruitment (Fig. 19). Hence, in myo-pathic diseases, an inappropriately large number of MUAPs is firing in the face of muscle contractions that generate only weak force. In this situation, the interference pattern remains full (but compared with normal, the amplitude is reduced because the pattern is generated by SASD MUAPs). Because activation, a central nervous system process—the ability to fire motor units faster—is unaffected in myopathy, the ratio of firing frequency to number of MUAPs will typically be less than normal (<5).

3.2.5. Clinical Significance and Differential Diagnosis of "Myopathic" MUAPs

Overall, just as fibrillation potentials are indicative of the disease activity, MUAP changes are indicative of disease severity. Of the various MUAP alterations, an increased proportion of polyphasic MUAP is often reported to be the earliest recognizable change with myopathies. Decreased MUAP duration and early recruitment are considered the most reliable

Guillian Barre Syndrome Hisptopathogy

(Guillain-Barré syndrome)

2. Regeneration after axon loss mononeuropathy or polyneuropathy.

(myasthenia gravis)

(myasthenic syndrome)

1. Muscle inactivation (periodic paralysis)

2. Muscle degeneration (polymyositis)

3. Variations in muscle fiber conduction velocity (polymyositis)

Muscle fiber

Fig. 20. Differential diagnosis of the short duration MUAP. Schematic representation of the motor unit and specific targets of disease processes that lead to failure to generate muscle fiber action potentials. From Ferrante and Wilbourn, 2000 with permission.

1. Nerve fiber conduction block

(Guillain-Barré syndrome)

2. Regeneration after axon loss mononeuropathy or polyneuropathy.

A Neuromuscular block

(myasthenia gravis)

(myasthenic syndrome)

1. Muscle inactivation (periodic paralysis)

2. Muscle degeneration (polymyositis)

3. Variations in muscle fiber

Muscle fiber conduction velocity (polymyositis)

Fig. 20. Differential diagnosis of the short duration MUAP. Schematic representation of the motor unit and specific targets of disease processes that lead to failure to generate muscle fiber action potentials. From Ferrante and Wilbourn, 2000 with permission.

changes. Decreased MUAP amplitude is considered least reliable, because it is dependent on various needle electrode factors.

In addition to myopathies, short-duration MUAPs can also be observed in NMJ disorders such as myasthenia gravis, Lambert-Eaton myasthenic syndrome (LEMS), and botulism (Fig. 20). In these cases, the "myopathic" MUAP occur because of the failure of action potential generation secondary to a defect in the NMJ. SASD MUAPs may also be observed with nascent motor units after denervation and reinnervation. However, nascent MUAPs reveal markedly reduced recruitment in contrast to the early recruitment observed in myopathies.

4. THE WORKUP FOR MYOPATHY 4.1. Advantages of Electrodiagnosis

EMG provides a much wider source of sampling than other diagnostic procedures, such as muscle biopsy. EMG also helps enormously in the differential diagnosis of weakness, distinguishing myopathic disorders from diseases of peripheral nerve/anterior horn cell or NMJ. For example, IBM and amyotrophic lateral sclerosis may share clinical features of asymmetric muscle atrophy and weakness, but the former would be more likely to demonstrate SASD MUAPs and early recruitment. EMG is also useful in identifying certain electrophysiological abnormalities, such as myotonic discharges, that may not have a clinical counterpart, thereby providing an important clue for the diagnostic process. In addition, EMG findings may provide important information that helps in the selection of a muscle for biopsy. For example, a muscle involved by an inflammatory myopathy might be expected to reveal needle electrode findings of fibrillation potentials and SASD MUAPs. Finally, EMG findings may be the only objective evidence of motor unit dysfunction and is especially useful in the early stages of a disease or if the disease is mild. For example, early in the course of an inflammatory myopathy,

Table 3

Recommended Electrodiagnostic Studies for the Patient With a Suspected Myopathy"

Recommended nerve conduction studies for myopathy:

At least one motor and one sensory conduction, with corresponding F-wave from the arm (e.g., median sensory and motor, median F-wave) At least one motor and one sensory conduction, with corresponding F-wave from the leg (e.g., sural sensory and tibial motor, tibial F-wave) (if generalized decrease in CMAP, proceed with workup for neuromuscular junction disorders) Recommended needle electrode examination for myopathy (perform examination on muscles on one side of the body, leaving the other side for muscle biopsy, if needed):

At least two proximal and two distal muscles in the lower extremity (e.g., tibialis anterior, gastrocnemius, vastus lateralis, and iliopsoas) At least two proximal and two distal muscles in the upper extremity (e.g., first dorsal interosseus, flexor carpi radialis, biceps, and deltoid) At least one paraspinal muscle

"Adapted from Preston and Shapiro.

when weakness is minimal and limited, fibrillation potential activity might be mild but widespread, including paraspinal muscles.

4.2. Limitations of Electrodiagnosis

The findings of EMG are not diagnostic of any one illness. No waveforms are pathognomonic of a specific disease. The EMG findings are diverse; some disorders, such as congenital or endocrine myopathies, do not produce extensive EMG changes (probably because they mainly affect the contractile properties of the muscle fibers without modifying their electrical activity), whereas others, such as inflammatory myopathy, may produce striking findings. The EMG appearance may differ depending on the stages of the disease. A coexisting neuro-genic disorder also limits the usefulness of the EMG. Therefore, before arriving at a specific diagnosis, EMG results should be integrated with the clinical findings.

4.3. Planning the EMG Study

Just before the EMG examination we explain the purpose of the EMG and the procedure itself to the patient. We tailor testing conditions to patient's comfort, ensuring that the room temperature is warm and the patient appropriately clothed. Once the clinical impression of a myopathy is confirmed, it is reasonable to proceed with the first of the two-part EMG, the nerve conduction study (NCS) (Table 3). It is a common practice to perform the NCS before the needle examination.

4.3.1. Nerve Conduction Studies in Myopathy

4.3.1.1. Nerve Conduction Studies

Because most myopathies tend to be characterized by proximal more than distal muscle involvement, the results of routine motor studies recording from distal small muscles are usually normal, unless the myopathy is severe. Proximal and intermediate muscles (deltoid, biceps, and tibialis anterior) certainly may be evaluated, and some reductions in compound muscle action potentials (CMAPs) may be found more readily in those muscles. The reduction in CMAP amplitude is explained by the fact that the CMAP is a summation of individual muscle action potentials. More importantly, a generalized reduction in the CMAP amplitudes should alert the electromyographer to the possibility of disorders involving either the presynaptic portion of the NMJ, motor polyradiculopathies, or motor neuron diseases. It is then essential to perform repetitive nerve stimulation (RNS) testing and postactivation facilitation testing to look for LEMS. Another reason to perform RNS in the workup of a myopathy is that myasthenia gravis may simulate myopathy in some patients if it presents with proximal muscle weakness without symptomatic cranial nerve signs.

Late responses, such as H-reflexes and F-waves, are usually normal in myopathies. They may be rarely reduced if the recorded muscles are severely affected. Sensory NCS results are generally normal in myopathy and when attenuated or absent suggest a coexisting neuropathy that may be part of a systemic disease. 4.3.1.2. Repetitive Nerve Stimulations

RNS are generally expected to be normal in disease of the muscle alone. The usefulness of RNS in myopathies is mainly to differentiate myopathies from diseases such as myasthenia gravis, especially when it presents with proximal muscle weakness alone without any ocular or bulbar symptoms, or LEMS. A few points regarding RNS in myopathies are worth noting:

• A decremental response may be observed with the myotonic disorders. However, it is more prominent, with repetition rates of 5 Hz, rather than the usual 2-Hz repetition rate.

• An incremental response may be observed during attacks of periodic paralysis (where a low-amplitude CMAP increases with repetitive rates of 10 Hz).

• Both decremental and incremental responses have been reported with polymyositis.

• Decremental responses have also been noted with myophosphorylase deficiency (McArdle's disease).

4.3.2. Needle Electrode Examination in Myopathy

The NCS is followed by the needle electrode examination (NEE). Here, a monopolar or concentric bipolar needle is inserted into selected muscles to assess the insertional activity, spontaneous activity, and the motor unit morphology on voluntary activity. Certain key points are worth remembering during the needle examination, taking inflammatory muscle disease as an example. In this regard, we find the approach of Dr. Wilbourn very useful. The most proximal muscles, such as iliacus, glutei, and paraspinal muscles, are the ones most likely to show abnormalities, rather than biceps, deltoid, and the vasti. Certain mid-limb muscles, particularly brachioradialis and tibialis anterior, more often show abnormalities than muscles that are more proximal, such as the vasti. In addition, whenever possible, the needle examination should be confined to one side of the body, leaving the other for a muscle biopsy, if needed. It is important to avoid any needle-induced muscle fiber trauma that could potentially influence the muscle biopsy results.

4.3.3. Single-Fiber EMG in Myopathy

Single-fiber EMG is not commonly pursued in the evaluation of myopathy. However, abnormal jitter and blocking will be identified because these findings are the result of nonspecific damage to the end terminal.

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Responses

  • eglantine
    What does an emg test look like for upper extremity normal and abnormal?
    6 years ago
  • reiss
    What is the specific origin of the electrical activity detected by the EMG?
    5 years ago

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