Electrodiagnostic Measures

Electrodiagnostic Measures E lectrodiagnostic assessments are sensitive, specific, and reproducible measures of the presence and severity of peripheral nerve involvement in patients with diabetes (1). Nevertheless, important assumptions and issues must be considered if data are to be meaningfully interpreted and compared with other studies. The following emphasizes the electrodiagnostic evaluation of symmetric distal diabetic polyneuropathy (polyneuropathy) in patients as individuals or in populations. A different strategy would be necessary for the evaluation of patients with mononeuropathy, asymmetric proximal neuropathy (diabetic amyotrophy), or symmetric proximal neuropathy, and is not further discussed. Various electrophysiological procedures can be performed in the electrodiagnostic evaluation of diabetic polyneuropathy (2). The two used most frequently are nerve conduction studies and conventional needle electromyography. Nerve conduction studies are considered noninvasive and more appropriate for longitudinal or populations evaluations, and they are reported most often in the literature (3). To avoid contamination of results, it is important to identify and separate patients who have other types of diabetic neuropathy or other coexisting peripheral nerve disorders from those with diabetic polyneuropathy alone. For example, diabetic polyradiculopathy or lumbar canal stenosis involving the L5 and SI roots bilaterally can affect the lower limb motor nerve conduction studies. Also, superimposed carpal tunnel syndrome is often found in patients with diabetic polyneuropathy (4). ESSENTIAL FEATURES In gen eral, a combination of motor and sensory nerve conduction studies should be performed in upper and lower limbs. In a patient with known polyneuropathy, testing a small number of nerves may suffice in serial assessments. A sample protocol would include unilateral studies of median, ulnar, peroneal, and tibial motor nerves with F wave recordings, and median, ulnar, and sural sensory nerves. H reflex studies are frequently abnormal in diabetic polyneuropathy, but this finding is so nonspecific that they have limited application (4). Additional studies may be appropriate to characterize abnormalities based on clinical symptoms or signs. Nerve conduction studies can be performed with surface or needle electrodes for recording and stimulating (5). Although near-nerve recordings of action potentials may provide useful information, the technique has not had general application in individual or longitudinal evaluations. Surface techniques are more widely used, technically easier to perform, more comfortable, and the results are easier to measure. Results include amplitude, distal latency of compound muscle action potentials (CMAPs) and sensory nerve action potentials (SNAPs), conduction velocity of the fastest conducting fibers, and minimal F wave latencies. Measurements of CMAP area and duration are readily available and the number of active nerve fibers may be better represented by area than by amplitude alone. Regardless of the technique used, the location of recording and stimulating electrodes should be standardized. Temperature influences all of ADDRESS CORRESPONDENCE AND REPRINT REQUESTS TO DR. RICHARD KAHN, AMERICAN DIABETES ASSO- CIATION, 1660 DUKE STREET, ALEXANDRIA, VA 22314. THIS MATERIAL IS BEING PUBLISHED SIMULTANEOUSLY IN NEUROLOGY AND MUSCLE AND NERVE. the results, and limb temperature must be controlled. A thorough electrodiagnostic evaluation of the individual patient ordinarily includes needle electromyography. Important measures include the presence and amount of fibrillation potentials and positive sharp waves (single-fiber discharges) and motor unit action potential recruitment, amplitude, duration, and configuration. Because these measures are subjective, the primary role of needle electromyography is diagnostic. Quantitative needle examination techniques may be useful in evaluating longitudinal changes. In epidemiological evaluations for the presence of polyneuropathy, it may be sufficient to evaluate one or two nerves. In clinical trials, a more extensive evaluation may be required. In the investigation of clinically mild polyneuropathy, evaluation should be directed at the most susceptible nerves. Conversely, in severe disease, absent lower limb responses provide limited useful information to evaluate progression. STANDARDIZATION AND QUANTITATION Although there may be differences among laboratories, all aspects of nerve conduction studies can be standardized. Reliable electrodiagnostic evaluation requires meticulous attention to detail (5). Filter settings, type and size of electrodes, the location of recording and stimulating electrodes, and measurement methods are important and should be defined. Limb temperature should be rigidly controlled throughout the study, with cool limbs warmed when necessary. For longitudinal evaluations, permanent records of conduction studies are required. The conventional needle examination, subjective and semiquantitative at best, is less suitable for standardization. Other important factors that can be standardized are the qualifications of the electromyographer, methods for data analysis and description, and population-based reference values. DIABETES CARE, VOLUME 15, SUPPLEMENT 3, AUGUST 1992 1087

The results of nerve conduction studies can be quantitated and are suitable for longitudinal study, although in adults virtually all demonstrate slow, progressive change with aging. The conventional needle examination is poorly suited for longitudinal examinations. Quantitative needle examination, although appropriate for longitudinal studies, may be poorly tolerated. To ensure that acquired data are accurate and reliable, it is important that well-trained individuals perform nerve conduction studies. These studies should be performed by an electromyographer or an EMG technician designated by the electromyographer. Guidelines for specifying the qualifications of the electromyographer or technician are beyond the scope of this document, but standards have been developed by the American Board of Electrodiagnostic Medicine, the American Board of Psychiatry and Neurology (added qualifications in clinical neurophysiology), and the American Association of Electrodiagnostic Technologists. Deciding how many and which nerves to assess is as important as selecting specific techniques for performing the study. Although studies generally are performed unilaterally, bilateral studies may be helpful to assess patients with coexisting focal lesions or to confirm symmetrical involvement. Considerations include which nerves provide the sensitivity and specificity of information needed and which are easiest to evaluate with fewest technical problems. To some extent, all nerves have potential for localized abnormality, anomalous innervation, or technical difficulty. Factors that can be controlled to minimize variability include limb temperature (6), use of appropriate equipment, specified stimulation and recording sites, and standardized techniques for measuring SNAP and CMAP amplitude and latency. Surface temperatures should be maintained above 31 C for the foot and leg and above 32 C for the hand and forearm. Optimal range is between 32 and 36 C, although occasionally it may not be possible to maintain such limb temperature. Warming techniques include submerging the limb in warm water (optimal for uniform warming), as well as use of a hydrocollator pack, an electric heating pad, or an infrared heating unit. Surface temperatures should be taken several minutes after warming to allow stabilization. For standardization in longitudinal evaluations, temperatures may be recorded immediately before and on completion of the nerve conduction study and averaged to approximate the temperature during the study. Large differences in the before and after temperatures imply poor equilibration and should be avoided. Commercially available equipment fulfill conventional standards for patient use. Recommended filter settings (approximate values) are 20-2000 Hz bandpass for sensory studies, 2-10,000 Hz bandpass for motor studies, and 20-10,000 Hz bandpass for needle electromyography. Averaging of sensory responses may be used to improve the signal-noise ratio, although an averaged response must be reproducible to be valid. Averaging is unnecessary for motor conduction studies. Supramaximal percutaneous stimulation is used for all nerve conduction studies, except for H reflexes. The use of 20% greater intensity than maximal is adequate and minimizes the chance of inadvertent stimulus spread. Care also must be taken to prevent stimulation of adjacent nerves. Many of the described nerve conduction techniques vary only in minor details, reflecting the individual electromyographer's preference or training. The following recommendations are made for standardized evaluations, although we recognize that alternatives exist: 1. Amplitude: The CMAP amplitude is measured from the baseline to the peak of the negative wave (M wave). An initial positive deflection usually indicates an improper recording site and the active electrode should be repositioned over the motor point. The SNAP amplitude is measured from the baseline (or peak of the initial positivity, if present) to the peak of the negative wave. A sloping baseline makes SNAP amplitude measurement unreliable and should be avoided with proper technique. 2. Distal latency: Distal motor latency is measured to the onset of the M wave. Distal sensory latency may be measured to the peak of SNAPnegative wave when a standardized distance is used, although this measure is inappropriate for conduction velocity calculation. The SNAP onset latency can be measured to the onset of the initial negative deflection and used to calculate a distal sensory conduction velocity. 3. Distance: Distance is measured between the distal stimulation site (cathode) and the midpoint of the active recording electrode and should be standardized. Distance also is measured between stimulation sites when additional stimulation is performed. Inaccurate measurements are a major source of error. 4. Conduction velocity: The velocity of the fastest nerve fibers is calculated with SNAP or CMAP onset latencies between two stimulation (or recording) sites. The same gain and sweep speed are used for distal and proximal stimulation. At both stimulation sites the CMAP configurations should be similar. For sensory studies, a distal conduction velocity can be calculated by dividing the distance between the stimulation and recording sites by the onset latency. 5. F wave latency: The minimal latency is measured to the onset of the earliest F wave after 5-15 antidromic motor nerve stimulations from the distal site. A minimum of 5 acceptable F waves are recorded. 1088 DIABETES CARE, VOLUME 15, SUPPLEMENT 3, AUGUST 1992

Electrodiagtxostic measures Table 1 Sample protocol of electrodiagnostic tests NERVE MEDIAN S ULNAR S SURAL S MEDIAN M MEDIAN F WAVE ULNAR M ULNAR F WAVE PERONEAL M PERONEAL F WAVE TIBIAL M TlBlAL F WAVE STIMULATE ANTECUBITAL FOSSA MIDCALF ANTECUBITAL FOSSA BELOW ELBOW; 1 CM DISTAL TO CONDYLAR GROOVE* ANTERIOR ANKLE LOWER EDGE OF FIBULAR HEAD* ANKLE MEDIAL MALLEOLUS POPLITEAL FOSSA ANKLE T o avoid common sices of compression. The F wave is considered unobtainable if there are no responses with >10 stimulations. F waves must be distinguished from A waves which demonstrate no latency or waveform variability. 6. Other measurements: Duration, area, and area/amplitude differences between two stimulation sites can be measured. It is premature to recommend these measurements because there are limited reference data. A sample protocol of possible nerves for evaluation is shown in Table 1, indicating stimulation sites, recording sites, and distances, although we appreciate that individual electromyographers have varying preferences. DIGIT 2 RECORD DIGIT 5 LATERAL MALLEOLUS ABDUCTOR POLLICIS BREVIS ABDUCTOR POLLICIS BREVIS ABDUCTOR DIGIT MINIMI ABDUCTOR DIGIT MINIMI EXTENSOR DIGITORUM BREVIS EXTENSOR DIGITORUM BREVIS ABDUCTOR HALLUCIS ABDUCTOR HALLUCIS DISTANCE 7 CM 7 CM 9 CM 9 CM SENSITIVITY, SPECIFICITY, AND REPRODUCIBIUTY No electrodiagnostic results are specific for diabetic polyneuropathy. However, electrodiagnostic evidence of axonal degeneration and substantial conduction slowing in the proper clinical setting is suggestive of diabetic polyneuropathy. A reduced conduction velocity has a high sensitivity (7) but a low specificity in detecting diabetic polyneuropathy. A reduced SNAP amplitude (especially the sural) has a high specificity and sensitivity in detecting any sensorimotor polyneuropathy (8). Electrodiagnostic abnormalities documenting subclinical diabetic polyneuropathy are well established for group comparisons (9,10). The sensitivity of nerve conduction studies has been demonstrated in diabetic patients without neurological symptoms or signs (11). In such patients, abnormalities of conduction velocity may be prominent, reflecting a metabolic abnormality in diabetic nerves or segmental demyelination and remyelination. Reduced SNAP amplitude is another sensitive finding in subclinical and clinical involvement; reduced CMAP amplitude has lower sensitivity in general, but is probably more specific for disabling polyneuropathy (7). The sensitivity and specificity of F wave latency is not established. H reflex abnormalities have high sensitivity but low specificity because they are found in so many other disorders, as well as with advanced age alone (4). Electromyography may reveal partial denervation in intrinsic foot muscles as an early sign of diabetic polyneuropathy. As a sensitive indicator of axonal degeneration, the needle examination may demonstrate the only abnormality in some patients with early diabetic polyneuropathy (4). There are few reports of nerve conduction study reproducibility (12), although it is known that some nerve conduction studies are technically more difficult to perform and therefore less reproducible than others. The reports that exist usually have been for normal nerves, and they may not reflect what occurs in longitudinal studies of diabetic polyneuropathy. No studies have been reported comparing reproducibility among laboratories. Even though amplitude measures have good reproducibility for groups, they may vary substantially in the same individual at even short intertest intervals. In general, nerve conduction velocities have excellent reproducibility for groups and good reproducibility for individuals. F and II wave latencies are less subject to intertest variability. DATA REPORTING AND STATISTICAL ANALYSIS The format and extent of the report of the data will vary depending on their use. In general, the reported data should be adequate for independent interpretation of the results. The results of amplitude (mv or AV), conduction velocity (m/s), distal latency (ms), and F wave latency (ms) should be reported at minimum as individual values for a single patient or as the mean and range for a study population. Reference values should be included for all reported measures. Data usually should be presented for each studied nerve. Pooling or combining the results from each patient into a single summary measure occasionally has been used (13). If data are to be pooled, careful consideration must be given to the exact method, in consultation with a biostatistician. Individual val- DIABETES CARE, VOLUME 15, SUPPLEMENT 3, AUGUST 1992 1089

ues that belong to the same category (e.g., SNAP amplitude) may be pooled. Combined values likely improve reproducibly but potentially decrease sensitivity. For example, pooled results may conceal mild abnormalities that appear in some nerves before others. Because the distribution of most measures is not Gaussian (normal) or even similar from nerve to nerve, expressing the data as a percentage of the upper or lower limit of normal may limit subsequent statistical analyses. It may be possible to transform the data to make the distributions more Gaussian, and then express individual measures in terms of standard deviation intervals from the mean. Such data could then be pooled for similar physiological measures. The ultimate usefulness of such data reduction is unknown at this time. Consideration must be given to factors such as age and height. Patient data may be expressed as a percentile of a reference group, adjusting for age and other important factors. Attempts have been made to express each individual study by the number of abnormalities for a fixed number of sensory and motor measures (13). Summated data of electrodiagnostic attributes have demonstrated high concordance with other tests in the detection and staging of polyneuropathy (7). Although this technique has been used successfully, it has the apparent disadvantage of changing quantitative data into a single nonparametric measure. There is a role for both individual data and pooled data in the study of diabetic polyneuropathy, although pooled analysis techniques should be used with caution. Whenever individual results are expressed as a continuous variable, the distribution of the data should be examined. Parametric statistics can be used only if the distribution is normal. If the distribution is not normal, attempts may be made to transform the data to a more Gaussian distribution. Transformation procedures are not always appropriate. Alternatively, nonparametric statistics may be used to analyze data that are not expressed as continuous variables, are not normally distributed, or combine different categories of information. When results from a battery of nerve conduction studies are evaluated, statistical correction for multiple comparisons should be applied. CORRELATES OF ELECTROPHYSIOLOGIC S Most electrodiagnostic abnormalities correlate with underlying pathophysiological changes to a variable degree. The information can be used to define the nature, distribution, and severity of the peripheral nervous system disorder. Some abnormalities may reflect metabolic changes not associated with symptoms or signs, whereas some clinical symptoms (e.g., transient paresthesias) are not associated with unequivocal electrodiagnostic changes. Needle electromyographic evidence of fibrillation potentials and positive sharp waves (single-fiber discharges related to denervation hypersensitivity) may be the most sensitive electrophysiological indicator of active axonal degeneration. Examination of proximal and distal muscles in the upper and lower limbs as well as bilateral studies, when necessary, provide information useful for localizing and grading the severity of axonal lesions. The CMAP and SNAP amplitude and area primarily reflect the number of active nerve fibers as estimated from summated fiber action potentials. Because lesions proximal to the dorsal root ganglia have no effect on the distal sensory nerve, SNAP abnormalities are useful in identifying more distal involvement. Abnormalities of CMAP and SNAP amplitude characteristically are associated with clinical sensory and motor deficits. Conduction velocity measurements are a poor indicator of axonal degeneration, but may reflect specific metabolic abnormalities or segmental demyelination and remyelination. Decreased Na + -K + -ATPase activity results in decreased Na + permeability and a decreased Na + transmembrane gradient with a resultant decrease in conduction velocity (14). Remyelination results in shorter intemodal distances and is associated with permanently slowed conduction velocity. Measures of conduction velocity have no direct clinical correlates. References 1. Report and recommendations of the San Antonio Conference on Diabetic Neuropathy. Diabetes 37:259-65, 1988 2. Daube JR: Electrophysiologic testing in diabetic neuropathy. In Diabetic Neuropathy. Dyck PJ, Thomas PK, Asbury A, Winegrad A, Porte D, Eds. Philadelphia, PA, Saunders, 1987, p. 162-76 3. Dyck PG, Kratz KM, Lehman RA, Karnes JL, Melton LJ, O'Brien PC, Litchy WJ, Windebank AJ, Smith BE, Low PA, Service FJ, Rizza RA, Zimmerman BR: The Rochester Diabetic Neuropathy Study: design, criteria for types of neuropathy, selection bias, and reproducibility of neuropathic test. Neurology 41:799-807, 1991 4. Wilboum AJ: The diabetic neuropathies. In Clinical Electromyography. Brown W, Bolton C, Eds. New York, Butterworths, 1985, p. 329-62 5. Kimura J: Electrodiagnosis in Diseases of Nerve and Muscle. Ed. 2. Philadelphia, PA, Davis, 1989 6. Denys EH: AAEM Minimonegraph #14. The Influence of Temperature in Clinical Neurophysiology. Muscle Nerve 14:795-851, 1991 7. Dyck PJ, Karnes JL, O'Brien PC, Litchy WJ, Low PA, Melton LJ: The Rochester Diabetic Neuropathy Study: reassessment of tests and criteria for diagnosis and staged severity. Neurology. In press 8. Behse F, Buchtal F, Carlsen F: Nerve biopsy and conduction studies in diabetic neuropathy. J Neurol Neurosurg Psychiatry 40:1072-82, 1977 9. Dyck PJ, Kames JL, Daube JR, O'Brien PJ, Service FJ: Clinical and neuropathologic criteria for the diagnosis and staging of diabetic polyneuropathy. Brain 108:861-80, 1985 10. The DCCT Research Group: Factors in the development of diabetic neuropathy: baseline analysis of neuropathy in the 1090 DIABETES CARE, VOLUME 15, SUPPLEMENT 3, AUGUST 1992

feasibility phase of the Diabetes Control and Complications Trial (DCCT). Diabetes 37:476-81, 1988 11. Mulder DW, Lambert EH, Bastron JA, Sprague RG: The neuropathies associated with diabetes mellitus: a clinical and electromyographic study of 103 unselected diabetic patients. Neurology 11: 275-84, 1961 12. Chaudry V, Comblath DR, Mellits Ed, Avila O, Freimer ML, Glass JD, Reim J, Ronnett GV, Quaskey SA, Kuncl RW: Inter- and intra-examiner reliability of nerve conduction measurements in normal subjects. Ann Neurol 30:841-43,1991 13. Dyck PJ, KamesJ, O'Brien PC: Diagnosis, staging, and classification of diabetic neuropathy and associations with other complications. In Diabetic Neuropathy. Dyck PJ, Thomas PK, Asbury A, Winegrad A, Porte A, Eds. Philadelphia, PA, Saunders, 1987, p. 36-44 14. Brismar T, Sima AAF: Changes in nodal function in nerve in nerve fibers of the spontaneously diabetic BB Wistar rat: potential clamp analysis. Ada Physio! Scand 113:499-510, 1981 DIABETES CARE, VOLUME 15, SUPPLEMENT 3, AUGUST 1992 1091