Recommendations for the clinical use of somatosensory-evoked potentials

Clinical Neurophysiology 119 (2008) 1705–1719 www.elsevier.com/locate/clinph

Invited review

Recommendations for the clinical use of somatosensory-evoked potentials G. Cruccua,*, M.J. Aminoffb, G. Curioc, J.M. Gueritd, R. Kakigie, F. Mauguieref,j, P.M. Rossinig,h, R.-D. Treedei, L. Garcia-Larreaf,j a

Department of Neurological Sciences, La Sapienza University, viale Universita` 30, 00185 Rome, Italy b Department of Neurology, School of Medicine, University of California, San Francisco, CA, USA c Department of Neurology and Clinical Neurophysiology, Campus Benjamin Franklin, Charite´ – University Medicine Berlin, Berlin, Germany d Neurology, Clinical Neurophysiology Unit, CHIREC, Brussels, Belgium e Department of Integrative Physiology, National Institute for Physiological Sciences, Okazaki, Japan f Universite´ de Lyon 1, Lyon, France g Neurology, Universita` Campus Bio-Medico, Rome, Italy h IRCCS, S.Giovanni di Dio, Fatebenefratelli, Brescia, Italy i Institute of Physiology and Pathophysiology, Johannes Gutenberg University, Mainz, Germany j INSERM U879 – Central Integration of Pain Unit, Neurological Hospital Lyon, France Accepted 20 March 2008 Available online 16 May 2008

Abstract The International Federation of Clinical Neurophysiology (IFCN) is in the process of updating its Recommendations for clinical practice published in 1999. These new recommendations dedicated to somatosensory-evoked potentials (SEPs) update the methodological aspects and general clinical applications of standard SEPs, and introduce new sections dedicated to the anatomical–functional organization of the somatosensory system and to special clinical applications, such as intraoperative monitoring, recordings in the intensive care unit, pain-related evoked potentials, and trigeminal and pudendal SEPs. Standard SEPs have gained an established role in the health system, and the special clinical applications we describe here are drawing increasing interest. However, to prove clinically useful each of them requires a dedicated knowledge, both technical and pathophysiological. In this article we give technical advice, report normative values, and discuss clinical applications. Ó 2008 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved. Keywords: Somatosensory-evoked potentials; Recommendations; CNS disease; Coma; Intensive care; Intraoperative monitoring; Pain; Pain-evoked potentials; Laser-evoked potentials; Trigeminal-evoked potentials; Pudendal-evoked potentials

1. Anatomy and physiology of the somatosensory system The somatosensory system subserves the fifth sense ‘‘Das Gefu¨hl”, which consists of five submodalities: mechanoreception, thermoreception, nociception, proprioception and visceroception. These submodalities provide conscious perception of sensory information from the skin, the musculo-skeletal system and the viscera (Table 1). In addition, somatosensory afferents are involved in *

Corresponding author. Tel.: +39 06 49694209; fax: +39 064991 4758. E-mail address: [email protected] (G. Cruccu).

numerous motor and autonomous reflex pathways and feedback loops with reflex centers in the spinal cord, brainstem and forebrain. Somatosensory afferents also provide a powerful excitatory input to the ascending reticular activating system (ARAS) that regulates sleep and wakefulness. The somatosensory system consists of two major parts: the dorsal column–lemniscal system and the spinothalamic system (Fig. 1). The dorsal column–lemniscal system subserves mechanoreception (tactile object recognition, localization of skin contact, detection of vibration and texture) and proprioception (joint position, movement and force).

1388-2457/$34.00 Ó 2008 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.clinph.2008.03.016

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Table 1 The five somatosensory submodalities Submodality

Afferent nerve fibres

CNS tract

Group

Skin nerve

Mechanoreception Proprioception Thermoreception Nociception Visceroception

II (Ab) Ia, Ib, II III (Ad), IV (C) III (Ad), IV (C) III (Ad), IV (C)

+

Muscle nerve

Visceral nerve

+ + +

+

+ +

Function Exteroception

DC–ML DC–ML STT STT STT*

Interoception

+ + +

+ + + +

Nerve fibre groups according to Lloyd and Hunt: I–III myelinated axons of different diameter and conduction velocity; IV, unmyelinated axons; fibre groups according to Erlanger and Gasser are given in brackets; DC–ML, dorsal columns and medial lemniscus; STT, spinothalamic tract. STT*, the vagus nerve provides another pathway for visceral afferent input to the brain, mostly for autonomic reflexes and non-painful percepts (from Treede, 2007).

The spinothalamic tract system (also called extralemniscal system) subserves thermoreception (coolness and warmth), nociception (impending tissue damage and pain) and visceroception. Each of the two systems can be divided into four neuronal populations. The somata of the first-order neuron are situated in the dorsal root ganglia, the trigeminal ganglion, the midbrain trigeminal nucleus and the vagal ganglion nodosum. The second-order neuron lies in the dorsal column nuclei (lemniscal system) or the dorsal horn of the spinal cord (spinothalamic tract system); axons of the second neuron cross the midline. Both systems project

to the ventroposterior nuclei of the thalamus (third-order neuron) and from there into the network of somatosensory cortex areas (‘‘fourth-order neurons”), which include primary and secondary somatosensory cortex, posterior parietal cortex, posterior and mid-insula and mid-cingulate cortex (Treede, 2007). Besides these two main systems, other pathways have been suggested to be involved in mediating somatosensory functions, such as the dorsal spino-cerebellar tract (lower limb proprioception), postsynaptic dorsal column pathway (pelvic organ pain), and vagus nerve (non-painful visceral percepts).

Fig. 1. Schematic drawing of the somatosensory system. The somatosensory system consists of two major parallel pathways. The lemniscal system (black lines) subserves mechanoreception and proprioception. The spinothalamic tract system (red) subserves nociception, thermoreception and visceroception (from Treede, 2007).

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When reading these recommendations, it should be kept in mind that the standard SEP techniques only assess function of the dorsal column–lemniscal system. Whereas the presence of SEP abnormalities provides good evidence for an impairment of the somatosensory system, normal SEP findings cannot exclude a selective impairment of the spinothalamic system (see Section 6). 1.1. The lemniscal system: mechanoreception and proprioception Primary afferent nerve fibres that project into the lemniscal system are of large diameter and myelinated (groups I and II, or Aa and Ab) with conduction velocities of 30– 80 m/s. Their peripheral terminals are corpuscular nerve endings in the skin, joint capsule and muscle. These afferents have the lowest threshold for electrical stimulation and hence are preferentially activated by the techniques listed in Section 2. Since electrical stimulation directly excites the axons, deficits of the transduction process in the nerve terminals are not assessed by SEPs. The large afferent fibres are the first to be blocked or damaged by nerve compression. The central axon branches of the first neuron travel a long distance in the ipsilateral dorsal column pathways until they reach the second neuron in the dorsal column nuclei of the lower brainstem. The P13–P14 subcortical SEP component, recorded as a far-field potential from the scalp, is generated at or near this first synaptic relay of the lemniscal system. Axons of the second neuron cross the midline and project as medial lemniscus to the ventroposterior thalamus. 1.2. The spinothalamic tract system: nociception, thermoreception and visceroception Primary afferent nerve fibres that project into the spinothalamic tract system are of small diameter, either thinly myelinated (group III, or Ad) with conduction velocities of 2–33 m/s, or unmyelinated (group IV or C) with conduction velocities of 0.4–1.8 m/s. Their peripheral terminals are free nerve endings in the skin (including the superficial epidermis), bone, joint capsule, tendon, muscle, and many visceral organs. These afferents have high thresholds for electrical stimulation and hence are not activated by the techniques listed in Section 2.1. Many small diameter afferents can be excited by heat stimuli above 40 °C (group IV) or above 45 °C (group III). The small afferent fibres are very sensitive to blockade by local anesthetics. The central axon branches of the first neuron travel only a short distance within the ipsilateral spinal cord before they enter the dorsal horn at segmental level, where they reach the second neuron. A part of the second neuron population in the dorsal horn receives convergent input also from collaterals of large fibre afferents of the lemniscal system (Fig. 1). The N13 spinal component of SEPs is generated at or near this first synaptic relay of the spinothalamic

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system. Axons of the second neuron cross the midline and project as spinothalamic tract to the ventroposterior thalamus. 1.3. The somatosensory thalamus and cortex Fibres in the medial lemniscus reach the ventroposterior thalamus (VPL, or Vc in humans) which in turn projects to the primary somatosensory cortex (SI) in the postcentral gyrus. Within SI, Brodmann areas 3b and 1 mainly receive mechanoreceptive inputs from the skin, whereas areas 3a and 2 mainly receive proprioceptive inputs. Tactile object recognition starts with simple feature extraction in SI (detection of edges, line orientation and movement direction). Object recognition continues in a ventral stream directed towards the secondary somatosensory cortex (SII) in the parietal operculum and further into the insula; these regions receive bilateral input. Stimulus location is further processed in a dorsal stream comprising Brodmann areas 5 and 7 in the posterior parietal cortex. The distinction of dorsal and ventral streams in the somatosensory system is comparable to that in the visual system, the ventral stream being mostly involved in tactile object recognition and the dorsal one in somatosensory–visual integration. The thalamocortical projections of the spinothalamic tract system are organized somewhat differently. Most spinothalamic projections reach the principal thalamic somatosensory nucleus (ventrobasal group, VPL/VPM/ VPI in monkey or Vc in humans) as clusters of terminals. These zones are separate from the region of medial lemniscus terminals. Other spinothalamic terminations are observed posterior and inferior to Vc including the recently described VMpo. Thalamic neurons receiving nociceptive input project to SI, SII, the dorsal insula and the frontal operculum. Nociceptive neurons in SI with input from the ventrobasal thalamus are mainly found in area 1, but there is also some evidence that area 3a may have nociceptive input. SII has a substantial nociceptive input directly from the thalamus, whereas its tactile input mainly derives from SI. The insula is an important region for integration of nociceptive, thermoreceptive and visceroceptive signals. There is also a nociceptive projection from the medio-dorsal thalamic nucleus (MD) to the mid-cingulate cortex. Finally, polysynaptic nociceptive inputs to the non-specific intralaminar nuclei, parafascicular (Pf) and centrolateral (CL), may have widespread effects on large parts of the cortex. 2. Methods of recording and nomenclature 2.1. Stimulation SEPs are usually evoked by bipolar transcutaneous electrical stimulation applied on the skin over the selected nerve. Monophasic square-wave electrical pulses of 0.1– 0.2 ms should be delivered, preferably by a constant cur-

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rent stimulator. In routine recording, stimulus parameters include a stimulus intensity able to produce a clear but tolerable sensation: in cutaneous nerves (e.g. sural or superficial radial nerves) 2–3 times the sensory threshold is generally high enough to obtain adequate SEPs; in mixed nerves it is useful to sum the intensities needed for motor and sensory thresholds, which usually yields a reproducible muscle twitch. Stimulation rate should be 3–5 Hz. As far as possible, the same intensity should be kept for both sides. The cathode should be proximal to reduce the likelihood of anodal block, and to minimize stimulus artifact a ground electrode is placed on the stimulated limb between the stimulation site and the recording electrodes. For median-nerve SEPs the anode should be placed on the wrist crease and the cathode some 2 cm proximal. For tibialnerve SEPs the cathode should be placed midway between the medial border of the Achilles’ tendon and the posterior border of the medial malleolus and the anode some 3 cm distal. 2.2. Recording Recording electrodes are standard EEG disk electrodes. Skin-electrode impedance should be less than 5000 X. Since the most clinically useful SEP components peak before 50 and 100 ms, respectively, for upper and lower limb stimulation, there is no necessity to extend the analysis time beyond 100 ms in most clinical settings. The optimal condition to record clinically-relevant SEP components is a highpass filter at less than 3 Hz and a low-pass filter over 2000 Hz (Rossini et al., 1981). To ensure reproducibility of the waves and measure their latency and amplitude correctly, we recommend to average at least 500 trials for the main cortical SEP waves, and to repeat at least two blocks of stimuli (Fig. 2). Spinal and subcortical components may require 1000–2000 stimuli, even for routine diagnostic purposes. 2.2.1. Median nerve SEP 2.2.1.1. Recording electrode locations. For standard clinical recordings we recommend at least four channels designed to highlight one or more component each: peripheral (Erb’s point) channel (N9), cervical channel (N13), parietal channel (P14 and N20) and frontal channel (P14, P20 and N30). Peripheral Erb’s point electrodes are designated as EP and must be placed within the angle formed by the posterior border of the clavicular head of the sternomastoid muscle and the clavicle, 2–3 cm above the clavicle (Erb’s point). The active electrode is ipsilateral to stimulation (EPi), and the reference is either the contralateral EP electrode (EPc) or a scalp electrode (generally Fz). In this latter case the montage allows recording, in addition to the plexus volley, an inverted image of P14. The posterior spinal cervical electrode is commonly located over the 6th (Cv6) or 7th (Cv7) cervical spinous process. Recommended reference for cervical spine recordings is on the anterior neck at the level of the glottis (Gl). The P14 wave is gener-

ated at or near the foramen magnum, and is itself composed of two peaks, commonly labelled P13 and P14 proper. Although their generation is perhaps respectively pre- and post-synaptic relative to the nucleus cuneatus relay, P13 and P14 are most commonly associated and respond similarly to clinical conditions, so the label ‘‘P14” will be used to design the complex of the two (see Fig. 2). The location of scalp electrodes follows the 10–20 international system of EEG electrode placement. Parietal scalp electrodes are placed at CP3 and CP4 and are designated as Pc (contralateral to stimulation) and Pi (ipsilateral to stimulation). The frontal scalp electrode is located at the site Fz of the 10–20 system, or alternatively at F3–F4 (contralateral to stimulation). An acceptable reference for scalp electrodes is the earlobe ipsilateral to stimulation. Recordings with a non-cephalic reference (shoulder or EPc) are more informative because they demonstrate the whole sequence of subcortical far-field potentials (Cracco and Cracco, 1976; Desmedt and Cheron, 1981), but recordings are technically more difficult to obtain (Fig. 2). The separate electrode at contralateral frontal leads (F3 or F4) is useful to record frontal components P22 and N30 (Desmedt and Cheron, 1981) which reflect different generators than parietal SEPs. When using an extracephalic reference, the subcortical N18 may sometimes be confounded with the cortical N20, especially with low-pass filters being too high (thus transforming the broad N18 wave in an artificial ‘‘peak”). This may be especially worrisome in SEP assessment during intraoperative monitoring or for prognostic evaluation of comatose patients. Comparing recordings from contralateral and ipsilateral parietal leads (Pc and Pi) is an easy way to ascertain whether the ‘N20’ is genuine. Alternatively, a parieto–parietal montage (Pc–Pi) permits the recording of cortical N20 without contamination from subcortical waves, and may be used for monitoring purposes. Later cortical waves (P45, N60 and P/N100) are less reliable, more susceptible to changes by cognitive factors, and not currently used in clinical routine. 2.2.2. Tibial nerve SEP 2.2.2.1. Recording electrode locations. For standard clinical recordings we recommend four channels designed to highlight one component each: peripheral (N8), lumbar (N22), subcortical (P30) and cortical (P39) The peripheral recording electrode is placed in the popliteal fossa (PF) 4–6 cm above the popliteal crease. A reference electrode may be placed either on the medial surface of the knee, over the medial femoral condyle or 3 cm above the active electrode. Lumbar electrodes should be placed on the skin overlying the spinous processes of a lumbar vertebra, most often L1. The L3 spinous process, the supra-umbilical region (Um), or the iliac crest (Ic) contralateral to stimulation are used as reference. If the investigator wishes to record the spinal volley, a thoracic channel (T12–T10) may be added. A scalp non-cephalic channel (for instance Fz– Cv7) is used to record supraspinal–subcortical responses,

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Fig. 2. Waveforms of median-nerve (A) and tibial-nerve (B) SEPs using montages advocated in these guidelines. (A) Median SEPs: the ipsilateral-tocontralateral Erb’s point montage (EPi–EPc, bottom) allows the recording of the proximal peripheral volley from the brachial plexus. The posterior– anterior cervical derivation (Cv6–AC) records a negative post-synaptic potential generated segmentally in the dorsal horn (N13). Both the parietal and frontal non-cephalic montages, referenced to the contralateral shoulder (Pc-Sh and Fc-Sh), record a series of positive far-fields reflecting the passage of the ascending volley through the plexus (P9), the dorsal root entry zone (P11) and the cervico–medullary junction (P14). Note that the P14 wave is itself composed of two peaks giving rise to the ‘P13–P14’ complex. Only the contralateral parietal electrode (Pc) records the somatosensory complex N20–P25, arising from primary somatosensory cortex, while the frontal electrode (Fc) records the phase inversion of these two potentials, followed by a cortical negative wave (N30) reflecting precentral activation. The bipolar parieto–frontal montage (Pc–Fc) eliminates all subcortical far-field activity and isolates the parietal N20. This montage yields less information than those using non-cephalic or earlobe reference, but is more resistant to aggressive environments such as the ICU or operating theatre. (B) Posterior tibial SEPs: The popliteal fossa electrode referenced to the knee (PF-K, bottom) records the peripheral ascending volley. The lumbar electrode (referenced to nombril, L1–Um) records a peripheral positive P17, probably arising from the proximal sciatic nerve (Desmedt and Cheron, 1983; Sonoo et al., 1992, followed by a post-synaptic segmental negative wave (N22) which is the equivalent of the N13 in median SEPs. The fronto–cervical montage (Fz–Cv6) allows the recording of the positive far-field P30, generated at the cervico–medullary junction. The P30 potential (equivalent to P14 for upper limb SEPs) may also be recorded with a posterior vertex–ear montage (Cz0 –Ei, uppermost traces) that also catches the cortical complex P39–N50–P60, of which only the P39 has definite clinical value. See text for possible variants of these montages (traces adapted from Mauguie`re et al., 1999).

mainly those generated at the cervico–medullary junction. The principal scalp recording electrode is at the CPz position (midway between Cz and Pz, sometimes labelled Cz0 ) and the reference electrode may be located on the forehead at Fz, Fpz or Fpz0 (2 cm above Fpz) or on the earlobe ipsilateral to stimulation (Ei). The topographic scalp distribution of the parietal response P39 (often labelled P40 too) is subject to considerable variation. Its maximum amplitude on the scalp tends to be ipsilateral, rather than contralateral to the stimulated limb due to the oblique orientation in the interhemispheric fissure of the P39 generators (Rossini et al., 1981; Baumgartner et al., 1998). There is good evidence that two different sources contribute to the scalp-recorded P39: the earlier one can be modeled as a horizontal dipole (P/N37) whose positive tail points towards the ipsilateral parietal region and its negative counterpart toward the contralateral fronto–temporal scalp. This early response can be enhanced using an oblique montage that links the ipsilateral parietal and the contralateral frontal or temporal electrodes

(Valeriani et al., 2000). The second component, or P39 proper, has a more vertical orientation and points to the vertex (Baumgartner et al., 1998). Separation of these two subcomponents is irrelevant as a routine procedure. On practical grounds if the P39 wave is indistinct or of low amplitude, the recording electrode should be moved slightly laterally (some 2 cm) toward the side ipsilateral to stimulation. 2.3. Wave labeling, generators and normal values In the nomenclature of SEP waveforms, N or P followed by an integer are, respectively, used to indicate the polarity and the nominal post-stimulus latency (ms) of the recorded wave in the healthy population (e.g. N20). The potentials can be recognized by their typical distribution, reflecting the activation of their generators, and can be measured in terms of latency (ms), amplitude (lV) and intervals between peaks. Please note that median and tibial SEPs should not be considered the only nerves to be explored.

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The diagnostic value of SEPs is highly enhanced by adapting the nerve stimulated to the clinical problem: thus, superficial radial and ulnar nerve stimulation should be preferred to median nerve to explore respectively C6 and C8 dermatomes, and common peroneal and sural nerves preferred to tibial stimulation to explore selectively L5 and S1. Each laboratory should set its own standards for amplitude and latency in a sufficient number of healthy subjects. Typical latency and amplitude values of SEPs for young adult testing (Mauguie`re et al., 1999) as well as generators of peripheral and central components of median and tibial SEPs are shown in Tables 2 and 3. It is crucial to obtain at least two repetitions of each waveform to show that any identified peak is reproducible. The reader may find complementary and supplementary information in Clinical Neurophysiology textbooks such as Binnie et al. (2003) and Chiappa (1997). 3. General clinical applications Somatosensory-evoked potentials (SEPs) are used to evaluate both the central and peripheral nervous systems. The findings may be helpful in showing that a lesion is present in the somatosensory pathways, helping to localize it, and providing a prognostic guide. However, the SEP findings do not in themselves lead to a specific diagnosis and organic disease cannot be excluded simply because the SEP findings are normal (Aminoff and Eisen, 1998).

3.1. Peripheral disorders SEPs have been used to evaluate peripheral nerves that cannot be studied by conventional nerve conduction studies, and the proximal portions of peripheral nerves that are otherwise inaccessible for study. They have been used to detect proximal involvement in patients with Guillain–Barre´ syndrome, although F-wave studies are more useful for this purpose. They may permit recognition of a lesion in patients with such proximal entrapment neuropathies as meralgia paresthetica. They have been used to assess brachial plexus lesions, but their utility is less than that of EMG. For example, although often abnormal (Yiannikas and Walsh, 1983; Aminoff et al., 1988), SEPs are usually not required for the electrophysiologic diagnosis of neurogenic thoracic outlet syndrome as conventional EMG studies are sufficient for this purpose (Veilleux et al., 1988; Aminoff et al., 1988). SEPs are normal in patients with non-neurogenic thoracic outlet syndrome (Aminoff et al., 1988). In patients with traumatic plexopathy, SEPs may not disclose pre-ganglionic lesions if a severe post-ganglionic lesion also exists. In patients with an isolated radiculopathy and only ‘positive’ symptoms (such as pain and paresthesias), both SEPs and EMG are of little help (Yiannikas et al., 1986). Even when signs of root compression are present, SEPs derived by stimulation of major nerve trunks (e.g. median and ulnar nerves in the arms, peroneal and tibial nerves in the legs) are

Table 2 Median nerve SEPs Peaks (ms)

Mean (ms)

Upper limit of normal (means + 3SD)

Upper limit of normal side-to-side difference

Putative generators of waves and notes

N9 (EPi-EPc) P9 (Pc-EPc) N13 (Cv7-Gl)

9.8 10.1 13.3

11.5 12.0 14.5

– – –

P14 (Pc-Extraceph or earlobe)

14.3

16.7

0.8

N20 (Pc-Extraceph or earlobe)

19.8

23.0

1.4

Brachial plexus Proximal brachial plexus Stationary, non-propagated, cervical post-synaptic potential triggered in the dorsal horn grey matter Far-field potential generated close to the cervico–medullary junction, at or near the lower brainstem Primary somatosensory cortex in the posterior wall of the central fissure (SI area)

23.5 35.9

3.7

29.9 3.5 4.5 5.6 9.3 5.7

4.5 6.0 6.6 10.8 7.2

1.3 1.1 1.2 0.9 1.0

P22 (Cc-Extraceph or earlobe) N30 (Fc-Extraceph or earlobe) Intervals N9–N13 P9–P14 (Pc-extraceph) P14–N20 (Pc-extraceph) N9–N20 N13–N20

Lower normal limit Amplitude (lV) N9 N13 N20 (Pc-Pi, baseline to peak) N20-P25 (peak to peak) Amplitude ratios (%) N13/P9 (Cv7-Gl) P14/P9 (Pc-EPc)

4.8 2.3 2.2 3.2

1.0 0.5 0.6 0.8

50% – 47% –

1.1 1.3

Typical values of SEPs for young adult testing (body height 1.70 ± 0.1) (modified from Mauguie`re, 1996 and Mauguie`re et al., 1999).

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Table 3 Tibial nerve SEPs Peak (ms)

Mean (ms)

Upper limit of normal (mean + 3SD)

Upper limit of normal side-to-side difference

Height < or > 175 cm

Putative generators of waves and notes

N8 (PF-K) N22 (T12–T10 or L1-Um) P30 (Fz–Cv6)

8.5 21.8

10.5 25.2

– 1.1

±0.15 ms/cm ±0.18 ms/cm

29.2

34.7

1.4

38.0

43.9

2.1

Tibial nerve or sciatic nerve Post-synaptic response in the dorsal grey matter of the lumbosacral cord Likely to have same origin of the median nerve P14 potential at the cervico–medullary junction Post-central somatosensory cortex. Predominant over the hemisphere ipsilateral to stimulation

7.4 8.7 16.0

10.2 13.4 21.0

1.5 1.8 2.1

P39 (Cz0 -Fz or Cz0 -Ei) Intervals N22–P30 P30–P39 N22–P39

Lower normal limit Amplitude (lV) N22 P30 P39–N50

1.1 0.6 1.8

0.3 – 0.5

Typical values of SEPs for young adult testing (body height 1.70 ± 0.1). (modified from Mauguie`re et al., 1999).

generally normal because of the polysegmental nature of these nerves. Stimulation of cutaneous nerves, e.g. the superficial radial (C6), saphenous (L4), superficial peroneal (L5) and sural (S1), is more segmentally specific but the findings are abnormal in only about half of all cases, and dermatomal stimulation does not appear sufficiently sensitive or specific to be helpful in this context. Special techniques have been developed to stimulate the lateral femoral cutaneous, iliohypogastric, saphenous and intercostal nerves (Synek, 1987; Dreyfuss et al., 1993; Mobbs et al., 2002; Rabie and Drory, 2005) and several reports have described their diagnostic relevance in cases of nerve entrapment or monoradiculopathy in which neither clinical evaluation nor standard EMG techniques were useful (Synek, 1987; Tranier et al., 1992). A possible reason for discordance between normal SEPs and abnormal sensory symptoms is the existence of a pure small-fibre neuropathy, which cannot be excluded by standard SEPs, and needs specific investigations (cf. Section 6). 3.2. Central nervous system In patients with possible multiple sclerosis (MS) who do not have clinical involvement of the central somatosensory pathways, the tibial-derived SEP may be abnormal in about one-third of cases depending upon the series and investigator. However, multifocal involvement of central white matter either clinically or electrophysiologically is not specific to multiple sclerosis but may occur in patients with human immunodeficiency virus (HIV) infection (Iragui et al., 1994; Tagliati et al., 2000), vitamin B12 or vitamin E deficiency (Misra et al., 2003), neurosyphilis, hereditary ataxic syndromes (Nuwer et al., 1983), hereditary spastic paraplegia (Thomas et al., 1981), and other neurological disorders. The findings must therefore be interpreted in the context in

which they are obtained. Evoked potential studies and MRI are complementary techniques for detecting lesions in patients with MS, but at the present time SEPs are not recommended for the detection of subclinical lesions unless imaging facilities are unavailable. SEPs may be useful, however, to test the integrity of pathways in MS patients with vague symptoms of uncertain significance. SEPs have also been used for monitoring disease progression and evaluating novel therapeutic agents in patients with suspected or definite MS, and some have found them useful in predicting later clinical changes (Nuwer et al., 1987). However, discrepancies may occur between the clinical and electrophysiological findings, as electrophysiological changes may occur despite clinical stability, and SEP abnormalities may change with clinical exacerbations that do not involve the somatosensory pathway (Matthews and Small, 1979; Likosky and Elmore, 1982; Aminoff et al., 1984). Changes in previously abnormal SEPs do not necessarily reflect the site of new lesions and the electrophysiological changes accompanying clinical exacerbations may be in clinically unaffected pathways (Aminoff et al., 1984). Accordingly, SEPs are not recommended for following the course of established MS because of the ambiguities that exist when interpreting the results. Delayed SEPs, usually symmetrical over the two sides, are common in patients with hereditary ataxic syndromes (Nuwer et al., 1983). In patients with spinal injury, SEPs may be helpful in showing the completeness of the lesion. Immediately after spinal injury, it may not be possible to record cortical responses to stimulation below the level of even incomplete lesions (Sedgwick et al., 1980). Thus, it may not be possible to determine reliably the completeness of the spinal cord lesion, although an incomplete lesion, and thus a good prognosis, is suggested by preserved responses or their early recovery after injury (Rowed et al., 1978). In patients

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with spinal cord tumors or other structural lesions involving the dorsal column pathways (pure spinothalamic tract lesions can be assessed by laser-evoked potentials), SEPs may be abnormal and help to localize the lesion (Linden and Berlit, 1996; Li et al., 1996) but they are usually unnecessary because imaging studies are more useful in this regard. In patients with intractable pain being considered for spinal cord stimulation, good functional status of the dorsal columns is mandatory if a good clinical result is to be achieved. Accordingly, the finding of abnormal preoperative SEPs may be taken to reliably predict a lack of clinical effect and is thus a contraindication to spinal cord stimulation (Sindou et al., 2003). In patients with lesions in the brainstem, diencephalon, or cerebral hemispheres, SEPs are abnormal when they involve the lemniscal pathways, generally paralleling the clinical findings (Mauguiere, 1987). Moreover, the patterns of SEP abnormality are essentially similar for brainstem, thalamic and thalamo-capsular lesions. For these reasons, SEPs are not widely used for diagnostic or prognostic purposes except in comatose patients (see Section 4). Enhanced SEPs are found in patients with cortical myoclonus, such as in the myoclonus epilepsies (Shibasaki, 2000), but are usually not required to make the diagnosis. 4. Intensive care unit This section summarizes the SEP aspects of the two most recent IFCN-recommended standards for electrophysiologic monitoring in comatose and other unresponsive states (Chatrian et al., 1993; Gue´rit et al., 1999) and the results of a recent European Task Force for the Use of Neurophysiological tests in ICU (Gue´rit, 2005). 4.1. Basic principles of SEP analysis in the ICU Median-nerve SEPs in the ICU provide simultaneous evaluation of subcortical lemniscal somatosensory afferents (including brainstem, diencephalic and thalamocortical pathways) and function of the cerebral cortex. The main principles of SEP interpretation in the ICU are summarized in Table 4.

4.1.1. Assessment of subcortical somatosensory afferents (SA) It is mandatory to use an ear (or extra-cephalic) reference in order to disclose the P14 wave. This serves both as a quality control of peripheral and spinal-cord conductions and as the caudal landmark of subcortical conductions, which are evaluated from P14 to (and including) the N20 peak. Especially when symmetrical, a mere increase in the central conduction time (CCT) (defined as the P14–N20 interpeak latency) without any N20 distortion usually indicates reversible dysfunction. Only unilateral or bilateral N20 major distortion or disappearance with an intact P14 is suggestive of a subcortical, usually irreversible, lesion. 4.1.2. Assessment of the cerebral cortex (CA) As a rule of thumb, an increasing level of encephalopathy is paralleled by the successive disappearance of earlier peaks of cortical origin. Noteworthy, N20 remains present even at a sedation level sufficient to induce an isoelectric EEG. A good way to optimize SEP interpretation is to consider these in parallel with other neurophysiologic tools, e.g. brainstem auditory EPs (BAEPs) and/or blink reflex for brainstem assessment, visual EPs and/or EEG for cortical assessment. 4.2. Clinical applications of SEPs in the ICU 4.2.1. Diagnosis Diagnosis is usually not the primary aim of SEPs in ICU, except in some circumstances: the identification of a possible structural brainstem lesion in a coma of unknown aetiology (when MRI is unavailable), as a contributory tool for the diagnosis of de-efferented states and psychogenic unresponsiveness, and, together with other neurophysiologic and/or angiographic tools, to confirm a clinically suspected brain death. Brain death is associated with the loss of all cortical and subcortical SEP components, including P14, with preserved sensory nerve action potential, spinal N13 and P13. Noteworthy, the resistance of N20 to sedative drugs makes SEPs, together with BAE-

Table 4 Basic principles of SEP analysis in the ICU Subcortical assessment (SA)

Remarks

Cortical assessment (CA)

Level

Description

0 1a

Normal Normal P14, increased P14–N20 interval without N20 distortion

1b

Abnormal N20, absent P14

Uncertain pattern, first requires proof of integrity of receptors and spinal pathways

2

2

Normal P14, unilateral or bilateral N20 distortion, Normal P14, unilateral or bilateral N20 disappearance

Brainstem or subcortical lesion, usually irreversible

3

3

Brainstem or subcortical dysfunction, usually reversible (drugs, metabolic disturbances, hypothermia)

Level

Description

0 1

Normal P45 disappearance Preserved N20, P24, P27 (parietal), N30 (frontal) P45, P27 (parietal), N30 (frontal) disappearance Preserved N20, P24 Preserved N20 All other peaks absent Absent N20

4

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Table 5 Prognostic value of SEPs in anoxic and traumatic coma Prognosis

Brain anoxia Description

Remarks

Description

Death or vegetative state

Bilateral absence of N20 with P14 preservation more then 6 hours after coma onset Level 4 (CA) Level 3 (CA) Preservation of cortical SEPs Level 1–2 (CA). Level 1a (SA)

0% good recovery Justifies waiving resuscitation

SEP pattern of brain death

<10% good recovery 40–65% good recovery

Bilateral absence of N20 Level 1a (SA) Midbrain dysfunction with N20 preservation Level 0 (SA) and Level 1 or 2 (CA)

Ominous Uncertain patterns

Good prognosis

–

Head trauma

Other tools should be used (longlatency cortical EPs)

Remarks

<15% good recovery Requires simultaneous VEP and BAEP recording >80% good recovery

CA, cortical assessment; SA, subcortical assessment.

Ps, the best neurophysiologic tool for brain death confirmation in sedated patients. 4.2.2. Prognosis The prognostic value of SEPs differs in anoxic and traumatic coma. Guidelines for SEP interpretation are provided in Table 5. Briefly speaking, SEPs are the most powerful tool to provide bad (but not good) news in brain anoxia, and an excellent tool to provide good (but not bad) news in head trauma. 4.2.3. Anoxic coma The bilateral absence of N20 (with P14 preservation) more than 12 (and, probably six) hours after coma onset in anoxic coma has always been associated with death or permanent vegetative state and there is no sufficiently documented counterexample to this rule. This makes SEPs the most powerful tool for an unfavorable prognosis in anoxic coma. Conversely, mildly altered SEPs (CA Level 1) do not allow drawing any conclusion in terms of prognosis. 4.2.4. Head trauma One major difference between brain anoxia and head trauma is that, in the latter situation, the bilateral absence of N20 has been associated with recovery in about 15% of cases (Gue´rit, 2005). The most likely explanation is that, in head trauma, a transient N20 disappearance may be consecutive to focal midbrain dysfunction due to edema. Conversely, mildly altered SEPs in the absence of brainstem dysfunction has been associated with a good recovery in more than 80% (Level 2 CA) to 90% (Level 1 CA) of cases. Most importantly, SEPs should never be considered in isolation but integrated with other neurophysiologic tools (VEPs, BAEPs and ERPs) and clinical examination. 4.2.5. Follow-up One major contribution of EPs is to provide quantitative data, which can be considered for follow-up studies. The technique is still in its infancy. An overview of methods and feasibility of continuous SEP monitoring can be found in Fossi et al. (2006).

5. Use of SEPs for intraoperative monitoring Like other neurophysiologic tools, SEPs can be used in the operating room (OR) for three main purposes: to prevent neurological damage, to follow-up induced physiological changes, and to locate the central sulcus (Deletis and Shils, 2002; Emerson and Adams, 2003; Smith and Prior, 2003). 5.1. Prevention of neurological damage As a preventing tool of neurological damage, neuromonitoring must fulfill two criteria to be successful: the method must actually test the neural structures at risk, and it must be sensitive to the pathophysiological process feared. SEPs are, indeed, sensitive to the two pathophysiological processes that have to be detected in the OR: mechanical damage and ischemia. 5.1.1. Ischemia While pure grey-matter ischemia just causes distortion, without any latency changes, of peaks generated by these brain structures that have become non-functional, whitematter ischemia usually first causes a latency increase of upstream peaks, followed by wave-form distortion as soon as conduction block extinguishes the corresponding generator(s). 5.1.2. Mechanical damage Although nerve or spinal-cord concussion has been rarely studied in humans, it is common experience that spine hammering during scoliosis surgery may cause transient SEP changes; this may justify a pause in the surgical procedure until recovery. Acute compression first causes a drop in conduction velocity, which may be followed by complete conduction block within some tens of minutes. Beyond disappearance of upstream peaks, nervous disruption may cause the ‘‘killed-end effect”, which consists of the appearance of high-amplitude positivities immediately rostral to the lesion. Which nervous structures are, or are not, tested by SEPs? Table 6 summarizes the structures that are sensitive

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Table 6 Basic principles of SEP analysis for intra-operative monitoring Structure

Tested

Clinical applications

Untested

Alternative tool

Peripheral nerve

Large sensory fibres

Spinal cord

Posterior columns

Small sensory fibres Motor fibres and roots Motor pathways

Laser EPs EMG Motor EPs

Brainstem

Lemniscal pathways (midline)

Prevention of peripheral-nerve lesions in peripheral surgery Scoliosis surgery Thoracic and thoracoabdominal aorta surgery Brainstem surgery (in association with BAEPs and motor EPs)

Extralemniscal pathways (lateral) Motor pathways (anterior) Motor pathways (perforating arteries) Motor cortex

Laser EPs

Thalamo–cortical pathways Cerebral cortex

Middle cerebral artery territory (median nerve) Anterior cerebral artery territory (tibial nerve)

Carotid endarterectomy Intracranial aneurism surgery Cardiac surgery

Motor EPs Motor EPs Motor EPs

and, therefore, amenable to SEP monitoring, together with the main applications of SEPs in the OR. The prevention of peripheral-nerve lesions probably constitutes an underexploited application, considering the deleterious effect of some complications (for example, brachial plexopathies, sciatic nerve lesion in total hip arthroplasty) (Happel and Kline, 2002). To prevent spinal cord damage, after the introduction of motor EPs to multiple-pulse electrical transcranial stimulation, most authors recommend using SEPs simultaneously with motor EPs in order to check both posterior and antero-lateral spinal-cord (Deletis and Shils, 2002). This holds especially true for descending thoracic or thoracoabdominal aortic surgery and scoliosis surgery (Schwartz et al., 2007). Finally, provided that their recording includes that of frontal N30 and parietal P45, median-nerve SEPs probably constitute the most sensitive tool to prevent ischemia in the territory of the middle cerebral artery, which makes the technique irreplaceable in carotid surgery and repair of intracranial aneurysms involving the carotid or sylvian artery (Florence et al., 2004). By contrast, SEPs may remain unchanged in pure motor damage consecutive to ischemia in the territory of perforating arteries. Noteworthy, SEPs are much less sensitive than EEG to sedation. In particular, as mentioned previously, primary SEP components are still present when the EEG has been made suppressive for brain protection during aneurysm surgery. This makes SEPs the only available method in these circumstances. Cortical SEP components may seldom be lost due to the anaesthetic regimen, in which case the recording of P14 to median-nerve stimulation, or P30 to posterior-tibial-nerve stimulation, may be the only way to use SEPs to perform spinal-cord monitoring.

enough to avoid brain ischemia but not so low as to cause the iatrogenic complications specific to hypothermia. One way to achieve this goal is to use the disappearance of brain electrical activity as an index of sufficient cooling. Two advantages of SEPs vs EEG are, first, that SEPs assess both brainstem and cerebral cortex (the endpoint for circulatory arrest is P14 disappearance) and, secondly, SEPs are much less sensitive than EEG to environmental noise (Gue´rit et al., 1994).

5.2. Follow-up of induced physiological changes

6.1. Physiology and biophysics of laser stimulation

Operations involving the aortic arch can only be performed under deep hypothermic circulatory arrest. A compromise has to be found between a body temperature low

Laser stimulators deliver brief heat pulses (1–100 ms) that ensure synchronous activation of Ad and C thermonociceptors. By changing the stimulus characteristics

5.3. Location of central sulcus The central sulcus can be localized with flexible strips placed directly on the cortex on the basis of a polarity reversal of the primary component of the median-nerve SEPs from a postcentral N20 to a precentral P20 (Allison et al., 1989). This holds especially true when the motor cortex has to be located for cortical precentral stimulation of chronic pain patients (Neuloh and Schramm, 2002). 6. Pain- and laser-evoked potentials Radiant heat stimulations using laser allow selective activation of A-delta and C thermosensitive nociceptors in the hairy skin, without concomitant activation of mechano-receptors and A-beta fibres. The corresponding cortical responses are called ‘‘laser-evoked potentials”, or LEPs (Treede et al., 2003; Cruccu and Garcia-Larrea, 2004; Kakigi et al., 2005; Garcia-Larrea, 2006). According to recent guidelines for pain assessment, LEPs are the most reliable neurophysiological tool to investigate patients with neuropathic pain (Cruccu et al., 2004).

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N2

Cz-nose

P2

T4-nose

N1 P1

Fp1-nose

T4-Fp1 N/P1-bip

0

200

400

600

800ms

Fig. 3. Laser-evoked potentials (LEPs) after stimulation of the left hand (C6) with a Nd:YAP laser (k = 1.34 lm). The vertex complex (N2–P2, upper traces) is best recorded over the midline, with a nose reference. An earlier negative wave (opercular N1) generated in the suprasylvian operculum can be recorded over the temporal region (top of the middle traces); this component inverts polarity across the midline and is recorded as a positive wave (opercular P1) from frontal or frontopolar electrodes ipsilateral to the stimulus (bottom of the middle traces). Taking advantage of such phase reversal, a bipolar montage linking the contralateral temporal to the ipsilateral frontopolar electrodes allows to maximise the amplitude of the opercular N1/P1 response (bottom traces).

(energy delivered, duration, area of the irradiated spot) it is possible to activate preferentially subsets of these systems. Most experimental and clinical LEP studies have been performed using CO2-laser stimulators (k = 10.6 lm), which remain the most validated and easily available lasers (Truini et al., 2005). Solid-state lasers (mainly Thulium or Neodinium-based) of 1–2 lm wavelength ensure a steeper slope of temperature rise, thus allowing the use of shorter pulses than CO2-lasers and a better synchronisation of the afferent volley, which enhances the amplitude of cortical responses (Iannetti et al., 2004). The shorter wavelength of solid-state lasers renders them easily conducted by optic fibres; also, their deeper penetration within the skin (relative to CO2 lasers) helps reducing superficial burns, and all this may be an advantage for clinical use. One disadvantage is however their sensitivity to skin pigmentation due to shorter wavelength (<3 lm), making the cutaneous energy distribution difficult to predict (Plaghki and Mouraux, 2003). Typical LEP waveforms are shown in Fig. 3. 6.2. A-d vs. C fibre stimulation Although laser stimuli excite simultaneously Ad and C receptors (Bromm and Treede, 1984), the cortical responses most often reflect Ad activation exclusively. To obtain evoked potentials specific of C-fibre stimulation, the Ad component of the afferent volley must be suppressed by pressure-block of A-fibres, or by a number of easier techniques such as stimulation of tiny skin areas, spectral anal-

ysis of expected time windows, selection of single trials devoid of Ad LEPs or stimulation of large areas at low intensities. At present, the most reliable methods are the ‘‘microspot” technique (0.15–0.30 mm2) for C-nociceptors, and the low-intensity pulses over a large irradiated area for C-warmth fibres (Cruccu et al., 2003; Plaghki and Mouraux, 2003; Kakigi et al., 2005). All these manipulations yield the so-called ‘‘ultra-late” LEPs, occurring 800– 1000 ms after a hand stimulus and depending exclusively on C-fibre activation. 6.3. Component structure and brain generators of LEPs The highest-amplitude scalp signal after a laser stimulus is a negative–positive complex maximal at the vertex. When using a CO2 laser, mean latencies of negative and positive vertex signals are 150–250 ms (face stimulation), 220–340 ms (hand), and 290–380 ms (foot). Latencies are slightly less when using solid-state lasers (see Table 7). Although this activity is in many ways analogous to the N1–P2 SEP complex, for historical reasons it is labelled ‘‘N2–P2” when obtained after laser stimulation. This vertex complex is the most commonly measured waveform to assess LEPs in clinical practice. Dipole modeling of scalp EEG signals and intracranial recordings suggests that the vertex LEP complex results from the simultaneous activity of several cortical generators, with a major participation of the middle parts of the cingulate gyrus (MCC) and variable contribution from the insular and/or frontal operculum

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areas (Lenz et al., 1998; Garcia-Larrea et al., 2003; Tsuji et al., 2006). An earlier, smaller negative wave (150– 180 ms after hand stimulation) is detected by the temporal leads, inverts polarity over the midline and is labelled ‘‘N1”. EEG/MEG dipole analysis and intracortical recordings indicate that this signal is mainly generated in the upper bank of the sylvian fissure, encompassing the secondary somatosensory area (SII) and the posterior insula (Garcia-Larrea et al., 2003; Schlereth et al., 2003; Kakigi et al., 2005; Frot et al., 2007). It also probably contains a small component from SI. The N1 response presents theoretical advantages for clinical application, such as its lower sensitivity to attention and vigilance as compared to the vertex complex (Garcia-Larrea et al., 1997). Although the small amplitude of N1 restricts its clinical use, its phase inversion between lateral and midline sites allows using a bipolar montage linking temporal and midline electrodes, which enhances this component and can render it sizeable enough for clinical use (Fig. 3).

end of the pulse); therefore, solid-state lasers using short stimuli give rise to earlier responses than CO2 lasers (Cruccu et al., 2003) (Table 7). LEP amplitude (10–50 lV) depends on the inter-stimulus interval (ISI) and vigilance/ attention, which must be maintained steady. Even under optimal conditions, there is substantial between- and within-subject variability in amplitude. There is little effect of age on LEP amplitude or latency up to 60 years. Beyond that, LEP amplitude decreases and latency increases with age. Keeping the eyes open minimises alpha contamination, but may enhance blinking in some patients. Earplugs or a white noise are useful to mask the slight but audible click (or beep) most lasers emit when they are triggered. Under the above conditions, absence of LEPs can be considered abnormal. Amplitude decrease should be evaluated by comparison with the healthy side, as absolute values are often much too variable among subjects. Given the above sources of variability, each laboratory must obtain its own normative data under the same conditions as used when recording patients.

6.4. LEP-recording technique 6.5. Clinical applications We recommend a minimum of four electrodes for clinical use (a) two midline sites (Fz–Cz) referred to the nose (or earlobes) to record the vertex N2 and P2 responses; (b) one contralateral temporal electrode referred to the midline (Fz or better Fpz) to record the early N1, taking advantage of its phase reversal (‘‘P1”) across lateral and midline sites; (c) one EOG site (same reference as midline electrodes) to detect and eliminate ocular artifacts. The ideal recording bandpass is between 0.1 and 200 Hz; It can be narrowed depending on s/n ratio, but should not be narrower than 0.3–30 Hz. Two runs of 20–30 stimuli are often enough to measure relevant components. The stimulated spot should be slightly moved between consecutive pulses to avoid skin lesions and reduce fatigue of peripheral nociceptors. Stimuli should not be delivered at intervals less than 6 s to avoid habituation. Peak latencies depend on distance from the stimulating point to the recording site and pulse duration (peak skin temperature is reached at the

LEPs can detect conduction abnormalities at any point in the pain-temperature pathways, from periphery to cortex, including very small lesions, provided that (a) they impinge upon spinothalamic conduction and (b) the laser stimulus is applied to the corresponding cutaneous territory. Even minute lesions such as thalamic lacunae, tiny brainstem infarctions or monoradiculopathies are easily detected with LEPs if they alter conduction in pain pathways (Treede et al., 2003; Truini et al., 2003; Kakigi et al., 2005; Montes et al., 2005; Garcia-Larrea, 2006). LEP abnormalities are closely associated to heat–pain hypesthesia; they provide an objective account of altered pain– temperature pathways, and may be used to assess functional spinothalamic abnormalities in clinically doubtful cases. LEPs are unchanged in purely psychogenic hypalgesia. Dissociation between normal SEPs and abnormal LEPs is the rule in pure spinothalamic lesions such as syringomyelia, brainstem syndromes or small-fibre neuropathy (Treede et al., 1991; Kakigi et al., 1991, 1992; Garcia-Larrea, 2006). Note however that if spinal lesions involve the cervical or lumbar dorsal horn the SEP N13 or N22 com-

Table 7 Normal values of LEPs Type of laser

Measure

Face

Hand

Foot

N1

N2

P2

N1

N2

P2

N2

P2

CO2 (k = 10.6 lm)

Latency (ms) Amplitude (lV)

_

164 (200) 22 (7)

248 (288)

171 (223) 4.5 (1)

236 (277) 18 (6)

341 (380)

275 (314) 16 (5)

361 (416)

Solid-state lasers (k = 1.34–2.00 lm)

Latency (ms) Amplitude (lV)

110 (128) 7.6 (3)

157 (184) 25 (10)

246 (336)

155 (184) 9.8 (3)

209 (252) 24 (8)

325 (415)

244 (321) 20 (8)

372 (475)

Latency at the peak, amplitude relative to baseline for N1 and peak-to-peak for N2/P2. Values are the mean and (in parentheses) the upper normal limit for latency and the lower normal limit for amplitude. Data for CO2 laser are from 100 healthy subjects, those for solid-state lasers from 67 healthy subjects (modified from Devos et al., 2000; Cruccu et al., 2003; Spiegel et al., 2003; and Truini et al., 2005).

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ponents will be altered or abolished (see Section 3.2) Different types of LEP abnormality have been associated to different modalities of central neuropathic pain (GarciaLarrea et al., 2002), but it remains unknown whether LEPs can be predictive of the development of neuropathic pain in patients at risk. The clinical sensitivity of LEPs may be enhanced by recording systematically the N1 potential, which reflects activation of opercular–insular areas. 7. SEPs from special territories SEPs to stimulation of skin dermatomes or superficial nerves different from classical median, ulnar or tibial nerves have been discussed in Section 3. This section will focus on two territories that are clinically important but technically difficult, namely the genital area and the face. 7.1. Pudendal SEPs Because of the impact of sexual impotence on the patient’s life, whenever a clear cause or effective therapy is not found easily, the patient undergoes all kinds of laboratory investigations. In a neurophysiological context, electromyography of the pelvic floor muscles and the bulbocavernous reflex are studied most. To assess the somatosensory peripheral and central pathways, however, pudendal SEPs may be used. These are recorded from the midline (2 cm behind the central vertex Cz) with an Fz reference, after stimulation at the base of the penis with ring electrodes (square wave single pulses of 0.1-ms duration, at 2-Hz frequency, and intensity three times the sensory threshold). With averages of 500 responses a stable and reproducible signal is obtained, the latency of which is measured at the first positive peak (P1). The mean normal latency is 37 ms, and values exceeding 48 ms (or 7 ms longer than the P39 peak of the tibial nerve SEP) are considered abnormal (Opsomer et al., 1986; Delodovici and Fowler, 1995). To study uro-sexual dysfunctions in women a bridge-stimulating electrode is manually kept on the clitoris, the scalp recording being the same as for penile stimulations. Whereas pudendal SEPs have a high sensitivity in impotence associated to diabetic neuropathy (Sartucci et al., 1999) or spinal cord injury (Ashraf et al., 2005), their usefulness in helping to diagnose erectile dysfunctions of unknown origin is debatable. A study in 126 patients showed a high specificity, in that pudendal SEPs were found abnormal only in patients with abnormal neurological examination, but at the same time suggested that they add little to clinical examination (Delodovici and Fowler, 1995). 7.2. Trigeminal SEPs Because several pain syndromes involve the trigeminal nerve territory, there are many articles about trigeminalevoked potentials. Unfortunately, most methods of stimulation are bound to evoke scalp signals contaminated by

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myogenic activity (Leandri et al., 1989; Cruccu and Truini, 2006). With electrical stimuli directed to the lips or facial skin, direct excitation of motor nerve fibres elicits smallmuscle potentials that, even without a visible twitch, are sufficient to obscure completely the brain activity in the first 0–10 ms, whereas excitation of sensory fibres elicits all sorts of trigeminal reflexes that contaminate the scalp signal from 10 ms on. Mechanical stimuli (or electrical stimuli directed to the gums or teeth) avoid the problem of direct motor responses, but still elicit trigeminal reflexes (Cruccu and Truini, 2006). This, besides explaining why the waveforms of the reported signals are so variable, has been demonstrated by recordings before and after curarization (Leandri et al., 1989). Myogenic contamination of trigeminal SEPs appears to be contradicted by the existence of side-to-side differences in patients with documented trigeminal lesions. Any asymmetry, however, might result from the concomitant abnormality of the trigeminal reflexes. Two kinds of trigeminal SEPs are certainly of neural origin. One method (Leandri and Gottlieb, 1996) requires the introduction of two needle-electrodes into the infraorbital canal. Electrical stimuli directly excite the trunk of the infraorbital nerve, yielding such an afferent volley that vertex recordings can pick up the far-fields from the trigeminal root and brainstem, before the reflex responses appear. This technique, which is used during surgical interventions for trigeminal neuralgia, is admittedly difficult (and painful in the awake subject). The other method uses laser stimuli directed to the perioral or supraorbital skin (Cruccu et al., 2003) and LEP recording (detailed in the previous section). Laser stimuli do not excite motor nerve fibres, and do not elicit reflex responses unless the intensity of stimulation is very high, far above that used for recording LEPs. Furthermore, because of the short conduction distance and a high density of receptors in the facial territory, high-amplitude and reproducible trigeminal LEPs are easily obtained after a small number of trials. Trigeminal LEPs were reliable and sensitive in several conditions, including trigeminal neuralgia, trigeminal neuropathy, and Wallenberg syndrome; in contrast, they are reportedly normal in craniofacial pains that are not caused by nervous structural lesions (Treede et al., 2003; Cruccu and Garcia-Larrea, 2004). Trigeminal LEPs, however, only assess small fibres, thus being so useful in pain syndromes, but they provide no information about Ab fibres, which are most sensitive to mechanical damage as it is produced by tumors of the skull base. Furthermore LEPs need laser stimulators, currently available in too few centres. Because of all the above difficulties, the easiest way to assess trigeminal function for clinical and diagnostic purposes is that of recording trigeminal reflexes rather than evoked potentials. References Allison T, McCarthy G, Wood CC, Darcey TM, Spencer DD, Williamson PD. Human cortical potentials evoked by stimulation of the median

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