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Neurophysiologic testing for pain
C H A P T E R
8
Neurophysiologic Testing for Pain Takashi Nishida, MD b Michael M. Minieka, MD
Electrophysiologic testing when properly applied is a useful tool for the evaluation of patients with pain. Understanding the indications and limitations of each test is absolutely essential for appropriate diagnosis and subsequent treatment. Electrophysiologic studies are a very sensitive indicator of central and peripheral nervous system involvement but do not indicate underlying disease. For example, testing can diagnose radiculopathy but cannot determine if it is caused by osteophytes, a herniated disc, or diabetes. This chapter describes conventional electrophysiologic tests such as electromyography (EMG), and short-latency somatosensory-evoked potentials (SSEPs), as well as newer techniques, including quantitative sensory testing (QST), laser-evoked potentials (LEPs), and contact heat–evoked potentials (CHEPs). Invasive testing such as microneurography will not be discussed here. The role of the sympathetic nervous system in the production of pain is complex and controversial; nonetheless, testing of the autonomic function is also important for the evaluation of pain complaints because it gives an objective measure of small nerve fiber involvement as well as evidence of therapeutic interventions such as sympathetic nerve blocks. The most frequent referrals to the autonomic laboratory are patients with painful peripheral neuropathy, such as diabetic polyneuropathy, and so-called complex regional pain syndrome/reflex sympathetic dystrophy (CRPS/RSD). Based on accuracy, reproducibility, and easiness to perform, sudomotor function tests such as the sympathetic skin response (SSR) and quantitative sudomotor axon reflex test (QSART), are discussed here. Other quantitative autonomic measures for adrenergic function (Valsalva maneuver, headup tilt) and for cardiovagal function (heart rate variability to deep breathing) are beyond the scope of this discussion. Finally, although controversial, the value of nociceptive reflexes, such as the blink reflex, masseter inhibitory reflex (MIR), and flexor reflex for the evaluation of neuropathic pain will be discussed briefly.
ELECTROMYOGRAPHY (EMG) When strictly defined, EMG indicates only a needle examination of muscles. However, EMG is often used to include both needle studies and nerve conduction studies. Nerve conduction studies are often referred to by the letters NCV, with “V” standing for velocity, although nerve conduction studies measure more than velocity. For clarity, we use EMG/NCV to indicate the combination of needle electromyography and nerve conduction studies.1,2 EMG/NCV is extremely useful in the evaluation of the peripheral nervous system. Indeed, the three most common diagnoses in EMG laboratories—peripheral neuropathy, carpal tunnel syndrome, and lumbosacral radiculopathy—all cause pain. EMG/NCV can identify the anatomic site of injury (anterior horn cell, spinal root, plexus, nerve, neuromuscular junction, or muscle), © Copyright 2011 Elsevier Inc., Ltd., BV. All rights reserved.
the type of neurons or fibers involved (motor, sensory, or autonomic), the nature of pathologic alteration (demyelination, or axonal degeneration), time course (acute, subacute, or chronic), and severity of injury.1,2 By stimulating a peripheral nerve with supramaximal intensity, compound muscle action potential (CMAP) for motor nerve and sensory nerve action potential (SNAP) for sensory nerve are recorded. The amplitude of action potentials as well as the time from stimulation to response is recorded. Latency is the interval between the onset of a stimulus and the onset of a response, expressed in milliseconds. Conduction velocity is obtained by dividing the distance between two stimulation points (mm) of the same nerve by the difference between proximal and distal latencies (ms). This calculated velocity, expressed in meters per second (m/s) represents the conduction velocity of the fastest nerve fibers between two points of stimulation. It is important to note that studies may be normal if a disorder is limited to small nerve fibers such as Ad and C-fibers.1,2 The amplitude of CMAP is measured from baseline to negative peak in millivolts, and the amplitude of SNAP is measured from the first positive peak to negative peak in microvolts. Most laboratories have their own normal values for major motor and sensory nerves with minor differences occurring among laboratories. A lower temperature will prolong distal latencies, reduce conduction velocities, and increase the amplitude of CMAP and SNAP. Age also affects NCVs. Adult values are not attained until 4 years of age, and they decline after age 60 years at a rate of 1 to 2 m/s per decade. Waveform analysis of CMAP and SNAP help estimate normal versus abnormal nerve function (Fig. 8-1). The amplitude of a response should be similar when the same nerve is stimulated proximally and distally. A 20% to 50% reduction between distal and proximal stimulation of a motor nerve suggests an abnormal block in conduction between two stimulation points. Many laboratories are now computerized and the area under an action potential curve can be calculated. Greater than 20% to 40% reduction in area also suggests conduction block. A significant reduction in amplitude from proximal to distal stimulation sites without a reduction in area under the response curve, and a significant increase in duration (.15%) suggest temporal dispersion resulting from a relative desynchronization of the components of an action potential, which is due to different rates of conduction of each nerve fiber. This also suggests nerve pathology between the proximal and distal stimulation sites.1,2 The H-reflex is the electrophysiologic equivalent of a muscle stretch reflex. A sensory nerve is stimulated with submaximal intensity, and a late motor response is recorded owing to reflex activation of motor neurons. In adults, H-reflexes are easily obtained from soleus muscle and less easily from flexor carpi radialis muscle following the stimulation of tibial and median nerves, respectively. The tibial H-reflex is useful in identifying S1 radiculopathy. 45
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FIGURE 8-1 Schematic representation of normal and pathologic findings obtained from an NCV study.
F-waves are late response recorded from muscle after supramaximal stimulation of a motor nerve. F-waves represent a response to a stimulus that travels first to and then from the cord via motor pathways; thus, F-waves are useful in studying the proximal portion of motor nerves (Fig. 8-2). Unfortunately, there is no consensus as to methodology for obtaining responses, and to the patterns of abnormality to be identified. Repetitive nerve stimulation (RNS) studies are used primarily for evaluation of neuromuscular junction disorders like myasthenia gravis. As such they are
not typically useful in the evaluation of pain, and therefore will not be discussed further. The electrical activity in a muscle can be measured using disposable needle electrodes. Needle examination is performed in proper steps. An examiner observes activity on insertion of a needle (insertion activity), activity when the needle is maintained in a relaxed muscle (spontaneous activity), and activity during varying degrees of voluntary muscle contraction. The electrical activity is evaluated by sight and sound, as specific activities have specific wave forms and characteristic sounds. Observations are made by the electromyographer during the study; therefore the results of a needle examination are dependent on the experience of the examiner.1,2 Insertion activity, also referred to as injury potential, is caused by movement of the needle electrode, resulting in mechanical damage to the muscle fibers. Increased insertion activity consists of unsustained fibrillation potentials and positive sharp waves. A muscle at rest should be electrically silent. Spontaneous activity in a resting muscle usually suggests a pathologic condition. The type and significance of various spontaneous activities are summarized in Table 8-1, and some examples are shown in Figure 8-3. As a muscle contracts, motor unit action potentials (MUAPs) are observed. MUAP represents the summation of muscle fiber action potentials of a given motor unit. With increasing voluntary muscle contraction, individual motor units fire more frequently, and more motor units are recruited to fire. The term “onset frequency” is used to describe the firing rate of a single MUAP maintained at the lowest voluntary muscle contraction (normally ,10 Hz). Recruitment frequency is defined as the frequency of first MUAP when the second MUAP is recruited (normally ,15 Hz). A reduced number of MUAPs (high recruitment frequency) can be seen in neuropathic processes. An increased number of MUAPs (low recruitment frequency), however, can be seen in myopathic disorders or defects of the neuromuscular junction. During maximum contraction, a full interference pattern consisting of overlapping motor units is seen. MUAPs are analyzed in terms of amplitude, duration, number of phases, and stability. The morphology of the MUAPs is affected by the type of needle electrode used, location of the needle within the motor unit territory, age, temperature, and specific muscle being examined. Large, long-duration polyphasic units suggest denervation and reinnervation. Short-duration, small polyphasic units can be seen in myopathic processes. EMG findings in neuropathic and myopathic disorders are summarized in Table 8-2.1,2 While performing an EMG/NCV study, several questions must be answered by the examiner.
LOCALIZATION: WHERE IS THE LESION?
FIGURE 8-2 H-reflex with tibial nerve stimulation (top); time marker 10 ms; amplitude marker 5 mV. F-response with median nerve stimulation (bottom); time marker 10 ms; amplitude marker 1 mV.
EMG/NCV is very useful in localizing the specific anatomic site of a lesion that is causing pain. For example, a complaint of burning feet can be caused by a diffuse peripheral neuropathy (as in diabetes), by a plexus injury after surgery, or by a lumbosacral radiculopathy due to spinal stenosis. Each of these has different findings and can be localized by EMG/NCV. In general, changes in conduction, either a prolonged distal latency or a low velocity, suggest a pathologic lesion between the site of stimulation
CHAPTER 8 Neurophysiologic Testing for Pain
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TABLE 8–1 Potentials Recorded in Muscle at Rest
Spontaneous Activity Complex repetitive discharge Cramp discharge End plate noise End plate spike
Fasciculation potential Fibrillation potential Myokymic discharge
Firing Pattern
Frequency
Waveform
Amplitude
Regular, abrupt onset and cessation, “motor cycle idling” Increase and subside gradually
5–100 Hz
Polyphasic or serrated, MFAP
100 mV–1 mV
( 1) ,150 Hz (2) 4–15 Hz .150 Hz
MUAP
Dense and steady, “seashell hissing” Irregular short burst, “sputtering fat in a frying pan” Spontaneous, sporadic, “typing on cardboard” Regular, “rain on tin roof,” “ticking of clock” Semiregular, “marching soldiers”
Neurogenic (chronic), myopathic (dystrophy) ( 1) Ischemic, h Na (2) g Ca, g Mg, h K
10–20 mV
0.5–1 ms
Normal
50–100 Hz
100–300 mV
2–4 ms
0.1–10 Hz
MUAP
.1 mV
.5 ms
1–50 Hz
Biphasic (positive–negative) MFAP
,1 mV
,5 ms
Decrease in denervated muscle, increase in reinnervated muscle Normal, neurogenic (motor neuronopathy), myopathic Neurogenic, NMJ defect, myopathic
(1) 2–60 Hz brief (2) 1–5 Hz continuous 20–80 Hz
MUAP
Wax and wane, “dive bomber”
Neuromyotonic discharge
Start and stop abruptly, wane, “pinging” Regular
150–300 Hz
Irregular
30–100 Hz
Neurotonic discharge
Significance
Monophasic (negative), MEPP Biphasic (negative–positive) MFAP
Myotonic discharge
Positive sharp wave
Duration
1–50 Hz
Limb (entrapment, radiation), face (MS, brainstem tumor, Bell’s palsy)
(1) Biphasic (positive–negative) (2) positive MFAP MUAP
,1 mV ,1 mV
Biphasic (positive–negative) MFAP MUAP
,1 mV
( 1) ,5 ms (2) 5–20 ms
10–100 ms
Myopathic (myotonic syndromes), h K, Schwartz-Jampel Isaac’s syndrome, stiff-man syndrome, tetany Same as fibrillation
,200 ms
MFAP, muscle fiber action potential; MUAP, motor unit action potential; MEPP, miniature end plate potential; NMJ, neuromuscular junction.
FIGURE 8-3 Spontaneous activities. Fibrillation potential and positive wave (top panel), and complex repetitive discharges (middle panel); time marker 10 ms, amplitude marker 100 mV. Myotonic discharges (bottom panel); time marker 20 ms, amplitude marker 200 mV.
and the recording site. An abnormally small amplitude, however, can occur from an injury anywhere distal to the motor or sensory neuron. A sampling on needle examination of muscles representing different nerves and roots can further localize the site of injury. Using the example of burning feet, let us examine the differential diagnosis and its EMG/NCV findings. In radiculopathy, motor conduction velocity would be normal, and CMAP amplitude would be reduced if there were axonal degeneration from nerve root compromise. SNAP would be normal because the lesion is proximal to the dorsal root ganglion. (Note that most radiculopathies occur within the spinal canal. The dorsal root ganglion, which is located in the neuroforamina, is distal to most radicular pathologic lesions. The dorsal root ganglion is a bipolar neuron with one axon extending distally to the limb and one extending proximally to the spinal cord.) EMG abnormalities first appear in appropriate paraspinal muscles because of their proximity to the injury site. Abnormalities are next seen in the proximal and then distal muscles within the specific myotomal distribution of the injured nerve root. In a plexus injury, both CMAP and SNAP amplitudes would be decreased if axons were injured. The NCV is usually normal
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TABLE 8–2 EMG Findings in Neurogenic and Myopathic Disorders
EMG
Normal
Neurogenic (Axonal)
NMJ Defect
Myopathic
Insertional activity Spontaneous activity MUAP amplitude Duration Phase Stability
N 2 0.1–5 mV 3–15 ms ,5 N
h
h
h
1 h h h
1 g g h
1 g g h
N
N h
Variable
Recruitment
N
N g
MUAP, motor unit action potential; NMJ, neuromuscular junction; N, normal.
unless stimulation is applied proximal to the lesion. Paraspinal muscles are spared because posterior rami innervate these muscles while the plexus is in the anterior rami distribution. Combined motor and sensory NCV abnormalities are characteristic of most peripheral neuropathies. Needle findings would depend on the severity of motor nerve involvement, and these are usually normal unless the neuropathy is severe. Anatomic localization based on EMG/ NCV is summarized in Table 8-3.
FIBER TYPE SPECIFICITY: IS THE LESION MOTOR, SENSORY, OR AUTONOMIC? The NCV tests motor and sensory components separately. Many peripheral nervous system diseases affect both motor and sensory nerves. In a case of distal sensory or motor neuropathies, amplitudes as well as velocities are abnormal. With a dorsal root ganglia lesion or anterior horn cell disease, NCV studies show small amplitude SNAP or CMAP, respectively, and as a rule normal velocity. Routine EMG/ NCV studies do not test the integrity of the autonomic nervous system. Autonomic tests will be discussed separately.
PATHOPHYSIOLOGY: IS THE LESION AXONAL OR DEMYELINATING? Based on the EMG/NCV findings, this distinction can be made with relative ease. If an injury occurs at the cell body or axon, axonal degeneration results. If an injury is directed against the myelin, demyelination ensues. In the majority of peripheral neuropathy, both demyelination and axonal injury will occur, however, characterizing the primary pathological process is important to establish an etiology and to assess the extent of injury. Demyelinating neuropathies can be further divided into segmental (acquired) and uniform (hereditary) types. In the former, nonuniform slowing in individual myelinated nerve fibers results in conduction block and temporal dispersion. In the latter, prolonged latency and slowing of conduction predominate as a result of uniform involvement of all myelinated fibers. Table 8-4 summarizes the EMG/NCV characteristics of demyelinating and axonal injuries.
DISTRIBUTION: IS THE LESION FOCAL, MULTIFOCAL, OR DIFFUSE? By determining the distribution of abnormalities, neuropathy, for example, can be further divided into mononeuropathy, multifocal neuropathy, and polyneuropathy. A focal lesion such as carpal tunnel syndrome will result in abnormalities limited to the distal segment of a median nerve. If the same nerve is affected disproportionately in the opposite limb or one nerve is affected more than the other in the same limb, a multifocal disorder is suggested. In a fully developed polyneuropathy, motor and sensory nerves in both upper and lower extremities are affected in equal and symmetrical fashion; in milder cases, however, the abnormalities will be more significant in distal sensory nerves of the lower extremities.
TABLE 8–3 Anatomical Localization Based on EMG and NCV Studies
Lesion Dorsal root ganglia (sensory neuronopathy) Anterior horn cell (motor neuronopathy) Root (radiculopathy) Plexus (plexopathy) Nerve (neuropathy) NMJ defect Muscle (myopathy)
Motor Nerve Conduction
Sensory Nerve Conduction
RNS
EMG
N
N, g amp
N
N
N, g amp
N
N/Abn
Abn
N, g amp N, g amp Abn N, g amp N, g amp
N N, g amp Abn N
N N N Abn
Abn Abn Abn Abn
N
N/Abn
Abn
RNS, repetitive nerve stimulation; NMJ, neuromuscular junction; N, normal; Abn, abnormal.
CHAPTER 8 Neurophysiologic Testing for Pain
TABLE 8–4 NCV and EMG Characteristics of Demyelinating and Axonal Injuries
Demyelination
NCV
EMG
1. Prolonged latency, .13% of normal
1. Normal insertional activity, no spontaneous activity
2. Slow NCV, ,70% of normal 3. Conduction block
Axonal injury
2. Reduced recruitment with conduction block
4. Temporal dispersion
3. Normal MUAP morphology
1. Normal latency
1. Increased insertional activity, spontaneous activity
2. Slow NCV, .70% of normal 3. Small CMAP/ SNAP amplitude
2. Reduced recruitment 3. Large amplitude, long-duration polyphasics with reinnervation 4. Satellite potentials
CMAP, compound muscle action potential; SNAP, sensory nerve action potential; MUAP, motor unit action potential.
CHRONICITY: HOW OLD IS THE INJURY? Following an axonal injury, the nerve distal to the lesion undergoes Wallerian degeneration. For the first 2 to 3 days, motor conductions distal to a lesion will be normal. Then CMAP amplitude drops progressively, reaching a nadir at about 7 days. SNAP amplitudes distal to a lesion are unaffected for 5 to 6 days but by day 10 to 11, the nadir is reached. After an axonal motor nerve injury, EMG findings will change slowly. Initially, insertional activity is increased. Positive sharp waves and fibrillation potentials may not occur for 2 to 3 weeks following a nerve injury, depending on the length between site of nerve injury and corresponding muscles. The abnormal spontaneous activity can resolve in 3 to 6 months. Therefore needle studies performed less than 2 to 3 weeks after injury, or later than 3 to 6 months after injury, may be normal. Large-amplitude, long-duration polyphasic MUAPs seen in denervation and reinnervation develop 3 to 6 months after an injury. Table 8-5 summarizes the chronology of EMG/NCV findings after axonal injury.
SEVERITY AND PROGNOSIS: HOW BAD IS THE INJURY? The severity of an injury can be determined if EMG/NCV is done in a timely manner. The amplitude difference between the same nerve on affected and unaffected sides gives an idea of extent of injury and potential recovery if they are determined sequentially. A paucity of spontaneous activity in affected muscles 3 weeks after injury indicates an excellent outcome for the return of muscle function. Markedly reduced recruitment of MUAPs indicates severe lesion except for neurapraxia. In general, axonal injury has a worse prognosis than demyelinating disorders.
QUANTITATIVE SENSORY TESTING The quantitative sensory test (QST) provides a quantitative measure to detect large and small fiber dysfunction. Various stimuli at varying intensities are applied to the skin and a patient is asked to indicate when he or she begins to feel the stimulus. A consensus report defines “sensory detection threshold” as “the smallest stimulus that can be detected at least 50% of the time.” By increasing and decreasing stimulus intensity from the predetermined level, “appearance” and “disappearance” thresholds can be determined. Sensory modalities commonly used are vibration and thermal senses—warm, cold, heat pain, and cold pain (Fig. 8-4). The vibration threshold measures large myelinated fiber function, whereas warm, heat pain, and cold pain thresholds reflect the function of unmyelinated C-fibers. The cold threshold measures small myelinated Ad fiber function.3 QST measures not only peripheral nerve fiber function but also central pathway function. Vibratory sense is carried by the dorsal columns and thermal senses via the spinothalamic tract. Normal values depend on methodology, sensory modality tested, and site of test. The sensory detection threshold increases with age; therefore, results should be compared with age-matched reference values. QST can be used to detect subtle sensory changes that may be missed by NCV study. Increased or decreased thermal detection threshold (hypoesthesia or hyperesthesia) and thermal pain threshold (hypoalgesia or hyperalgesia)
TABLE 8–5 Chronology of NCV and EMG Findings after Axonal
Injury NCV
EMG
0–1 wk 1–2 wk
g amp, proximal g amp, proximal and distal
2–3 wk
g amp, proximal and distal
1–3 mo
h amp
3–6 mo
h amp
g recruitment g recruitment h insertional activity g recruitment h fibrillation potentials g fibrillation potentials g amp, h duration, h phase h recruitment h amp, h duration, h phase
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FIGURE 8-4 Example of a thermal QST in a normal subject. Temperature, in degrees Centigrade, on vertical scale. Solid bar represents each trial. Sen, sensation.
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have been reported in many painful neuropathies. Cold or heat hyperalgesia is a feature of complex regional pain syndrome. Heat hyperalgesia is common in erythromelalgia, and angry backfiring C-nociceptor (or ABC) syndrome. Cold hypoesthesia, cold hyperalgesia, and cold limb are features of the CCC syndrome, whereas thermal hypoesthesia and hyperalgesia (anesthesia dolorosa) are typical manifestations of postherpetic neuralgia.3 QST allows early detection of disease. Sequential testing can be used to monitor disease progression and therapeutic efficacy. However, QST is not objective and relies on patient cooperation. QST does not localize a lesion, as it tests the integrity of the entire sensory pathway from nerve ending to cortex.3
SHORT-LATENCY SOMATOSENSORYEVOKED POTENTIALS Conventional sensory NCV studies assess a lesion distal to the dorsal root ganglion. SSEPs provide a quantitative measure to study the entire sensory pathway. Typically, a mixed nerve such as median nerve at the wrist or tibial nerve at the ankle is repeatedly stimulated and responses are recorded along the sensory pathway. Those responses are averaged to improve signal-to-noise ratio. Stimulations of the skin within a dermatome or cutaneous nerve such as the superficial radial or sural nerve have more limited value because of the low amplitude response. Submaximal intensity and longer duration of stimulus are required to elicit an optimal response.4,5 Stimulations are mediated by group Ia and II sensory afferents, dorsal root ganglion (neuron I), dorsal columns, gracilis and cuneatus nuclei (neuron II), contralateral medial lemniscus, ventroposterolateral nucleus of the thalamus (neuron III), and sensory cortex. Clinically, touchpressure, position-movement senses are affected with the injury to the dorsal column pathway in both the central
and peripheral nervous system. Each identifiable component is labeled according to its polarity (negative or positive) and its mean peak latency (in milliseconds) following stimulation. Useful obligate potentials after median nerve stimulation include EP (Erb’s point), N13 (dorsal column of the cervical cord), P14 (caudal medial lemniscus), N18 (thalamus), and N20 (sensory cortex). Identifiable potentials after tibial nerve stimulation are PF (popliteal fossa), LP (lumbar potential), P31 (caudal medial lemniscus), N34 (thalamus), and P37 (sensory cortex) (Fig. 8-5). Knowledge of the generator source of these peaks allows us to localize lesions to parts of the pathway. Age, temperature, limb length, medications, level of attention, and sleep may alter latency and amplitude. Therefore every laboratory has its own normal values. Adult norms are reached at about 8 years of age. Criteria for abnormality include absence of any obligate waves and prolongation of interpeak intervals. For example, absence of N18, N20, or a prolonged P14–N20 interval suggests a lesion between the medulla and sensory cortex. Table 8-6 summarizes some typical SSEP findings and resulting localizations. Absolute latency is a less reliable indicator of abnormality because it varies with limb length. A side-to-side amplitude ratio less than half is considered abnormal by some. Application of SSEPs for a patient with pain is limited to the identification of a potential structural or compressive lesion involving peripheral or central sensory pathway.4,5
LASER-EVOKED POTENTIALS AND CONTACT HEAT–EVOKED POTENTIALS A CO2 laser can be used to generate pain-related cerebral potentials. The laser stimulator produces radiant heat quickly and activates Ad and C nociceptors. Twenty to 40 stimuli are delivered at the intervals of 6 to 10 s. The late component, which occurs at approximately 220 to 340 ms following stimulation of the hand, corresponds to Ad fiber conduction,
FIGURE 8-5 Median (left) and tibial (right) SSEPs in a normal subject. CPc, contralateral central–parietal; CPi, ipsilateral central–parietal; EPc, contralateral Erb’s point; EPi, ipsilateral Erb’s point; CS, cervical spine; CPz, midline central–parietal; Fpz, midline frontopolar; TS, thoracic spine; Pfd, popliteal fossa, distal; Pfp, popliteal fossa, proximal; EP, Erb’s potential; LP, lumbar potential; PF, popliteal fossa.
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TABLE 8–6 Lesion Localization Based on SSEP Findings
SSEPs
Abnormality
Lesion
Median nerve
1. Absent EP P14 N20 2. Prolonged EP–P14 P14–N20
Median nerve–brachial plexus Above plexus Above medulla Brachial plexus–medulla Medulla–sensory cortex
Tibial nerve
1. Absent LP P37
Tibial nerve–cauda equina Above lumbar spinal cord
2. Prolonged LP–P37
Spinal cord–sensory cortex
EP, Erb’s potential; LP, lumbar potential.
and the ultra-late component at 800 to 1000 ms corresponds to C-fiber; both components are maximum in amplitude (10–50 mV) at the vertex (Cz). LEPs provide an objective measure to assess the function of pain and temperature pathways in patients with neuropathic pain. In a lesion involving the spinothalamic tract including small fiber neuropathy, SSEPs are usually normal but LEPs are abnormal. LEPs are not yet available in most electrophysiologic laboratories because the measure is technically difficult to perform and causes skin burns and pigmentation. However, recent advances in technology enable us to use natural heat, which goes up quickly at the rate of 508C/s (CHEPs). Latencies and amplitudes are comparable to those of LEPs. CHEPs are easy to perform and cause no side effects. Therefore this testing will eventually become a standard method to assess nociceptive dysfunction.5,6
SYMPATHETIC SKIN RESPONSE The first report of the galvanic skin response appeared in 1890. Since then, various terminology has been introduced on the basis of different stimulating and recording methods (e.g., electrodermal activity, sympathetic skin response [SSR], peripheral autonomic surface potential, psychogalvanic reflex, and sympathogalvanic response [SGR]). A standard method of obtaining SSR is to place a recording electrode on the palmar and plantar surfaces, because these recording sites yield higher amplitudes. A stimulator is placed on either the median or the tibial nerve of the opposite limb, and the stimulus is given randomly at a rate of less than one per minute, and with a stimulus intensity that is sufficient to cause mild pain. A minimum of 5 to 10 responses should be recorded, and SSR responses are obtainable 60% to 100% of the time in normal subjects. Waveforms are usually triphasic, with an initial small negativity followed by a large positive wave, and a subsequent prolonged negative wave (Fig. 8-6). Waveforms can also be monophasic or diphasic with an initial negative or positive peak. Maximal peak-to-peak amplitudes and mean latencies are measured. Amplitude and latency variability can be minimized by reducing stimulus frequency, increasing stimulus intensity, and/or changing stimulus site or mode. Low skin temperature, low level of attention, medication (especially anticholinergics), age, and habituation will also attenuate the response. Normal amplitude is more than 1 mV for the hand, and more than 0.2 mV for the foot. Mean palmar
FIGURE 8-6 Normal sympathetic skin response (SSR) recorded simultaneously from the palm of the hand (top) and sole of the foot (bottom) by electrical stimulation.
latency is 1.4 6 0.1 second and plantar latency is 1.9 6 0.1 second. The SSR measures change of epidermal resistance due to sweat gland activity. The somatic afferent limb depends on the stimulus type (electrical shock, loud noise, visual threat, deep breathing); with the electrical stimulation, the afferent limb occurs via large myelinated fibers. The efferent limb is a sympathetic pathway, originating in the posterior hypothalamus, descending through the spinal cord to the intermediolateral cell column (T1 to L2), and paravertebral ganglia and then to the sweat gland via small unmyelinated fibers. Therefore it is important to note that neuropathy affecting large myelinated fibers exhibits abnormal SSR when electrical stimulation is used. Low amplitude or absent response indicates abnormal sympathetic reflex arc, and the lesion can be central or peripheral, preganglionic or postganglionic. A side-to-side amplitude difference of more than 50% is considered to be abnormal by some. In studies of diabetic, uremic, and amyloid neuropathies, the result of SSR correlated well with autonomic symptoms. As a rule, SSR is abnormal in axonal neuropathies. An exception is the demyelinating neuropathy with prominent autonomic features, such as Guillain-Barre syndrome. Some studies have reported abnormal SSR test results in patients with CRPS/RSD and others have not. Immediately following the sympathetic nerve block or sympathectomy, the SSR is absent or reduced in amplitude. The SSR is usually normal in entrapment neuropathy and radiculopathy. SSR evoked by magnetic stimulation in the neck bypasses the afferent limb and directly stimulates postganglionic fibers. This method has less propensity to habituate and therefore less fluctuation of amplitude and latency occurs.
QUANTITATIVE SUDOMOTOR AXON REFLEX TEST AND RESTING SWEAT OUTPUT TEST This is a sensitive, reproducible, and quantitative method to test sudomotor function. A multicompartment plastic “sweat cell” is tightly secured to the skin. The outer compartment
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SECTION II Clinical Evaluation and Diagnostic Examinations
is filled with acetylcholine solution, and nitrogen gas flows constantly to an inner compartment through an instrument that measures the change of humidity (sudorometer). A direct current is applied and the water content in the inner compartment is continuously measured before, during and after the stimulus. The basis of the test is that the axon terminal of the sweat gland under the outer compartment is activated by acetylcholine iontophoresis; the impulse travel centripetally to a branch point and then distally to the axon terminal under the inner compartment where acetylcholine is released and a sweating response results. Use of the term “axon reflex” should be discouraged, because only the postganglionic sympathetic sudomotor axon is considered to be involved in this setup. With a latency of 1 to 2 min after the induction of the stimulus, sweat output increases rapidly while stimulation continues; then the stimulator is turned off, and sweat output returns to its prestimulus baseline within 5 min (Fig. 8-7). The area under the curve represents the total amount of sweat output expressed in microliter per square centimeter, and the normal value varies depending on the site of testing, gender, and age of the subject. Distal limbs, male, and younger subjects tend to sweat more. Reduced or absent response indicates postganglionic disorder. Normal response does not rule out preganglionic involvement. Excessive and persistent sweating is also considered abnormal. Comparison is made between the two limbs, and an asymmetry of more than 25% is considered to be abnormal.7 The RSO test is basically similar to the QSART; a capsule with one chamber is attached to the skin, and the rate of water evaporation is continuously recorded for 5 min. The presence of RSO indicates that the sweat gland is spontaneously activated by the sympathetic fibers.7 In a patient with painful diabetic neuropathy, RSO studies show the presence of increased sweat activity, and QSART exhibits short latency, excessive, and persistent sweat patterns, which is evidence of sympathetic overactivity. Sweat test abnormalities correlate well with the symptoms of CRPS/RSD-related pain, for which the
pathophysiologic mechanism is uncertain; perhaps a lower firing threshold, or an increased firing frequency due to denervation hypersensitivity of the sudomotor axons may produce excitation of the sweat glands. Recently, the Food and Drug Administration (FDA) approved the Q-Sweat device. This device uses dry air instead of nitrogen gas to measure water content.7
NOCICEPTIVE REFLEXES The blink reflex is recorded by electrically stimulating the supraorbital branch of the trigeminal nerve. Ipsilateral R1 (10–13 ms) and bilateral R2 potentials (30–41 ms) are obtained from the orbicularis oculi muscles. The masseter inhibitory reflex is recorded from the masseter muscles bilaterally with stimulation of the mentalis nerve while the muscle is fully activated by clenching teeth. Ongoing EMG activity is interrupted by two silent periods—an early phase with a latency of 10 to 15 ms and a late phase with 40 to 50 ms. These trigeminal reflexes have been reported normal in tic douloureux, but abnormal in facial pain due to neuropathy, multiple sclerosis, and cerebellopontine angle tumor. However, its afferent path is at least in part mediated by non–nociceptive fibers. Flexion reflex or withdrawal reflex is obtained by painful stimulation of a nerve or skin. RIII flexion reflex (80–90 ms) recorded from the short head of biceps femoris by stimulating the sural nerve has been found useful to assess efficacy of pain medications.6,8
KEY POINTS l
l
l
l
l
l
l
Electrophysiologic studies are very sensitive indicators of central and peripheral nervous system involvement but do not indicate underlying disease. EMG/NCV studies can identify the anatomic site of injury, the type of neurons or fibers involved, the nature of the pathologic alteration, and severity of injury. In QST, cold threshold measures Ad fiber function, whereas warmth, heat pain, and cold pain thresholds reflect the function of C-fibers. SSEPs provide a quantitative measure to study the entire sensory pathway, mediated by Type Ia and II sensory afferents. LEPs and CHEPs measure the function of Ad and C-fibers. CHEPs have potential to become a standard neurophysiologic method. SSR and QSART have a limited role but are useful for the evaluation of painful diabetic neuropathy or CRPS/ RSD. Nociceptive reflexes have an extremely limited role.
REFERENCES FIGURE 8-7 Example of a normal quantitative sudomotor axon reflex test (QSART). On, off, stimulator on and off.
Access the reference list online at http://www.expertconsult. com
8
Neurophysiologic Testing for Pain Takashi Nishida, MD b Michael M. Minieka, MD
Electrophysiologic testing when properly applied is a useful tool for the evaluation of patients with pain. Understanding the indications and limitations of each test is absolutely essential for appropriate diagnosis and subsequent treatment. Electrophysiologic studies are a very sensitive indicator of central and peripheral nervous system involvement but do not indicate underlying disease. For example, testing can diagnose radiculopathy but cannot determine if it is caused by osteophytes, a herniated disc, or diabetes. This chapter describes conventional electrophysiologic tests such as electromyography (EMG), and short-latency somatosensory-evoked potentials (SSEPs), as well as newer techniques, including quantitative sensory testing (QST), laser-evoked potentials (LEPs), and contact heat–evoked potentials (CHEPs). Invasive testing such as microneurography will not be discussed here. The role of the sympathetic nervous system in the production of pain is complex and controversial; nonetheless, testing of the autonomic function is also important for the evaluation of pain complaints because it gives an objective measure of small nerve fiber involvement as well as evidence of therapeutic interventions such as sympathetic nerve blocks. The most frequent referrals to the autonomic laboratory are patients with painful peripheral neuropathy, such as diabetic polyneuropathy, and so-called complex regional pain syndrome/reflex sympathetic dystrophy (CRPS/RSD). Based on accuracy, reproducibility, and easiness to perform, sudomotor function tests such as the sympathetic skin response (SSR) and quantitative sudomotor axon reflex test (QSART), are discussed here. Other quantitative autonomic measures for adrenergic function (Valsalva maneuver, headup tilt) and for cardiovagal function (heart rate variability to deep breathing) are beyond the scope of this discussion. Finally, although controversial, the value of nociceptive reflexes, such as the blink reflex, masseter inhibitory reflex (MIR), and flexor reflex for the evaluation of neuropathic pain will be discussed briefly.
ELECTROMYOGRAPHY (EMG) When strictly defined, EMG indicates only a needle examination of muscles. However, EMG is often used to include both needle studies and nerve conduction studies. Nerve conduction studies are often referred to by the letters NCV, with “V” standing for velocity, although nerve conduction studies measure more than velocity. For clarity, we use EMG/NCV to indicate the combination of needle electromyography and nerve conduction studies.1,2 EMG/NCV is extremely useful in the evaluation of the peripheral nervous system. Indeed, the three most common diagnoses in EMG laboratories—peripheral neuropathy, carpal tunnel syndrome, and lumbosacral radiculopathy—all cause pain. EMG/NCV can identify the anatomic site of injury (anterior horn cell, spinal root, plexus, nerve, neuromuscular junction, or muscle), © Copyright 2011 Elsevier Inc., Ltd., BV. All rights reserved.
the type of neurons or fibers involved (motor, sensory, or autonomic), the nature of pathologic alteration (demyelination, or axonal degeneration), time course (acute, subacute, or chronic), and severity of injury.1,2 By stimulating a peripheral nerve with supramaximal intensity, compound muscle action potential (CMAP) for motor nerve and sensory nerve action potential (SNAP) for sensory nerve are recorded. The amplitude of action potentials as well as the time from stimulation to response is recorded. Latency is the interval between the onset of a stimulus and the onset of a response, expressed in milliseconds. Conduction velocity is obtained by dividing the distance between two stimulation points (mm) of the same nerve by the difference between proximal and distal latencies (ms). This calculated velocity, expressed in meters per second (m/s) represents the conduction velocity of the fastest nerve fibers between two points of stimulation. It is important to note that studies may be normal if a disorder is limited to small nerve fibers such as Ad and C-fibers.1,2 The amplitude of CMAP is measured from baseline to negative peak in millivolts, and the amplitude of SNAP is measured from the first positive peak to negative peak in microvolts. Most laboratories have their own normal values for major motor and sensory nerves with minor differences occurring among laboratories. A lower temperature will prolong distal latencies, reduce conduction velocities, and increase the amplitude of CMAP and SNAP. Age also affects NCVs. Adult values are not attained until 4 years of age, and they decline after age 60 years at a rate of 1 to 2 m/s per decade. Waveform analysis of CMAP and SNAP help estimate normal versus abnormal nerve function (Fig. 8-1). The amplitude of a response should be similar when the same nerve is stimulated proximally and distally. A 20% to 50% reduction between distal and proximal stimulation of a motor nerve suggests an abnormal block in conduction between two stimulation points. Many laboratories are now computerized and the area under an action potential curve can be calculated. Greater than 20% to 40% reduction in area also suggests conduction block. A significant reduction in amplitude from proximal to distal stimulation sites without a reduction in area under the response curve, and a significant increase in duration (.15%) suggest temporal dispersion resulting from a relative desynchronization of the components of an action potential, which is due to different rates of conduction of each nerve fiber. This also suggests nerve pathology between the proximal and distal stimulation sites.1,2 The H-reflex is the electrophysiologic equivalent of a muscle stretch reflex. A sensory nerve is stimulated with submaximal intensity, and a late motor response is recorded owing to reflex activation of motor neurons. In adults, H-reflexes are easily obtained from soleus muscle and less easily from flexor carpi radialis muscle following the stimulation of tibial and median nerves, respectively. The tibial H-reflex is useful in identifying S1 radiculopathy. 45
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SECTION II Clinical Evaluation and Diagnostic Examinations
FIGURE 8-1 Schematic representation of normal and pathologic findings obtained from an NCV study.
F-waves are late response recorded from muscle after supramaximal stimulation of a motor nerve. F-waves represent a response to a stimulus that travels first to and then from the cord via motor pathways; thus, F-waves are useful in studying the proximal portion of motor nerves (Fig. 8-2). Unfortunately, there is no consensus as to methodology for obtaining responses, and to the patterns of abnormality to be identified. Repetitive nerve stimulation (RNS) studies are used primarily for evaluation of neuromuscular junction disorders like myasthenia gravis. As such they are
not typically useful in the evaluation of pain, and therefore will not be discussed further. The electrical activity in a muscle can be measured using disposable needle electrodes. Needle examination is performed in proper steps. An examiner observes activity on insertion of a needle (insertion activity), activity when the needle is maintained in a relaxed muscle (spontaneous activity), and activity during varying degrees of voluntary muscle contraction. The electrical activity is evaluated by sight and sound, as specific activities have specific wave forms and characteristic sounds. Observations are made by the electromyographer during the study; therefore the results of a needle examination are dependent on the experience of the examiner.1,2 Insertion activity, also referred to as injury potential, is caused by movement of the needle electrode, resulting in mechanical damage to the muscle fibers. Increased insertion activity consists of unsustained fibrillation potentials and positive sharp waves. A muscle at rest should be electrically silent. Spontaneous activity in a resting muscle usually suggests a pathologic condition. The type and significance of various spontaneous activities are summarized in Table 8-1, and some examples are shown in Figure 8-3. As a muscle contracts, motor unit action potentials (MUAPs) are observed. MUAP represents the summation of muscle fiber action potentials of a given motor unit. With increasing voluntary muscle contraction, individual motor units fire more frequently, and more motor units are recruited to fire. The term “onset frequency” is used to describe the firing rate of a single MUAP maintained at the lowest voluntary muscle contraction (normally ,10 Hz). Recruitment frequency is defined as the frequency of first MUAP when the second MUAP is recruited (normally ,15 Hz). A reduced number of MUAPs (high recruitment frequency) can be seen in neuropathic processes. An increased number of MUAPs (low recruitment frequency), however, can be seen in myopathic disorders or defects of the neuromuscular junction. During maximum contraction, a full interference pattern consisting of overlapping motor units is seen. MUAPs are analyzed in terms of amplitude, duration, number of phases, and stability. The morphology of the MUAPs is affected by the type of needle electrode used, location of the needle within the motor unit territory, age, temperature, and specific muscle being examined. Large, long-duration polyphasic units suggest denervation and reinnervation. Short-duration, small polyphasic units can be seen in myopathic processes. EMG findings in neuropathic and myopathic disorders are summarized in Table 8-2.1,2 While performing an EMG/NCV study, several questions must be answered by the examiner.
LOCALIZATION: WHERE IS THE LESION?
FIGURE 8-2 H-reflex with tibial nerve stimulation (top); time marker 10 ms; amplitude marker 5 mV. F-response with median nerve stimulation (bottom); time marker 10 ms; amplitude marker 1 mV.
EMG/NCV is very useful in localizing the specific anatomic site of a lesion that is causing pain. For example, a complaint of burning feet can be caused by a diffuse peripheral neuropathy (as in diabetes), by a plexus injury after surgery, or by a lumbosacral radiculopathy due to spinal stenosis. Each of these has different findings and can be localized by EMG/NCV. In general, changes in conduction, either a prolonged distal latency or a low velocity, suggest a pathologic lesion between the site of stimulation
CHAPTER 8 Neurophysiologic Testing for Pain
47
TABLE 8–1 Potentials Recorded in Muscle at Rest
Spontaneous Activity Complex repetitive discharge Cramp discharge End plate noise End plate spike
Fasciculation potential Fibrillation potential Myokymic discharge
Firing Pattern
Frequency
Waveform
Amplitude
Regular, abrupt onset and cessation, “motor cycle idling” Increase and subside gradually
5–100 Hz
Polyphasic or serrated, MFAP
100 mV–1 mV
( 1) ,150 Hz (2) 4–15 Hz .150 Hz
MUAP
Dense and steady, “seashell hissing” Irregular short burst, “sputtering fat in a frying pan” Spontaneous, sporadic, “typing on cardboard” Regular, “rain on tin roof,” “ticking of clock” Semiregular, “marching soldiers”
Neurogenic (chronic), myopathic (dystrophy) ( 1) Ischemic, h Na (2) g Ca, g Mg, h K
10–20 mV
0.5–1 ms
Normal
50–100 Hz
100–300 mV
2–4 ms
0.1–10 Hz
MUAP
.1 mV
.5 ms
1–50 Hz
Biphasic (positive–negative) MFAP
,1 mV
,5 ms
Decrease in denervated muscle, increase in reinnervated muscle Normal, neurogenic (motor neuronopathy), myopathic Neurogenic, NMJ defect, myopathic
(1) 2–60 Hz brief (2) 1–5 Hz continuous 20–80 Hz
MUAP
Wax and wane, “dive bomber”
Neuromyotonic discharge
Start and stop abruptly, wane, “pinging” Regular
150–300 Hz
Irregular
30–100 Hz
Neurotonic discharge
Significance
Monophasic (negative), MEPP Biphasic (negative–positive) MFAP
Myotonic discharge
Positive sharp wave
Duration
1–50 Hz
Limb (entrapment, radiation), face (MS, brainstem tumor, Bell’s palsy)
(1) Biphasic (positive–negative) (2) positive MFAP MUAP
,1 mV ,1 mV
Biphasic (positive–negative) MFAP MUAP
,1 mV
( 1) ,5 ms (2) 5–20 ms
10–100 ms
Myopathic (myotonic syndromes), h K, Schwartz-Jampel Isaac’s syndrome, stiff-man syndrome, tetany Same as fibrillation
,200 ms
MFAP, muscle fiber action potential; MUAP, motor unit action potential; MEPP, miniature end plate potential; NMJ, neuromuscular junction.
FIGURE 8-3 Spontaneous activities. Fibrillation potential and positive wave (top panel), and complex repetitive discharges (middle panel); time marker 10 ms, amplitude marker 100 mV. Myotonic discharges (bottom panel); time marker 20 ms, amplitude marker 200 mV.
and the recording site. An abnormally small amplitude, however, can occur from an injury anywhere distal to the motor or sensory neuron. A sampling on needle examination of muscles representing different nerves and roots can further localize the site of injury. Using the example of burning feet, let us examine the differential diagnosis and its EMG/NCV findings. In radiculopathy, motor conduction velocity would be normal, and CMAP amplitude would be reduced if there were axonal degeneration from nerve root compromise. SNAP would be normal because the lesion is proximal to the dorsal root ganglion. (Note that most radiculopathies occur within the spinal canal. The dorsal root ganglion, which is located in the neuroforamina, is distal to most radicular pathologic lesions. The dorsal root ganglion is a bipolar neuron with one axon extending distally to the limb and one extending proximally to the spinal cord.) EMG abnormalities first appear in appropriate paraspinal muscles because of their proximity to the injury site. Abnormalities are next seen in the proximal and then distal muscles within the specific myotomal distribution of the injured nerve root. In a plexus injury, both CMAP and SNAP amplitudes would be decreased if axons were injured. The NCV is usually normal
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SECTION II Clinical Evaluation and Diagnostic Examinations
TABLE 8–2 EMG Findings in Neurogenic and Myopathic Disorders
EMG
Normal
Neurogenic (Axonal)
NMJ Defect
Myopathic
Insertional activity Spontaneous activity MUAP amplitude Duration Phase Stability
N 2 0.1–5 mV 3–15 ms ,5 N
h
h
h
1 h h h
1 g g h
1 g g h
N
N h
Variable
Recruitment
N
N g
MUAP, motor unit action potential; NMJ, neuromuscular junction; N, normal.
unless stimulation is applied proximal to the lesion. Paraspinal muscles are spared because posterior rami innervate these muscles while the plexus is in the anterior rami distribution. Combined motor and sensory NCV abnormalities are characteristic of most peripheral neuropathies. Needle findings would depend on the severity of motor nerve involvement, and these are usually normal unless the neuropathy is severe. Anatomic localization based on EMG/ NCV is summarized in Table 8-3.
FIBER TYPE SPECIFICITY: IS THE LESION MOTOR, SENSORY, OR AUTONOMIC? The NCV tests motor and sensory components separately. Many peripheral nervous system diseases affect both motor and sensory nerves. In a case of distal sensory or motor neuropathies, amplitudes as well as velocities are abnormal. With a dorsal root ganglia lesion or anterior horn cell disease, NCV studies show small amplitude SNAP or CMAP, respectively, and as a rule normal velocity. Routine EMG/ NCV studies do not test the integrity of the autonomic nervous system. Autonomic tests will be discussed separately.
PATHOPHYSIOLOGY: IS THE LESION AXONAL OR DEMYELINATING? Based on the EMG/NCV findings, this distinction can be made with relative ease. If an injury occurs at the cell body or axon, axonal degeneration results. If an injury is directed against the myelin, demyelination ensues. In the majority of peripheral neuropathy, both demyelination and axonal injury will occur, however, characterizing the primary pathological process is important to establish an etiology and to assess the extent of injury. Demyelinating neuropathies can be further divided into segmental (acquired) and uniform (hereditary) types. In the former, nonuniform slowing in individual myelinated nerve fibers results in conduction block and temporal dispersion. In the latter, prolonged latency and slowing of conduction predominate as a result of uniform involvement of all myelinated fibers. Table 8-4 summarizes the EMG/NCV characteristics of demyelinating and axonal injuries.
DISTRIBUTION: IS THE LESION FOCAL, MULTIFOCAL, OR DIFFUSE? By determining the distribution of abnormalities, neuropathy, for example, can be further divided into mononeuropathy, multifocal neuropathy, and polyneuropathy. A focal lesion such as carpal tunnel syndrome will result in abnormalities limited to the distal segment of a median nerve. If the same nerve is affected disproportionately in the opposite limb or one nerve is affected more than the other in the same limb, a multifocal disorder is suggested. In a fully developed polyneuropathy, motor and sensory nerves in both upper and lower extremities are affected in equal and symmetrical fashion; in milder cases, however, the abnormalities will be more significant in distal sensory nerves of the lower extremities.
TABLE 8–3 Anatomical Localization Based on EMG and NCV Studies
Lesion Dorsal root ganglia (sensory neuronopathy) Anterior horn cell (motor neuronopathy) Root (radiculopathy) Plexus (plexopathy) Nerve (neuropathy) NMJ defect Muscle (myopathy)
Motor Nerve Conduction
Sensory Nerve Conduction
RNS
EMG
N
N, g amp
N
N
N, g amp
N
N/Abn
Abn
N, g amp N, g amp Abn N, g amp N, g amp
N N, g amp Abn N
N N N Abn
Abn Abn Abn Abn
N
N/Abn
Abn
RNS, repetitive nerve stimulation; NMJ, neuromuscular junction; N, normal; Abn, abnormal.
CHAPTER 8 Neurophysiologic Testing for Pain
TABLE 8–4 NCV and EMG Characteristics of Demyelinating and Axonal Injuries
Demyelination
NCV
EMG
1. Prolonged latency, .13% of normal
1. Normal insertional activity, no spontaneous activity
2. Slow NCV, ,70% of normal 3. Conduction block
Axonal injury
2. Reduced recruitment with conduction block
4. Temporal dispersion
3. Normal MUAP morphology
1. Normal latency
1. Increased insertional activity, spontaneous activity
2. Slow NCV, .70% of normal 3. Small CMAP/ SNAP amplitude
2. Reduced recruitment 3. Large amplitude, long-duration polyphasics with reinnervation 4. Satellite potentials
CMAP, compound muscle action potential; SNAP, sensory nerve action potential; MUAP, motor unit action potential.
CHRONICITY: HOW OLD IS THE INJURY? Following an axonal injury, the nerve distal to the lesion undergoes Wallerian degeneration. For the first 2 to 3 days, motor conductions distal to a lesion will be normal. Then CMAP amplitude drops progressively, reaching a nadir at about 7 days. SNAP amplitudes distal to a lesion are unaffected for 5 to 6 days but by day 10 to 11, the nadir is reached. After an axonal motor nerve injury, EMG findings will change slowly. Initially, insertional activity is increased. Positive sharp waves and fibrillation potentials may not occur for 2 to 3 weeks following a nerve injury, depending on the length between site of nerve injury and corresponding muscles. The abnormal spontaneous activity can resolve in 3 to 6 months. Therefore needle studies performed less than 2 to 3 weeks after injury, or later than 3 to 6 months after injury, may be normal. Large-amplitude, long-duration polyphasic MUAPs seen in denervation and reinnervation develop 3 to 6 months after an injury. Table 8-5 summarizes the chronology of EMG/NCV findings after axonal injury.
SEVERITY AND PROGNOSIS: HOW BAD IS THE INJURY? The severity of an injury can be determined if EMG/NCV is done in a timely manner. The amplitude difference between the same nerve on affected and unaffected sides gives an idea of extent of injury and potential recovery if they are determined sequentially. A paucity of spontaneous activity in affected muscles 3 weeks after injury indicates an excellent outcome for the return of muscle function. Markedly reduced recruitment of MUAPs indicates severe lesion except for neurapraxia. In general, axonal injury has a worse prognosis than demyelinating disorders.
QUANTITATIVE SENSORY TESTING The quantitative sensory test (QST) provides a quantitative measure to detect large and small fiber dysfunction. Various stimuli at varying intensities are applied to the skin and a patient is asked to indicate when he or she begins to feel the stimulus. A consensus report defines “sensory detection threshold” as “the smallest stimulus that can be detected at least 50% of the time.” By increasing and decreasing stimulus intensity from the predetermined level, “appearance” and “disappearance” thresholds can be determined. Sensory modalities commonly used are vibration and thermal senses—warm, cold, heat pain, and cold pain (Fig. 8-4). The vibration threshold measures large myelinated fiber function, whereas warm, heat pain, and cold pain thresholds reflect the function of unmyelinated C-fibers. The cold threshold measures small myelinated Ad fiber function.3 QST measures not only peripheral nerve fiber function but also central pathway function. Vibratory sense is carried by the dorsal columns and thermal senses via the spinothalamic tract. Normal values depend on methodology, sensory modality tested, and site of test. The sensory detection threshold increases with age; therefore, results should be compared with age-matched reference values. QST can be used to detect subtle sensory changes that may be missed by NCV study. Increased or decreased thermal detection threshold (hypoesthesia or hyperesthesia) and thermal pain threshold (hypoalgesia or hyperalgesia)
TABLE 8–5 Chronology of NCV and EMG Findings after Axonal
Injury NCV
EMG
0–1 wk 1–2 wk
g amp, proximal g amp, proximal and distal
2–3 wk
g amp, proximal and distal
1–3 mo
h amp
3–6 mo
h amp
g recruitment g recruitment h insertional activity g recruitment h fibrillation potentials g fibrillation potentials g amp, h duration, h phase h recruitment h amp, h duration, h phase
49
FIGURE 8-4 Example of a thermal QST in a normal subject. Temperature, in degrees Centigrade, on vertical scale. Solid bar represents each trial. Sen, sensation.
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SECTION II Clinical Evaluation and Diagnostic Examinations
have been reported in many painful neuropathies. Cold or heat hyperalgesia is a feature of complex regional pain syndrome. Heat hyperalgesia is common in erythromelalgia, and angry backfiring C-nociceptor (or ABC) syndrome. Cold hypoesthesia, cold hyperalgesia, and cold limb are features of the CCC syndrome, whereas thermal hypoesthesia and hyperalgesia (anesthesia dolorosa) are typical manifestations of postherpetic neuralgia.3 QST allows early detection of disease. Sequential testing can be used to monitor disease progression and therapeutic efficacy. However, QST is not objective and relies on patient cooperation. QST does not localize a lesion, as it tests the integrity of the entire sensory pathway from nerve ending to cortex.3
SHORT-LATENCY SOMATOSENSORYEVOKED POTENTIALS Conventional sensory NCV studies assess a lesion distal to the dorsal root ganglion. SSEPs provide a quantitative measure to study the entire sensory pathway. Typically, a mixed nerve such as median nerve at the wrist or tibial nerve at the ankle is repeatedly stimulated and responses are recorded along the sensory pathway. Those responses are averaged to improve signal-to-noise ratio. Stimulations of the skin within a dermatome or cutaneous nerve such as the superficial radial or sural nerve have more limited value because of the low amplitude response. Submaximal intensity and longer duration of stimulus are required to elicit an optimal response.4,5 Stimulations are mediated by group Ia and II sensory afferents, dorsal root ganglion (neuron I), dorsal columns, gracilis and cuneatus nuclei (neuron II), contralateral medial lemniscus, ventroposterolateral nucleus of the thalamus (neuron III), and sensory cortex. Clinically, touchpressure, position-movement senses are affected with the injury to the dorsal column pathway in both the central
and peripheral nervous system. Each identifiable component is labeled according to its polarity (negative or positive) and its mean peak latency (in milliseconds) following stimulation. Useful obligate potentials after median nerve stimulation include EP (Erb’s point), N13 (dorsal column of the cervical cord), P14 (caudal medial lemniscus), N18 (thalamus), and N20 (sensory cortex). Identifiable potentials after tibial nerve stimulation are PF (popliteal fossa), LP (lumbar potential), P31 (caudal medial lemniscus), N34 (thalamus), and P37 (sensory cortex) (Fig. 8-5). Knowledge of the generator source of these peaks allows us to localize lesions to parts of the pathway. Age, temperature, limb length, medications, level of attention, and sleep may alter latency and amplitude. Therefore every laboratory has its own normal values. Adult norms are reached at about 8 years of age. Criteria for abnormality include absence of any obligate waves and prolongation of interpeak intervals. For example, absence of N18, N20, or a prolonged P14–N20 interval suggests a lesion between the medulla and sensory cortex. Table 8-6 summarizes some typical SSEP findings and resulting localizations. Absolute latency is a less reliable indicator of abnormality because it varies with limb length. A side-to-side amplitude ratio less than half is considered abnormal by some. Application of SSEPs for a patient with pain is limited to the identification of a potential structural or compressive lesion involving peripheral or central sensory pathway.4,5
LASER-EVOKED POTENTIALS AND CONTACT HEAT–EVOKED POTENTIALS A CO2 laser can be used to generate pain-related cerebral potentials. The laser stimulator produces radiant heat quickly and activates Ad and C nociceptors. Twenty to 40 stimuli are delivered at the intervals of 6 to 10 s. The late component, which occurs at approximately 220 to 340 ms following stimulation of the hand, corresponds to Ad fiber conduction,
FIGURE 8-5 Median (left) and tibial (right) SSEPs in a normal subject. CPc, contralateral central–parietal; CPi, ipsilateral central–parietal; EPc, contralateral Erb’s point; EPi, ipsilateral Erb’s point; CS, cervical spine; CPz, midline central–parietal; Fpz, midline frontopolar; TS, thoracic spine; Pfd, popliteal fossa, distal; Pfp, popliteal fossa, proximal; EP, Erb’s potential; LP, lumbar potential; PF, popliteal fossa.
CHAPTER 8 Neurophysiologic Testing for Pain
51
TABLE 8–6 Lesion Localization Based on SSEP Findings
SSEPs
Abnormality
Lesion
Median nerve
1. Absent EP P14 N20 2. Prolonged EP–P14 P14–N20
Median nerve–brachial plexus Above plexus Above medulla Brachial plexus–medulla Medulla–sensory cortex
Tibial nerve
1. Absent LP P37
Tibial nerve–cauda equina Above lumbar spinal cord
2. Prolonged LP–P37
Spinal cord–sensory cortex
EP, Erb’s potential; LP, lumbar potential.
and the ultra-late component at 800 to 1000 ms corresponds to C-fiber; both components are maximum in amplitude (10–50 mV) at the vertex (Cz). LEPs provide an objective measure to assess the function of pain and temperature pathways in patients with neuropathic pain. In a lesion involving the spinothalamic tract including small fiber neuropathy, SSEPs are usually normal but LEPs are abnormal. LEPs are not yet available in most electrophysiologic laboratories because the measure is technically difficult to perform and causes skin burns and pigmentation. However, recent advances in technology enable us to use natural heat, which goes up quickly at the rate of 508C/s (CHEPs). Latencies and amplitudes are comparable to those of LEPs. CHEPs are easy to perform and cause no side effects. Therefore this testing will eventually become a standard method to assess nociceptive dysfunction.5,6
SYMPATHETIC SKIN RESPONSE The first report of the galvanic skin response appeared in 1890. Since then, various terminology has been introduced on the basis of different stimulating and recording methods (e.g., electrodermal activity, sympathetic skin response [SSR], peripheral autonomic surface potential, psychogalvanic reflex, and sympathogalvanic response [SGR]). A standard method of obtaining SSR is to place a recording electrode on the palmar and plantar surfaces, because these recording sites yield higher amplitudes. A stimulator is placed on either the median or the tibial nerve of the opposite limb, and the stimulus is given randomly at a rate of less than one per minute, and with a stimulus intensity that is sufficient to cause mild pain. A minimum of 5 to 10 responses should be recorded, and SSR responses are obtainable 60% to 100% of the time in normal subjects. Waveforms are usually triphasic, with an initial small negativity followed by a large positive wave, and a subsequent prolonged negative wave (Fig. 8-6). Waveforms can also be monophasic or diphasic with an initial negative or positive peak. Maximal peak-to-peak amplitudes and mean latencies are measured. Amplitude and latency variability can be minimized by reducing stimulus frequency, increasing stimulus intensity, and/or changing stimulus site or mode. Low skin temperature, low level of attention, medication (especially anticholinergics), age, and habituation will also attenuate the response. Normal amplitude is more than 1 mV for the hand, and more than 0.2 mV for the foot. Mean palmar
FIGURE 8-6 Normal sympathetic skin response (SSR) recorded simultaneously from the palm of the hand (top) and sole of the foot (bottom) by electrical stimulation.
latency is 1.4 6 0.1 second and plantar latency is 1.9 6 0.1 second. The SSR measures change of epidermal resistance due to sweat gland activity. The somatic afferent limb depends on the stimulus type (electrical shock, loud noise, visual threat, deep breathing); with the electrical stimulation, the afferent limb occurs via large myelinated fibers. The efferent limb is a sympathetic pathway, originating in the posterior hypothalamus, descending through the spinal cord to the intermediolateral cell column (T1 to L2), and paravertebral ganglia and then to the sweat gland via small unmyelinated fibers. Therefore it is important to note that neuropathy affecting large myelinated fibers exhibits abnormal SSR when electrical stimulation is used. Low amplitude or absent response indicates abnormal sympathetic reflex arc, and the lesion can be central or peripheral, preganglionic or postganglionic. A side-to-side amplitude difference of more than 50% is considered to be abnormal by some. In studies of diabetic, uremic, and amyloid neuropathies, the result of SSR correlated well with autonomic symptoms. As a rule, SSR is abnormal in axonal neuropathies. An exception is the demyelinating neuropathy with prominent autonomic features, such as Guillain-Barre syndrome. Some studies have reported abnormal SSR test results in patients with CRPS/RSD and others have not. Immediately following the sympathetic nerve block or sympathectomy, the SSR is absent or reduced in amplitude. The SSR is usually normal in entrapment neuropathy and radiculopathy. SSR evoked by magnetic stimulation in the neck bypasses the afferent limb and directly stimulates postganglionic fibers. This method has less propensity to habituate and therefore less fluctuation of amplitude and latency occurs.
QUANTITATIVE SUDOMOTOR AXON REFLEX TEST AND RESTING SWEAT OUTPUT TEST This is a sensitive, reproducible, and quantitative method to test sudomotor function. A multicompartment plastic “sweat cell” is tightly secured to the skin. The outer compartment
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SECTION II Clinical Evaluation and Diagnostic Examinations
is filled with acetylcholine solution, and nitrogen gas flows constantly to an inner compartment through an instrument that measures the change of humidity (sudorometer). A direct current is applied and the water content in the inner compartment is continuously measured before, during and after the stimulus. The basis of the test is that the axon terminal of the sweat gland under the outer compartment is activated by acetylcholine iontophoresis; the impulse travel centripetally to a branch point and then distally to the axon terminal under the inner compartment where acetylcholine is released and a sweating response results. Use of the term “axon reflex” should be discouraged, because only the postganglionic sympathetic sudomotor axon is considered to be involved in this setup. With a latency of 1 to 2 min after the induction of the stimulus, sweat output increases rapidly while stimulation continues; then the stimulator is turned off, and sweat output returns to its prestimulus baseline within 5 min (Fig. 8-7). The area under the curve represents the total amount of sweat output expressed in microliter per square centimeter, and the normal value varies depending on the site of testing, gender, and age of the subject. Distal limbs, male, and younger subjects tend to sweat more. Reduced or absent response indicates postganglionic disorder. Normal response does not rule out preganglionic involvement. Excessive and persistent sweating is also considered abnormal. Comparison is made between the two limbs, and an asymmetry of more than 25% is considered to be abnormal.7 The RSO test is basically similar to the QSART; a capsule with one chamber is attached to the skin, and the rate of water evaporation is continuously recorded for 5 min. The presence of RSO indicates that the sweat gland is spontaneously activated by the sympathetic fibers.7 In a patient with painful diabetic neuropathy, RSO studies show the presence of increased sweat activity, and QSART exhibits short latency, excessive, and persistent sweat patterns, which is evidence of sympathetic overactivity. Sweat test abnormalities correlate well with the symptoms of CRPS/RSD-related pain, for which the
pathophysiologic mechanism is uncertain; perhaps a lower firing threshold, or an increased firing frequency due to denervation hypersensitivity of the sudomotor axons may produce excitation of the sweat glands. Recently, the Food and Drug Administration (FDA) approved the Q-Sweat device. This device uses dry air instead of nitrogen gas to measure water content.7
NOCICEPTIVE REFLEXES The blink reflex is recorded by electrically stimulating the supraorbital branch of the trigeminal nerve. Ipsilateral R1 (10–13 ms) and bilateral R2 potentials (30–41 ms) are obtained from the orbicularis oculi muscles. The masseter inhibitory reflex is recorded from the masseter muscles bilaterally with stimulation of the mentalis nerve while the muscle is fully activated by clenching teeth. Ongoing EMG activity is interrupted by two silent periods—an early phase with a latency of 10 to 15 ms and a late phase with 40 to 50 ms. These trigeminal reflexes have been reported normal in tic douloureux, but abnormal in facial pain due to neuropathy, multiple sclerosis, and cerebellopontine angle tumor. However, its afferent path is at least in part mediated by non–nociceptive fibers. Flexion reflex or withdrawal reflex is obtained by painful stimulation of a nerve or skin. RIII flexion reflex (80–90 ms) recorded from the short head of biceps femoris by stimulating the sural nerve has been found useful to assess efficacy of pain medications.6,8
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Electrophysiologic studies are very sensitive indicators of central and peripheral nervous system involvement but do not indicate underlying disease. EMG/NCV studies can identify the anatomic site of injury, the type of neurons or fibers involved, the nature of the pathologic alteration, and severity of injury. In QST, cold threshold measures Ad fiber function, whereas warmth, heat pain, and cold pain thresholds reflect the function of C-fibers. SSEPs provide a quantitative measure to study the entire sensory pathway, mediated by Type Ia and II sensory afferents. LEPs and CHEPs measure the function of Ad and C-fibers. CHEPs have potential to become a standard neurophysiologic method. SSR and QSART have a limited role but are useful for the evaluation of painful diabetic neuropathy or CRPS/ RSD. Nociceptive reflexes have an extremely limited role.
REFERENCES FIGURE 8-7 Example of a normal quantitative sudomotor axon reflex test (QSART). On, off, stimulator on and off.
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