Neurophysiology of Nerve Conduction Studies

12 Neurophysiology of Nerve Conduction Studies

James B. Caress, Gregory J. Esper, and Seward B. Rutkove

Summary The methodology for performing standard nerve conduction studies has been established by identifying the most helpful and consistent physiological data obtainable while being constrained by a variety of technical and practical limitations. Nerve stimulation occurs underneath the negatively charged anode of the applied stimulator and simultaneous hyperpolarization of the nerve occurs beneath the positively charged cathode. Referential or bipolar recording techniques are used for all types of measurements. Sensory conduction studies can be performed either antidromically or orthodromically, although, for technical reasons, the former are usually preferred; the recorded sensory nerve action potential is made up of the simultaneous depolarization of all of the cutaneous sensory axons. In motor studies, the compound motor action potential is recorded from the motor point of the muscle of interest and represents the depolarization of the underlying muscle fibers rather than the nerve itself and is, thus, of considerably greater amplitude and duration. F-waves and H-reflexes represent the two most commonly evaluated forms of late responses and assist with assessing the entire length of the neurons, from spinal cord to distal muscle.

Key Words: Compound motor action potential; depolarization; late responses; nerve conduction study; sensory nerve action potential; stimulation.

1. PHYSIOLOGY OF STIMULATION Stimulators used in routine nerve conduction studies (NCS) have a cathode and an anode and are, therefore, bipolar. The cathode is negatively charged, whereas the anode is positively charged. The depolarization of axons occurs under the cathode because the negativity in the region of the cathode leads to a reduction in the potential difference between the inside and the outside of the cell (the inside of the cell is relatively negative at baseline). On the other hand, the extracellular environment under the anode is positively charged, leading to hyperpolarization of the underlying axons. Much of the current supplied by the stimulator travels in the very low resistance extracellular space because current follows the path of least resistance. The cross-sectional resistance of an axon will determine whether some of that current will enter and depolarize the nerve. Cross-sectional resistance is reduced as diameter of the axon increases, resulting in a greater area in which current can flow. The result relevant to NCS is that large axons will depolarize with relatively less stimulus current than smaller axons. Hence, with low stimulus intensities, large axons will be preferentially stimulated.

From: The Clinical Neurophysiology Primer Edited by: A. S. Blum and S. B. Rutkove © Humana Press Inc., Totowa, NJ

207 208 Caress, Esper, and Rutkove

Fig. 1. A median sensory nerve action potential recorded from digit 2. The digitally averaged waveform is on top.

2. MEASUREMENT OF SENSORY POTENTIALS IN NCS Waveforms that are displayed during sensory NCS reflect the passage of current beneath surface electrodes that are at least a few millimeters distant from the current generators (that is, the depolarizing axons). Routine studies usually use a bipolar recording technique in which both the active and reference electrodes lie above the nerve. The potential measured by the active electrode is compared with that measured by the reference electrode, and both are compared with a ground electrode lying elsewhere on the patient. The reference electrode makes an important contribution to the observed compound sensory nerve action potential (SNAP) (Fig. 1). The nerve current is not directly measured in NCS but overlying loops of current in the soft tissue reflect the actual action potentials. This situation is referred to as volume conduction and is further described in Chapter 4. Temporal dispersion refers to the phenomenon that, as a sensory conduction study is performed over longer and longer segments of nerve, the recorded SNAP loses its sharpness (high amplitude and short duration) and becomes a broader, lower-amplitude potential. This occurs normally in any sensory NCS because individual sensory axons conduct at slightly different rates and because these slight differences are magnified when a NCS is performed over a large segment of nerve. In diseased states, such as polyneuropathies, temporal dispersion can be enhanced (abnormal temporal dispersion). Because sensory NCS are especially vulnerable to the effects of temporal dispersion in both health and disease, sensory studies are usually performed over shorter segments of nerve than motor studies, which tend to be less susceptible to these effects (described in Section 3). Sensory responses can be recorded with an orthodromic or an antidromic technique. In orthodromic studies, the recording electrodes are proximal to the stimulation site, and, in antidromic studies, stimulation is proximal to the recording position. In the hands, ring electrodes are used around the fingers to stimulate (orthodromic) or record (antidromic). Although orthodromic Nerve Conduction Studies 209

Fig. 2. A median compound muscle action potential. Recordings made with wrist and elbow stimulating APB, abductor pollicis brevis. responses reflect more accurately the physiology of sensory responses via afferent conduction, upper extremity orthodromic responses are usually considerably smaller than antidromic responses.

3. MEASUREMENT OF MOTOR POTENTIALS IN NCS The active electrode is placed over the motor point of the muscle, where the majority of the motor axons synapse with the end plates of the muscle fibers. Rather than measuring a compound nerve action potential, the summation of the muscle fiber action potentials is measured. This is called the compound motor action potential (CMAP) (Fig. 2). In this case, there is no leading edge of a dipole to cause an initial downward deflection, because the depolarization initiates directly beneath the recording electrode. The influx of Na+ at the muscle end plates generates extracellular negativity that is displayed as an abrupt upward deflection from the baseline. The waveform returns to the baseline as the resting membrane potential of the muscle fibers is reestablished. The distal latency is the time at which the depolarization of the fastest nerve fiber is recorded; this response is routinely recorded but does not directly measure the conduction velocity, as is the case with sensory recordings. This is because of the additional time it takes for acetylcholine to traverse the synapse, to attach to receptors, and to generate muscle fiber action potentials. Conduction velocity is calculated only in the proximal segments of nerve, by subtracting the distal latency and distance from the values obtained with proximal stimulation. However, by establishing normal values for distal latencies for specific distances, meaning can be given to the measurement that can assist in the evaluation of a variety nerve disorders, including distal compression neuropathies, such as carpal tunnel syndrome (median neuropathy at the wrist). One point that is frequently overlooked is that the recorded CMAP does not reflect muscle contraction. The CMAP is a purely electrical signal from the summation of muscle fiber action potentials, which occurs well before the actual contraction of the muscle takes place. 210 Caress, Esper, and Rutkove

The visible muscle contraction requires Ca2+ release cross-linking of actin and myosin fibers (so-called excitation–contraction coupling), which occurs much more slowly and is not measured in routine NCS. Also, as in sensory NCS, the reference electrode is not electrically inac- tive, and it contributes to the waveform, even though it is often placed over a bone, a region generally considered electrically silent. This is particularly clear during ulnar or tibial motor NCS, where the waveform characteristically exhibits a double-peaked negative phase. The second peak results from activity recorded at the reference electrode. Similar to sensory responses, normal temporal dispersion of the responses does occur because smaller motor neurons will conduct at slower velocities than larger, causing the recorded CMAP to spread out (increase in duration and decrease in amplitude) the longer the segment of nerve studied. However, the effects are not nearly as dramatic as those observed in sensory studies, because the duration of the CMAP is much larger than of the SNAP (~6 times longer). Hence, small increases in duration are not be readily apparent, and the amplitude of the response generally declines only modestly with increasing distance.

4. NEUROPHYSIOLOGY OF THE LATE RESPONSES

4.1. F-Waves The “F” stands for foot, because these responses were first recorded from intrinsic foot muscles. On stimulation of a single motor axon, the wave of depolarization will travel distally to be recorded as part of the CMAP, or “M-wave,” but also will travel proximally to its anterior horn cell (AHC). Retrograde depolarization of AHCs will result in regeneration of an action potential at the axon hillock in a small subset of neurons (~5–10%), which then travels back down the motor axon to the innervated muscle, recorded at the electrodes as the F-wave (Fig. 3). Although, for theoretical reasons, it is desirable to reverse the polarity of the stimulator, placing the anode distally and cathode proximally to avoid “anodal block,” this remains more of a theoretical rather than a practical consideration. F-waves are easily generated with the cathode in the distal position. At the level of the spinal cord, no synapse is involved, and an F-wave from a single axon has the same morphology and almost identical latency each time. However, a single axon will not generate an F-wave with each successive depolarization. The probability that an F-wave will be generated from any neuron is dependent on the variable excitability of the AHC membrane that can be increased with reinforcement maneuvers (clenching teeth or making a tight fist) and decreased by sleep and anesthesia. F-waves may be absent in sleeping, sedated, or comatose persons, and should not be interpreted as a sign of peripheral nervous system disease in these patients. During NCS, supramaximal stimulation of the peripheral nerve ensures that all motor axons capable of generating an F-wave are depolarized each time. Under normal conditions, several axons generate an F-wave, and the summation of these responses is recorded. The varying probability that a single axon will produce an F-wave results in varia- tion of the morphology and latency of the summated F-waves. In severe neuropathic conditions, when only one axon capable of generating an F-wave is surviving, it is recorded as an “all or none” response without variability. Also under neuropathic conditions, unusually high amplitude F-waves may be recorded because of reinnervation of the motor units. At least 10 F-waves are usually collected for analysis. The minimum F-wave latency is the parameter measured in most labs, but reflects only the fastest motor axon contributing to the F-wave; this value may be spared in pathological situations and, importantly, in acquired demyelinating neuropathies. Mean or median F-wave latencies provide better information concerning the proximal sections of the nerves in diseased states. However, most EMG Nerve Conduction Studies 211

Fig. 3. F-responses recorded from the tibial nerve; the bottom tracing shows the superimposed data. laboratories do not have normal values from which to interpret abnormalities in these parameters. Other F-wave parameters that may also be useful include chronodispersion and persistence. Chronodispersion is a measure of the range of minimum latencies and is normally less than 5 ms. This range can be exceeded in demyelinating neuropathies or radiculopathies. Persistence is a measure of the frequency of obtaining an F-wave after supramaximal stimulus, and varies for different motor nerves. Persistence is 80 to 100% for most nerves, but peroneal F-waves may be difficult to elicit, even in healthy persons. F-wave minimum latency is dependent on limb length, and nomograms are used to judge abnormality. If a height-adjusted table is not available, the appropriate F-wave latency cor- rected for height (±2.5 ms) can be estimated using the formula: F-estimate (ms) = [2 × F distance (mm)/CV (m/s)] + distal latency (ms) + 1 ms where F distance is from the stimulus site to the C7 spinal process (median, ulnar) or the xiphoid process (peroneal, tibial), and CV is the conduction velocity. The addition of 1 ms allows for the central conduction delay. F-estimates can also be useful for identifying proximal pathology in the proximal segments of a nerve. Because the calculation of the estimate relies on the conduction velocity, which is obtained distally, proximal pathology will create a longer measured F-wave latency than would be anticipated by the F-estimate calculation. Because F-waves probe the proximal portions of nerves, it seems reasonable that they should be useful in studying the plexus and nerve roots, which otherwise can only be directly stimulated using special techniques. Unfortunately, F-waves do have limitations for common pathology, such as structural radiculopathies, for several reasons. For example, the standard median and ulnar motor NCS evaluate only the C8 and T1 roots, which are not commonly damaged in structural radiculopathies, C5, C6, and C7 radiculopathies being much more common. Further, the shared root innervation (C8, T1) of abductor digiti quinti and abductor pollicis brevis muscles means that, in the setting of a completely transected C8 root, the F-wave latency may still be normal because of sparing of the T1 root. F-waves are likely to be more useful in detecting radiculopathies affecting the lower extremities, where standard 212 Caress, Esper, and Rutkove peroneal and tibial motor conduction studies evaluate L5 and S1 derived neurons. Finally, because the F-response is a pure motor phenomenon, radiculopathies affecting only the sensory root cannot be detected (although this also remains a limitation of needle EMG). Recall that the F-wave evaluates the proximal and distal segments of the nerve because it travels to the root level and then back to the distal muscle to be recorded. This implies that F-waves may be prolonged in distal entrapment neuropathies and polyneuropathies; thus, abnormal F-waves are not specific for proximal nerve pathology. F-waves have their greatest usefulness in the setting of demyelinating radiculoneu- ropathies, especially Guillain–Barré Syndrome (GBS). Early GBS is frequently characterized by prominent involvement of the spinal roots. In these cases, the distal motor nerve segments may be electrophysiologically normal despite clinical weakness and areflexia caused by demyelination at the root level. F-wave minimum latency is commonly prolonged, and persistence can be severely reduced or absent in this setting; this suggests demyelination with conduction block in the proximal segments of the nerves. The combination of a normal distal CMAP and absent F-waves is highly specific for proximal demyelination. F-wave latencies are most prolonged 3 to 5 wk after the onset of GBS, secondary to further demyelination throughout the length of the nerve.

4.2. H-Reflex “H” stands for Hoffman, after the investigator who first recorded the late response in 1918. The H-reflex is often said to be the NCS parallel of the clinical ankle tendon reflex, but the two tests are probably not evaluating the exact same group of nerve fibers. The tibial nerve is stimulated in the popliteal fossa, with the cathode proximal to the anode, and the response is recorded with the active electrode overlying the belly of the soleus muscle and the reference electrode placed at the calcaneal tendon. As with F-waves, the “reversed” cathode–anode ori- entation avoids the possibility of anodal block. The nerve is stimulated with a long-duration (1 ms) pulse rather than the short-duration pulse commonly used in routine NCS (0.05–0.2 ms) because the longer pulse is more effective at selectively stimulating the type 1A sensory fibers from muscle spindle organs that initiate the response. In clinical practice, the H-reflex in adults is generally mostly recorded from the soleus; however, it is also readily obtainable form flexor carpi radialis with medial nerve stimulation, but is generally not performed because it provides little additional information over conven- tional EMG. However, in children and in diseased states, H-reflexes may also be elicitable from many other nerves and muscles. The H-reflex is best studied by generating a recruitment curve, accomplished by gradually increasing stimulus intensities such that the variability of the H-reflex can be measured (Fig. 4). At very low stimulus intensities, no response can be elicited. At slightly higher intensity, a small H-reflex can be seen without the M-wave. This occurs because the type 1A fibers are being stimulated without direct depolarization of the adjacent alpha motor neurons. The 1A fibers conduct the stimulus to the spinal cord, where a monosynaptic reflex occurs, as it does with the clinical ankle jerk, where the afferent volley is initiated by the Golgi tendon organs. From the spinal cord, the response travels orthodromically down the motor neuron to the soleus, where the triphasic H-wave is recorded. With further increasing stimulation, the H- reflex continues to grow in amplitude as more and more 1A afferents are stimulated. Then, as motor fibers are directly depolarized, an M-wave begins to appear. The H-reflex then begins to decline in amplitude with increasing stimulus intensity caused by collision with the Nerve Conduction Studies 213

Fig. 4. H-reflex recruitment. Note how the potential comes in initially before the M-wave, maximizes just as the M-wave appears, and then gradually decreases in size as the M-wave becomes supramaximal. Once the M-wave is supramaximal, the only recorded late responses will be the F-waves. The bottom tracing shows the superimposed data. antidromic impulse being conducted along the motor neurons. Eventually, the H-reflex is completely abolished, as a supramaximal motor response is elicited and antidromic motor responses collide with all the descending motor input arriving via the sensory pathways. At this point, any late responses recorded will be F-waves only. The minimum onset latency (usually 25–34 ms) is the only routinely measured aspect of the H-reflex and, similar to the F-wave, is dependent on the height of the subject and the integrity of the nerves. Comparing the affected and unaffected leg reflexes is more useful than analysis of a unilateral response, and most laboratories consider up to a 1.5 ms difference as normal. Also, comparing bilateral H-reflex amplitudes can be informative, as can comparing the ratio of the H-reflex amplitude with the M-wave amplitude. The ratio may reflect the degree of AHC excitability. The ratio usually increases in upper motor neuron lesions and can be used to evaluate spasticity. Amplitude can be measured as long as care is taken to move the recording electrodes to ensure optimum positioning. The H-reflex suffers from a lack of specificity for similar reasons as outlined for F-waves. The absolute latency is increased in polyneuropathies (axonal and demyelinating), or the reflex may be absent. Comparison of the healthy and diseased legs may be useful for diag- nosing S1 radiculopathies.

4.3. A-Waves The A-wave (Fig. 5) is another late response; however, it is only prominent in pathological states. It can be distinguished from F-waves by its invariable latency and morphology with each stimulus. The A-wave latency is typically shorter than the F-wave but can be longer. A- waves can be seen in the setting of any neuropathic process, but are quite common in polyneuropathies and radiculopathies. 214 Caress, Esper, and Rutkove

Fig. 5. An example of A-wave (arrow), obtained while evaluating ulnar F-waves.

A number of potential explanations have been suggested for the occurrence of A-waves. One possibility is that an abnormal axon may give off a branch proximally. Stimulation of the nerve may result in antidromic excitation of the branch, leading to a descending orthodromic depolarization. This would essentially represent a so-called “axon reflex.” Another possibility is that ephaptic transmission is occurring between the axons proximally because of abnormal (crosstalk) demyelination. An impulse can then travel antidromically up one neuron and orthodromically down another, exciting the muscle at a constant latency.

SUGGESTED READING Albers JW, Donofrio PD, McGonagle TK. Sequential electrodiagnostic abnormalities in acute inflammatory demyelinating polyradiculoneuropathy. Muscle Nerve 1985;8:528–539. Dumitru D. Physiologic basis of potentials recorded in electromyography. Muscle Nerve 2000; 23:1667–1685. Fraser JL, Olney RK. The relative diagnostic sensitivity of different F-wave parameters in various polyneuropathies. Muscle Nerve 1992;15:912–918. Kincaid JC, Brasher A, Markand ON. The influence of the reference electrode on CMAP configura- tion. Muscle Nerve 1993;16:392–396. Preston DC, Shapiro BE. Electromyography and Neuromuscular Disorders. Butterworth-Heinemann, Boston, MA, 2000. Roth G. Clinical Motor Electroneurography: Evoked Responses Beyond the M-Wave Eectopic Activity. Elsevier, Amsterdam, Holland, 2000. REVIEW QUESTIONS 1. Which of the following statements concerning temporal dispersion is true? A. Abnormal temporal dispersion is typically observed only in sensory nerves. B. Normal temporal dispersion is independent of the length of nerve being studied. C. Abnormal temporal dispersion is the hallmark of axonal polyneuropathies. D. Abnormal temporal dispersion is usually accompanied by a drop in response amplitude. E. Marked abnormal temporal dispersion is typically seen in the median nerve of patients with carpal tunnel syndrome. Nerve Conduction Studies 215

2. Which of the following comments is true regarding nerve stimulation? A. Nerve depolarization typically occurs beneath the anode. B. Little of the applied electrical current typically flows through the extracellular space. C. Large and small nerve fibers have an equal propensity toward initiating an action potential with stimulation. D. Anodal black can theoretically interfere with the acquisition of F wave data. E. Standard nerve conduction study techniques rely on the use of submaximal stimulation. 3. Which of the following statements concerning the F-estimate is true? A. The F-estimate can assist in identifying the presence of a distal neuropathic process. B. The F-estimate is useful only in lower extremity studies where the F-waves are longer. C. In a patient with an isolated L5 radiculopathy, but otherwise a normal nerve conduction study, the F-estimate would likely provide a value of shorter latency than the measured F-waves. D. The distal latency is not used to help calculate the F-estimate. E. The F-estimate is likely to be elevated falsely in patients with axonal polyneuropathies. 4. The following statements concerning sensory nerve conduction studies are true, EXCEPT: A. They can be performed orthodromically or antidromically. B. They are more susceptible to normal temporal dispersion than motor studies. C. They rely on depolarization of the nerve beneath the anode. D. They rely on measurements from both the E1 and E2 electrodes in reference to the ground. E. They preferentially stimulate larger diameter nerve fibers at low stimulus intensities. 5. Motor nerve conduction studies: A. Require that E2 be replaced over the belly of the muscle and E1 be placed at a relatively inac- tive site. B. Result in waveforms that are the summation of muscle fiber action potentials. C. Allow nerve conduction velocity to be measured with distal stimulation. D. Are representative of muscle contraction. E. Are typically performed in the antidromic fashion. 6. F waves are: A. Late responses measured during sensory nerve conduction studies. B. Indicative of pathology at the root level only. C. Typically less than 31–32 ms in latency in the upper extremities and less than 56 ms in latency in the lower extremities. D. Independent of height. E. Of identical morphology with each stimulus. 7. A patient with Guillain Barré Syndrome, or acute inflammatory demyelinating polyneuropathy, might be expected to have: A. Prolonged distal latencies. B. Conduction velocity slowing. C. Abnormal temporal dispersion. D. Prolonged F wave latencies. E. All of the above. 8. The tibial H-reflex: A. Is electrophysiologically similar to the ankle reflex. B. Represents the contraction of gastrocnemius. C. Represents the contraction of the soleus. D. May be abnormal in an L5 radiculopathy. E. Is independent of height. 9. Sensory conduction studies are typically abnormal in: A. Myopathy. B. Compressive radiculopathies. C. Polyneuropathy. D. Myasthenia gravis. E. All of the above. 10. A patient with a decreased median nerve sensory response amplitude, prolonged median nerve F wave latency, and prolonged median nerve motor distal latency may have: 216 Caress, Esper, and Rutkove

A. Median neuropathy at the wrist. B. Generalized polyneuropathy. C. Generalized myopathy. D. C8-T1 radiculopathy from herniated disc. E. A and B. REVIEW ANSWERS 1. Answer: D. Abnormal temporal dispersion is usually accompanied by a drop in response amplitude. Normal temporal dispersion is very dependent on the length of the neuron. Abnormal temporal dispersion is the hall mark of demyelinating polyneuropathies and can be observed easily in motor conduction studies. It is not typically seen in patients with carpal tunnel syndrome. 2. Answer: D. Anodal block can theoretically interfere with the acquisition of F wave data, although this is usually not a practical concern. All the other statements are false. Nerve depolarization occurs beneath the cathode, most of the electrical current travels through the extracellular space, large diameter nerve fibers have the greater propensity toward action potential generation, and standard nerve conduction studies are supramaximal stimuli. 3. Answer C: In an isolated L5 radiculopathy, a peroneal F-estimatate would likely provide a shorter value than the actual F-waves, since the F-estimate would be calculated from the relatively unaffected distal latency and conduction velocity. F-estimates are most helpful in identifying the presence of a superimposed proximal process on a distal, can be performed in both the arms and legs, includes the distal latency and will not be adversely affected by the presence of an axonal neuropathy. 4. Answer: C. The nerve is depolarized beneath the cathode, not the anode. All the other statements are true. 5. Answer: B. The CMAP is the summation of all the muscle fiber action potentials. E1 is placed over the muscle belly, not E2. Nerve conduction velocity cannot be measured with distal stimulation alone. The muscle contraction is not being measured in standard motor conduction studies. Motor conduction studies cannot be performed antidromically since the muscle depolarization is being measured. 6. Answer: C. They are typically less than 31–32 ms in latency in the upper extremities and less than 56 ms in latency in the lower extremities. F waves are the late responses of motor, not sensory, nerve conduction studies. While prolonged F wave latencies are possibly indicative of pathology at specific root levels only, they can also be prolonged in focal compressive neuropathies (e.g. carpal tunnel syndrome) or generalized polyneuropathies. They are dependent on height, as taller people will have longer F wave latencies (increased distance for the action potential to travel). 7. Answer: E. All the statements are true. 8. Answer: A. The tibial H-reflex results from stimulation of Ia afferent tibial nerve fibers, which synapse in the spinal cord, travel back down the tibial nerve, and cause depolarization of the soleus muscle. It is therefore electrically similar to the ankle reflex (although not identical). It does not represent the actual contraction of a muscle, but rather the summed muscle fiber potentials of the recorded muscle. As the neurophysiologic equivalent of the ankle reflex, it may be abnormal in an S1 radiculopathy but not L5 radiculopathy. The H-reflex latency varies with different height: the latency is longer in people of taller stature, just like F-waves. 9. Answer: C. Sensory studies are typically abnormal in most, but not all, polyneuropathies. In myopathies, the motor responses can be normal or reduced. In compressive radiculopathies, the dor- sal root ganglion, which houses the pseudounipolar sensory cell bodies, lies outside of the zone of compression. Because sensory nerves do not have a neuromuscular junction, sensory responses will be normal in myasthenia gravis. 10. Answer: E. These findings can be seen in both focal compressive lesions of the median nerve at the wrist and generalized polyneuropathy. Sensory responses in a generalized should not be abnormal in myopathy. In addition, the sensory responses should not be abnormal in a C8-T1 radiculopathy for two reasons: 1) the sensory component of the median nerve is derived from the C6-7 dermatomes and 2) sensory responses are typically normal in compressive radiculopathies.