Neurophysiologie clinique 33 (2003) 303314

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Original article

Clinical usefulness of laser-evoked potentials

Rolf-Detlef Treede a,*, Jrgen Lorenz b, Ulf Baumgrtner a
a
Institute of Physiology and Pathophysiology, Johannes Gutenberg University, Saarstr. 21, 55099 Mainz, Germany
b
Institute of Neurophysiology and Pathophysiology, University Clinic Hamburg Eppendorf, Martinistr.52, 20246 Hamburg, Germany
Received 30 July 2003; accepted 14 October 2003

Abstract

In contrast to the function of the visual or auditory pathways which are electrophysiologically accessible by visual or auditory evoked
potentials, the somatosensory pathway cannot be investigated as a whole by conventional somatosensory evoked potentials (SEP), because
these only reflect function of large fibers, dorsal columns, medial lemniscus and their thalamo-cortical projections mediating sensations like
touch and vibration. The other half of the somatosensory system, signaling temperature and pain perception, uses a different set of afferents
and different central pathways, the function of which is accessible by laser-evoked potentials (LEPs). LEP can document lesions of the
spinothalamic tract and (lateral) brainstem and of thalamo-cortical projections conveying thermo-nociceptive signals. In the peripheral nerve,
LEP can help distinguish between large and small fiber neuropathies. The rapid heating of the skin by infrared laser pulses can easily be applied
to non-glabrous skin in any dermatome. In recent years, many clinical studies have demonstrated that LEP can supply evidence for establishing
clinical diagnoses when deficits of the nociceptive system are present. This review outlines principles and recording techniques for LEP in
patients and compiles typical LEP findings in patients with lesions due to different diseases at various levels of the nociceptive pathways.
Limitations for the use of LEP are pointed out, too, like the uncertainty of lesion location along these pathways and the fact that LEP can
reliably show correlates of reduced nociceptive function but only rarely of enhanced transmission (like in hyperalgesia).
2003 ditions scientifiques et mdicales Elsevier SAS. All rights reserved.

Rsum

Contrairement aux fonctions visuelles ou auditives, facilement accessibles sur le plan lectrophysiologique via les potentiels voqus
correspondants, les voies somesthsiques ne peuvent pas tre explores compltement avec les potentiels voqus somesthsiques (PES), car
ceux-ci ne refltent que la fonction des fibres de plus gros calibre, les cordons postrieurs, le lemniscus mdian et les projections
thalamo-corticales sous-tendant des sensations comme le toucher et la vibration. Lautre moiti du systme somesthsique, qui a la charge de
signaler les sensations de douleur et de temprature, utilise des groupes diffrents de fibres affrentes dans la priphrie et des projections
diffrentes au niveau central, dont la fonction est accessible par les potentiels voqus par pulsation laser (PEL). Les PEL dtectent les lsions
du systme spinothalamique dans la moelle et le tronc crbral latral, ainsi que celles des projections thalamo-corticales conduisant les
signaux thermo-nociceptifs. Dans le systme priphrique, les PEL aident distinguer les neuropathies concernant les fibres de gros ou de petit
calibre. La stimulation laser entrane un rchauffement cutan trs rapide, qui peut tre appliqu la peau poilue sur pratiquement tous les
dermatomes. Des nombreuses tudes cliniques ont montr limportance des PEL comme aide au diagnostique clinique en cas de dficit patent
ou suspect du systme nociceptif. Cette revue sintresse dabord aux principes et techniques de lenregistrement des PEL chez le patient, et
compile des rsultats typiques chez des patients porteurs de lsions diffrents niveaux des voies thermo-nociceptives. Nous signalons
galement certaines limites de ce type dexamen, comme les incertitudes quant la localisation topographique des lsions dtectes, ainsi que
le fait que les PEL montrent de faon fiable des signes de diminution des fonctions nociceptives, mais tmoignent rarement des augmentations
de la transmission douloureuse (comme lhyperalgesie).
2003 ditions scientifiques et mdicales Elsevier SAS. All rights reserved.

Keywords: Laser-evoked potentials; Somatosensory system; Pain; Temperature; Sensory testing

Mots cls : Douleur ; Potentiels voqus par laser ; PEL ; Nociception ; Spinothalamique ; Thalamus

* Corresponding author.
E-mail address: treede@uni-mainz.de (R.-D. Treede).

2003 ditions scientifiques et mdicales Elsevier SAS. All rights reserved.

doi:10.1016/j.neucli.2003.10.009
304 R.-D. Treede et al. / Neurophysiologie clinique 33 (2003) 303314
1. General considerations
The visual and auditory pathways are projecting one mo-
dality only, and can thus be easily tested using visual and
auditory evoked potentials (VEP, AEP). Pain pathways are a
part of the somatosensory system. Therefore, neurophysi-
ological studies of pain pathways may be expected to be
related to the recording of somatosensory evoked potentials
(SEP). However, the somatosensory system includes more
than one modality and cannot electrophysiologically be
tested by only one type of evoked potential. The pathways by
which information on painful stimuli is transmitted, differ in
many important aspects from those pathways that are as-
sessed by standard SEP:
Ad- and C-fibers instead of A-fibers in the peripheral
nerve,
first synaptic relay in the spinal cord instead of the
brainstem,
rostral projection in the contralateral spinothalamic tract
instead of the ipsilateral dorsal column,
different representation in somatosensory and limbic
cortex.
Because of these differences, evoked potentials following
painful stimuli may provide important additional informa-
tion beyond standard SEP for topological diagnostics in
neurology, particularly in peripheral nerve, plexus, root, spi-
nal and brainstem disorders. At the thalamo-cortical level,
pain pathways partly converge with other somatosensory
pathways. Therefore, the diagnostic value of pain related
evoked potentials are less evident for supratentorial lesions.
As differences between the cortical representation of touch
and pain become more and more apparent, a clinical role for
laser-evoked potentials (LEP) testing in thalamo-cortical le-
sions may develop in the near future, e.g. for characterization
of insular lesions. For documentation of supratentorial le-
sions, MRI is still regarded as gold standard. However, de-
spite the increasing spatial resolution of MRI, electrophysi-
ological testing using evoked potentials is still most
Fig. 1. LEP recording montage. Recording montage for late (Fz, Cz, Pz vs. earlobes) and early LEPs (T3-Fz, T4-Fz). Modified from Ref. [73].
important as functional test for the peripheral nervous system
and tracts of the central nervous system. In this context, LEP
are the tool for functional testing of the integrity of the
nociceptive pathway. They can help differentiate between
neurogenic and psychogenic hypoalgesia and, in patients
with spontaneous neuropathic pain, may allow conclusions
upon the underlying mechanisms (i.e. deafferentation vs.
central sensitization).
2. Stimulation and recording techniques
2.1. Stimulation
In normal skin, the sensation evoked by laser stimuli near
pain threshold is comparable to a weak pinprick or pulling a
single hair follicle. In order to obtain reproducible evoked
potentials, it is necessary to use suprathreshold stimuli, which
are usually perceived as slightly stinging and/or burning
[13,57], and are less uncomfortable than the standard electri-
cal nerve stimuli used for SEP recording. Within the range of
750 ms stimulus duration and 39 mm beam diameter, pain
threshold is nearly constant when expressed as energy per
unit of skin area (1014 mJ/mm2; [9]). LEPs are usually
recorded with fixed stimulus intensities at 1.52 times the
mean pain threshold of healthy subjects [14,28,69]. For ex-
ample, a common suprathreshold stimulus would be 540 mJ
applied to a spot of 5 mm diameter (approx. 25 mJ/mm2;
duration: 35 ms; Fig. 1). If a low-power CO2 laser is used,
the stimulus duration may be prolonged up to 100 ms (or
even longer). This will lead to an increase in LEP latencies,
as the nociceptors are activated towards the end of the heat
stimulus. The longer the stimulus duration, the greater the
jitter becomes with the result of smaller LEP amplitudes
[78]. In contrast to electrical nerve stimulation, individual
tayloring of stimulus intensities is not necessary due to the
superficial termination of the afferents activated [71].
As an untoward effect, the skin may transiently turn red as
a sign of a first degree burn. This harmless discoloration
 R.-D. Treede et al. / Neurophysiologie clinique 33 (2003) 303314 305

disappears within a few days. However, in patients prone to

skin ulcerations, such as in diabetic neuropathy or in Be-
hets disease, there may be a relative contraindication for
LEP. Superficial burns are less likely to occur with thulium
lasers (2.03 m wavelength) than with carbon dioxide lasers
(10.6 m wavelength), due to the different temperature dis-
tribution in the skin [69] (see Plaghki and Mouraux, this
volume). In order to minimize nociceptor fatigue which leads
to amplitude reduction, stimuli should not be applied to the
same spot all the time, but slightly vary across the stimulation
area. Variation of interstimulus intervals between e.g. 8 and
12 s is advisable to reduce habituation. Additionally, atten-
tion has a strong impact on LEP amplitudes (for review see
Lorenz, this volume) and thus should be controlled by the
investigator by using a standard task. As an example, it is
convenient to have the patient give pain ratings following
each stimulus to keep the same level of attention.

2.2. Recording techniques for late LEP components

In clinical studies, only the late LEP components are

routinely evaluated (Fig. 2). These components are maximal
between the vertex Cz and the midline parietal lead Pz vs.
linked earlobes or nose (for sources see Garca-Larrea et al.,
this volume). It is a negativepositive complex comprising
the so-called N2 and P2, measured individually from base-
line (or both together peak-to-peak). The recording bandpass
should be not narrower than 0.270 Hz with a digitization
rate of at least 200 Hz (Fig. 1). In order to detect and
eliminate ocular artefacts, the EOG should be recorded in Fig. 2. LEP components and attention effects. Early component N1, late
parallel. Most investigators record the LEP while patients vertex components N2P2 and endogenous component P3 from a single
have their eyes closed, however in individual patients with subject (data from Ref. [65]). The effect of focused attention by means of a
large alpha-waves it may improve the signal when the eyes spatial discrimination task shows higher amplitudes (bold line) for all
are left open and patients fixate a point. Averaging across components compared to active distraction during stimulation (thin line). P3
is evoked in the task (attend) condition only.
2040 trials in 23 runs (for reproducibility) is sufficient to
measure these LEP components. Their latency depends on Table 1
stimulus duration, since the peak skin temperature is reached Normative values of LEPs (thulium-YAG laser)
at the end of the laser pulse [80], and their amplitude depends Absolute mean Normal range
on interstimulus interval and the task performed by the sub- S.D. (3.0 S.D.)
ject. Therefore, each laboratory needs to determine their own Hand stimulation (n = 36 areas)
normative values. Roughly, hand stimulation using a Tm- N2-peak latency (ms) 208 18 154262
laser yields N2 latencies of about 210 ms and P2 latencies of P2-peak latency (ms) 329 34 227431
330 ms. Amplitudes vary between 12 and 67 V; see Table 1 Peak-to-peak-amplitude (V) 30.3 10.9 10.379.9 a
[68]. Using a carbon dioxide laser, the LEP N2 occurs at
Foot stimulation (n = 36 areas)
about 240 ms and the P2 at about 380 ms [41,76]. There is
N2-peak latency (ms) 248 27 167329
little effect of age on LEP amplitudes or latencies up to P2-peak latency (ms) 381 41 258504
60 years. Beyond that, LEP amplitudes decrease and laten- Peak-to-peak-amplitude (V) 22.5 6.7 8.554.2 a
cies increase with age [32].
From Spiegel et al. [68].
Under the conditions mentioned above, the absence of late a
Range calculated with log transformed data.
LEP can be considered abnormal. In addition, intraindividual
differences in amplitude and latency between a clinically eral terms appears following rare task-relevant stimuli [70].
affected and a healthy control site may be evaluated, too As the LEP P2 has a peak latency near 300 ms, it has been
[7,12,69]. suggested that it may be functionally equivalent to the audi-
2.3. P300-like components tory P300 [92]. This proposal ignores the differences in
afferent conduction times in auditory and nociceptive path-
The P300 is usually evoked in an oddball paradigm that ways. Studies with appropriate tasks have indeed shown that
alternates between tones of different frequency, and in gen- the LEP P3 appears at longer peak latency near 600 ms with
306 R.-D. Treede et al. / Neurophysiologie clinique 33 (2003) 303314
an amplitude maximum further posterior compared to the P2
[46,52,67,72]. Because of its endogenous character not spe-
cific for nociception, the LEP P3 is usually not being evalu-
ated in clinical settings, but may be useful in disorders with
attention deficits.
2.4. Ultralate LEP components
Although heating the skin by laser pulses activates C-fiber
nociceptors [13] (see Plaghki and Mouraux, this volume),
corresponding LEP components were difficult to isolate,
possibly due to a central inhibitory interaction with the pre-
ceding afferent volley carried by Ad-fibers. To make ultralate
LEP components visible in healthy subjects, it is necessary to
unmask these components through one of the following
techniques: (1) controlled temperature steps to 40 C or low
intensity stimulation of a large surface, leading to activation
of C-nociceptors and C-warm receptors only [25,57], (2) tiny
beams ( 0.5 mm), taking advantage of the more dense
distribution of C-nociceptors in the skin [10], (3) ischemic
nerve block that reversibly knocks out conduction of myeli-
nated fibers but sparing unmyelinated C-fiber conduction
[15]. Based on the same principle, it is possible to retrieve
C-fiber responses from patients suffering from demyelinat-
ing neuropathy (for details see Plaghki and Mouraux, this
volume). Only then these ultralate components appear as a
vertex positivity (same recording setup as for late compo-
nents) at a latency of about 1000 ms. Since ultralate LEPs are
not reliably present in all healthy subjects, they have not been
used to test for intactness of nociceptive C-fiber afferents in
patients. Axon reflex measurements may be more useful for
that purpose [5,59]. However, if ultralate LEP components
are directly visible in patients while Ad-LEP is absent, this is
a sign for selective loss of myelinated nociceptive fibers (see
below).
2.5. Early LEP components
Early subcortical LEP components have not been de-
scribed, in contrast to the well known subcortical SEP com-
ponents following electrical nerve stimulation. This is prob-
ably due to latency jitter in the afferent volley elicited by
laser heat pulses [13]. The earliest cortical LEP component is
negativity N1 (Fig. 2) with a peak latency of about 170 ms
[76], and maximum amplitude bilaterally at the temporal
leads [50]. The N1 is best recorded in a bipolar montage with
Fz as reference electrode, because there is a nearly simulta-
neous positivity in the frontal midline region. The underlying
generator is located in the parasylvian cortex (c.f. Garca-
Larrea et al., this volume). Because of their small amplitude,
the early LEP components have not yet been used clinically.
2.6. Dermatomal LEP
Because type II Ad-fiber nociceptors are missing in the
glabrous skin of hands and feet [13,81], late LEPs are not
useful to assess the innervation of the palm of the hand or the
sole of the foot. Laser stimuli can easily be applied to all
other dermatomes including the innervation territory of the
trigeminal nerve [26,55,79]. As a shorter conduction distance
is associated with lower latency jitter, the signal-to-noise
ratio for LEP is even better for proximal dermatome stimu-
lation than for distal limb stimulation [57]. A major advan-
tage for the use of LEP in the trigeminal system is the
absence of a stimulus artefact, which often interferes with the
recording when an electrical stimulus is employed. These
properties make LEP an attractive tool in documenting the
segmental level of a lesion and assessing fiber function in
radiculopathies. The clinical utility of dermatomal SEP is
compromised by the fact that their signal-to-noise ratio de-
pends on the size of the nerve stimulated and its cortical
representation in the sensory homunculus, whereas late LEP
components are not dependent on these factors. An elegant
application of LEP for estimating conduction velocity of the
spinothalamic tract is to stimulate at different dermatomal
levels at the back and use the latency differences for calcula-
tion [38]. Dermatomal LEP are also useful in single spinal
root lesions, because pain dermatomes are smaller than tac-
tile dermatomes [55].
3. Pathological LEP changes
The anatomical specificity of the peripheral and central
thermoreceptive and nociceptive pathways represents the
major rationale of a clinical use of the LEP method. Many
groups documented disturbances of pain and temperature
sensitivity by abnormal LEP that are typically missed by the
standard SEP method in a variety of pathologies (Table 2).
Evidence strongly indicates, and will be reviewed below, that
LEP usefully supplement standard electrical SEP when
minus-signs of the pain and temperature sense dissociate
from the touch and joint position sense, which occur for
certain lesions of the peripheral, radicular, spinal, midbrain
and supraspinal neuraxis. A second group of studies explored
the use of the LEP method to monitor the plus-signs of the
pain sense, thus described LEP changes in pathologies char-
acterized by the presence of pain or enhanced pain sensitivity
such as hyperalgesia and allodynia. However, the review of
results in this approach indicates that LEP reflect only par-
ticular aspects of nociceptive function being more strongly
activated in some, but suppressed in the majority of other
conditions substantiating the diversity of pathophysiological
mechanisms underlying these phenomena.
3.1. LEP in patients with peripheral nerve, plexus or root
lesions
Peripheral neuropathies (PNP) comprise a heterogeneous
group of pathologies among which the small fiber disease
exhibits a characteristic predominance of loss in temperature
and pain sensitivity and autonomous peripheral nerve func-
 R.-D. Treede et al. / Neurophysiologie clinique 33 (2003) 303314 307

Table 2
LEP results in patients
Disease n Pain Latency Amplitude Comment Reference
Postherpetic neuralgia 40 Yes Normal [82]
Diabetic neuropathy 21 No Asymptomatic [63]
Diabetic neuropathy 45 No Normal [2]
Large-fiber neuropathy 1 No Normal Normal [21]
HTLV-myelopathy 19 No /Normal No data [40]
SBMA 6 No [3]
Radiculopathy 1 No No data Absent [55]
Syringomyelia 8 No /absent /absent [43]
Syringomyelia 10 Some /absent /absent [77]
Wallenbergs syndrome 6 No /absent /absent [47]
Wallenbergs syndrome 5 No Normal /absent [36]
Wallenbergs syndrome 2 No Absent Absent [64]
Multiple sclerosis 12 No /absent [39]
Multiple sclerosis 20 No Mostly asymptomatic [68]
Thalamo-cortical stroke 12 1/12 Some delayed/absent [89]
Trigeminal neuralgia 67 Yes [24]
Temporo-mand. disorder 15 Yes Normal [62]
Tension-type headache 12 Yes Normal Significant pericranially [27]
Tension-type headache 19 Yes Normal Normal [85]
Migraine 24 Yes Normal Normal Less habituation [85]
Central neuropathic pain 11 Yes Normal Normal/ [18]
Central neuropathic pain 42 Yes Normal [30]
Non-organic chron. pain 12 Yes Normal Normal/ [30]
Fibromyalgia 10 Yes Normal [33]
Fibromyalgia 10 Yes Normal [54]
Conversion disorder 1 No Normal Normal Sensory loss in left hand [56]
BPD 10 No Normal Normal Strong hypoalgesia [6]
Dementia 25 No /absent /absent Abnormality in severe [90]
cases
SBMA, spino-bulbar muscular atrophy (Kennedys disease); BPD, borderline personality disorder.

tion. In such conditions (Fig. 3, lesion site 1 and Fig. 4), the
late LEPs may be absent, attenuated in amplitude or delayed
in latency [1,2,42]. The severity of latency and amplitude
changes were found to correlate with the loss of thin myeli-
nated nerve fibers in sural nerve biopsy and with the degree
of hypoalgesia [45]. Although a study of 45 patients with
diabetic PNP showed more frequent impairment of vibratory
than pinprick sensation, LEP yielded similar abnormalities
like the electrical sensory nerve action potentials pointing to
higher diagnostic sensitivity of LEP compared to clinical
examination in detecting small-afferent dysfunction [1]. A
complete loss of all LEP components in PNP probably indi-
cates impaired function of both Ad- and C-fibers. However,
in some cases of PNP and in a reported case of tabes dorsalis
late LEP components were abnormal and ultralate LEP com-
ponents became unmasked indicating loss of Ad-fiber at the
presence of intact C-fiber function [51,60,79]. In contrast to
nerve biopsies that do not yield quantitative information on
C-fibers, unless electron microscopic studies are performed,
LEP may thus provide some indirect evidence on C-fiber
function. Yet, the inverse constellation of an isolated C-fiber
pathology with normal Ad-function is difficult to evaluate by
LEP because ultralate LEP typically fail to occur in normal
subjects unless the Ad-responses are experimentally abol-
ished by a selective A-fiber block, a procedure that cannot be
applied in patients. Single rare cases of selective large-fiber
neuropathies exhibited loss of electrical SEP and preserva-
tion of late LEP indicating the remaining function of small
myelinated afferents [21,75,91].
Monosegmental dorsal root affections represent another
condition in which LEP exhibit greater diagnostic sensitivity
compared to SEP because small fibers of the nociceptive
system do not overlap between adjacent spinal segments to
the same extent as large fibers of the tactile system. There-
fore, LEP components may provide objective evidence for
the border between intact and affected dermatomes [55]. In
patients with carpal tunnel syndrome, LEP amplitude was
reduced for stimulation of the third finger that is innervated
by the median nerve, but not the fifth finger that is innervated
by the ulnar nerve [4]. Therefore, even when both small and
large fibers are similarly affected dermatomal LEPs may be
indicated in segmental dorsal root or single nerve lesions
because laser unlike electrical stimuli recruit significantly
less intact neighboring afferents and, therefore, more likely
yield abnormal EP.
3.2. LEP in patients with spinal lesions
Whereas localized structural damage to neural tissue in
the periphery most often results in uniform sensory deficits
308 R.-D. Treede et al. / Neurophysiologie clinique 33 (2003) 303314
Fig. 3. Somatosensory pathways and lesion sites assessed by LEPs. The
tactile and proprioceptive systems project via large fibers in the peripheral
nerve, the dorsal columns of the spinal cord and the medial lemniscus in the
brainstem. The nociceptive and thermoreceptive systems project via small
fibers in the peripheral nerve and via the spinothalamic tract in the spinal
cord and brainstem. Both pathways project via VPL to the SI and via VPI to
the secondary somatosensory cortex. In addition, the nociceptive and ther-
moreceptive systems project via VMpo to the dorsal insula. Lesion sites that
lead to impaired LEPs: (1) small-fiber neuropathies. (2) Crossing fibers in
the anterior commissure (e.g. Syringomyelia). (3) Spinothalamic tract in the
anterolateral spinal cord. (4) Spinothalamic tract in the dorsolateral brains-
tem. (5) Thalamo-cortical lesions. VPL, ventro-postero-lateral nucleus; VPI,
ventro-postero-inferior nucleus; VMpo, posterior part of the ventro-medial
nucleus. From Ref. [73].
due to the close anatomical association of small and large
diameter fibers within the mixed nerve, the extent of an
intramedullary spinal damage critically determines the de-
gree of dissociation of sensory symptoms. This is because the
ascending spinal pathways separate into the ipsilateral dorsal
column and the contralateral spinothalamic tract mediating
respective mechanoreceptive and thermoreceptive/nocicep-
tive functions. Spinal lesions are, therefore, among the most
important indications for LEP testing (Fig. 3, lesion sites
2 and 3). Studies indicate that LEPs provide a sensitive and
specific clinical neurophysiological correlate for dissociated
sensory loss in patients with a variety of spinal lesions due to
syringomyelia, arterio-venous malformations, and inflam-
matory myelopathies, though the latter apparently yield more
variable LEP findings with less consistent relationship to
sensory symptoms [12,43,77]. LEP have also been used to
document the dermatomal level of focal spinal cord lesions
[37]. Most patients with syringomyelia present with a total
loss of LEPs for stimulation of affected skin areas, in some
patients only the amplitudes are reduced or the latencies
increased [43,77]. Often, sensory loss and impairment of the
LEP are unilateral, in spite of symmetric appearance of the
lesion on MRI. Surgical treatment by a shunt between syrinx
and subarachnoid space reduced the LEP abnormalities [43].
Normal LEP was only reported in two patients with syringo-
myelia: one patient had completely normal sensory testing
[61], the other patient had thermal hypoaesthesia but normal
pain sensitivity [77].
In a series of patients with clinically definite multiple
sclerosis, LEP testing of the foot was more sensitive than
testing the hand and yielded pathological findings in seven out
of 12 cases [39]. Most of these patients had mild sensory
deficits that involved both pain and touch. In another study
that compared the sensitivity of LEP and SEP testing in
patients with clinically definite multiple sclerosis [68], LEPs
were more sensitive both to document an objective correlate
of sensory deficits (86% vs. 50%) and in discovering clinically
silent lesions (seven vs. five cases). Subclinical lesions have
also been documented in HTLV-I-associated myelopathy
(tropical spastic paraparesis), where LEP latencies were pro-
longed for foot stimulation in spite of normal sensory testing
[40]. These findings may indicate slowed conduction velocity
in the spinothalamic tract by demyelinating lesions [23].
3.3. LEP in patients with brainstem lesions
In the lower brainstem, the spinothalamic tract is situated
laterally near the descending autonomic pathways, whereas
the tactile pathways are located in the medial lemniscus near
the midline. For that reason, similar to a lesion at spinal cord
level, lesions of the lower lateral brainstem (Fig. 3, lesion site
4) can lead to a dissociated sensory loss. Pain and tempera-
ture sensation may be disturbed while tactile sensitivity re-
mains intact, yielding LEP that are abolished or reduced in
amplitude, but normal SEP [36,47,64]. A typical clinical
picture reflecting these changes is that of Wallenbergs syn-
drome. In cases like these, LEP can also reflect the time
course of improved function due to treatment or spontaneous
remission of brainstem lesions (Fig. 5). If the descending
trigeminal spinal tract is included in the lesion, an abolished
blink reflex is a further clinical neurophysiological test that
allows objective documentation of the functional nociceptive
deficit when the afferent limb of the reflex is affected. This
type of deficit may be a predictive factor for the development
of neuropathic facial pain [29]. In patients with lacunar
infarctions in the ventrolateral medullary tegmentum that
spare the spinal trigeminal tract and nucleus, impaired LEP
sometimes are the only objective functional sign for the
lesion of the spinothalamic tract [83].
 R.-D. Treede et al. / Neurophysiologie clinique 33 (2003) 303314 309

Fig. 4. LEP in large fiber and small fiber neuropathy. LEPs and standard SEP in peripheral neuropathy (PNP). Upper panel: 39-year-old patient with loss of
thickly myelinated afferents due to PNP following infectious mononucleosis. Sense of touch and proprioception as well as early and late SEP-components were
lost. Pain perception and late LEP components were preserved. Lower panel: 53-year- old patient with diabetic neuropathy, predominantly affecting the thin
afferents. No LEP was obtainable, pain perception was strongly impaired. In spite of the clinically affected sense of touch and proprioception, the tibial nerve
SEP was normal (modified from Ref. [74]).

3.4. LEP in patients with thalamo-cortical lesions
It is still controversial, whether the converging tactile and
nociceptive afferents form separate clusters in the ventrobasal
relay nucleus of the thalamus or not [53]. Thalamic infarc-
tions often exhibit non-selective sensory deficits that corre-
late well with early SEP abnormalities [87], but may some-
times cause a dissociated loss of pain sensation with intact
touch sensation. In those cases, standard SEP are normal
[58]. LEP were found to be abnormal in two patients with
thalamic infarctions that led to altered pain sensitivity, and
the LEP of one patient with normal pain sensation in spite of
a thalamic infarction was normal [89]. LEP studies may thus
also be useful in patients with thalamic lesions, but this
potential indication has not been investigated well enough.
Although the primary somatosensory cortex (SI) contains
some nociceptive neurons [48], cortical lesions most often do
not change pain sensitivity, and it is yet still controversial,
whether SI substantially contributes to the generation of LEP
(c.f. Garca-Larrea et al., this volume). There is some evi-
dence that lesions in the fronto-parietal operculum may be
associated with a reduced pain sensitivity [35]. In a few
cases, late LEPs were found to be reduced in patients with
lesions that included this area [8,88]. Since the early LEP
component N1 is generated in the fronto-parietal operculum,
it may provide a more specific sign for lesions in that area
than the late N2P2, but the small amplitude has so far
impeded clinical use.
3.5. LEP in patients with psychiatric disorders
Psychiatric conditions rarely yield specific abnormalities
of pain perception or sensitivity nor would one expect a pain
test to significantly contribute to the differentiation of psy-
chiatric diagnoses. Yet, a few studies of LEP in psychiatric
patients, such as conversion disorder with circumscribed
sensory deficit [56] and borderline personality disorder with
self-destructive behaviors [6] found normal LEP and sub-
stantiated the diagnostic validity of this method to verify an
organic cause of thermo-nociceptive symptoms as outlined in
the previous sections. Severe cases of dementia yield abnor-
mal or absent LEP [90]. Notably, Lorenz et al. [56] and
Yamamoto et al. [90] observed abnormalities of the cognitive
P3 potential following auditory oddball stimuli that allowed
delineating cognitive rather than perceptual abnormalities in
conversion disorder and dementia patients, whereas
Baumgrtner et al. [6], who elicited a laser-P3 in a specific
laser task found it to be normal in borderline personality
disorder patients.
310 R.-D. Treede et al. / Neurophysiologie clinique 33 (2003) 303314

Fig. 5. LEP in lower lateral brainstem lesion with recovery. Clinical data and evoked responses in a patient with brain-stem encephalitis. On the first examination
(S1, left panel), the patient had hemihypalgesia and thermhypaesthesia accompanied by cranial nerve signs on the right side plus Horners syndrome on the left
side. Corresponding side-to-side asymmetry was reproducibly found in the LEPs, but not in early components of tibial nerve SEPs (normal latency and
symmetrical amplitude of P40). After complete recovery of the sensory findings 3 years later (S2, right panel), LEPs could again be elicited in the formerly
affected right side, with no significant difference in the left side (LF, left foot; RF, right foot; RT, right tibial nerve; LT, left tibial nerve; from Ref. [36]).

3.6. LEP in patients with chronic pain, headaches
and enhanced pain sensitivity
LEPs were investigated in patients with chronic or recur-
rent episodes of pain or different types of hyperalgesia and
allodynia due to fibromyalgia [32,34,55], trigeminal neural-
gia [24], headache [27,62,85] and peripheral or central neu-
ropathic pain [18,30,82,88]. So far, fibromyalgia is the pro-
totypical disease, for which an increase in LEP amplitude has
been documented at a group level by comparisons with
healthy subjects [33,54]. The abnormal amplitude increase
was present for early (N1) and late (P2) LEP components,
and it was associated with reduced heat pain thresholds and
greater suprathreshold laser intensity ratings. These findings
may indicate a primary hyperalgesia to heat due to peripheral
sensitization, but alternative mechanisms include central
sensitization, deficient descending inhibition, or enhanced
attentional modulation. The latter, sometimes misleadingly
referred to as hypervigilance, regards a general liability of
patients with fibromyalgia to process threatening and aver-
sive stimuli with heightened attentional engagement.
Patients suffering from migraine headache exhibit abnor-
mally high LEP amplitudes, involving the N1 and N2P2
components, exclusively over repeated blocks, thus reflect-
ing a lack of normal time-dependent habituation [85]. This
phenomenon, as tested in non-nociceptive paradigms to elicit
the contingent negative variation (CNV = a slow negative
ERP preceding an expected and task-relevant stimulus), ap-
pears to indicate the impending migraine attack in the pain-
free period, but not shortly after it [49]. This points to a
migraine-specific pathophysiological mechanism of abnor-
mal (exteroceptive) excitability. It would be interesting to
study whether reduced habituation of LEP amplitudes also
shows a systematic relationship to the changes in CNV and
the episodic variability of migraine. Notably, attentional en-
hancement of LEP due to presentation of pain descriptor vs.
neutral words (semantic priming) is not different in migraine
patients compared to healthy controls [86].
Late LEP in patients with neuropathic pain of peripheral
and central origins were in most cases found to be decreased
in amplitude rather than increased [18,31,82,88], and hence
reflected the sensory deficit rather than the ongoing pain and
 R.-D. Treede et al. / Neurophysiologie clinique 33 (2003) 303314 311

hyperalgesia. In some patients LEP were absent or reduced

although the laser stimulus was perceived more intense than
in a non-affected control dermatome [18,30,88]. This para-
dox suggests that pathways required for the normal elicita-
tion of LEP are disturbed whereas alternative pathways may
project the laser-induced hyperalgesic response. Rousseaux
et al. [64] observed residual ill-defined pain perception when
touching very hot objects in patients suffering lateral brain-
stem infarction (Wallenbergs syndrome) even though LEP
were completely abolished. Due to the main projection of
laser evoked nociceptive activity via the spinothalamic tract
into lateral thalamic nuclei and the somatosensory cortex
LEP appear to primarily represent a correlate of the lateral
pain pathway that subserves a patients ability to adequately
discriminate the location, duration and intensity of the laser
pulse as a discrete exteroceptive pain event. Neuropathic pain
may involve an increased recruitment of the medial pain
system represented by multi-synaptic spinal pathways to
brainstem homeostatic centers and medial thalamic nuclei
that relay nociceptive input to the limbic forebrain [22]. In
accordance with this view, it was reported that neuropathic
pain patients with hyperalgesic phenomena to laser could Fig. 6. Association and dissociation of LEP amplitudes and pain ratings.
exhibit ultralate LEP after stimulation of the affected side Modulation of attention (top): distraction from the laser stimulus results in
smaller LEP amplitudes and reduced pain ratings (data from Ref. [65]).
[30,88]. On practical grounds, chronic pain associated with Double stimulation (bottom): LEP amplitude following the second stimulus
circumscribed hypoalgesia or hyperalgesia to laser stimuli at a short interstimulus interval (860 ms) is reduced, but subjective pain
and reduced late LEP substantiates the neuropathic nature of ratings remain unchanged (data from Ref. [16]). * p < 0.05; ** p < 0.01.
the condition [30].
In patients with familiar progressive myoclonus epilepsy However, at brainstem level (medulla oblongata), the STT is
the amplitude of both early and late components of standard somatotopically organized with afferent fibers from lower
SEP is markedly enhanced [66]. In a small group of patients body parts on the lateral part and afferents from the upper
with this disease, late LEP amplitudes were found to be body in medial parts of the STT [11]. Thus, a right sided
normal [44]. Facilitation of the somatosensory system in this lateral medullary infarction (Wallenbergs syndrome) sparing
disease thus appears to be specific to the tactile or proprio- the medial part of the STT would lead to the same symptoms
ceptive pathways, sparing the nociceptive pathways. and LEP abnormality, as described by Urban et al. [83].
However, together with the result of a thoroughly done neu-
rological examination (and MRI), the picture becomes clear.
4. Clinical use and misuse of LEP
4.2. LEP as a measure for subjective pain?
4.1. Topodiagnosis of lesions using LEP
One of the most fascinating findings in the early days of
As shown in the previous section, LEP can document LEP was that amplitudes correlate better with subjective pain
lesions anywhere along the nociceptive pathway (Fig. 3). ratings than with stimulus intensity [17]. Similar findings
Although all dermatomes are accessible, the absence of an were reported for tooth pulp evoked potentials [20], which
LEP in a patient cannot necessarily provide the exact level of led to the hypothesis, that LEP reflected neural processing of
the lesion without additional clinical, electrophysiological or pain perception rather than stimulus encoding. Further evi-
imaging data. The absence of an LEP may be due to a lesion dence supporting this hypothesis came from studies, where
anywhere between the cortex and the dermatomal level of the attention was modulated which led to changes in LEP ampli-
spinal cord where the stimulation is done, or even in the tudes and perceived pain without changes of stimulus inten-
periphery. It is important to keep in mind, that even unilateral sity [31,52,65]. When interstimulus intervals become shorter,
stimulation on two different levels with normal LEP from a however, amplitudes decrease while subjective pain ratings
higher level and absent LEP from the lower level does not remain the same. This is shown in Fig. 6 (lower part) where
necessarily mean that the lesion is between those two levels in double pulses were given on the hand dorsum. It demon-
the spinal cord: for instance, a clinical deficit of pain and strates, that despite a normally close relationship, LEP and
temperature perception of the left leg with reduced or absent subjective pain perception can be dissociated. Similar results
LEP from the foot and normal LEP from the hand could well were obtained in tooth pulp stimulation, where evoked poten-
be due to a spinal lesion at lumbar level affecting the STT. tials became reduced in amplitude while pain ratings were
312 R.-D. Treede et al. / Neurophysiologie clinique 33 (2003) 303314
unchanged, and, in the same study, the same dissociation was
shown for AEP amplitudes and ratings of perceived loudness
[19]. Overall, evoked potentials obviously rather reflect the
state of the sensory pathway and not subjective perception
[6,56].
4.3. LEP in hyperalgesia and chronic pain
LEP are useful to demonstrate lesions along the pain
pathway. As a lesion in combination with a sensory deficit
like hypoalgesia usually results in prolonged latency and/or
decreased amplitude, one could expect that in hyperalgesia
with increased pain transmission amplitudes might be en-
hanced. Apart from tension type headache with higher ampli-
tudes from pericranial stimulation sites [27], only fibromyal-
gia has been shown to yield generally higher LEP amplitudes
compared to healthy subjects [33,54]. It is still questionable,
whether the basis of this disease is directly related to in-
creased pain perception (or reduced inhibition), or to a higher
level of attention. Usually, in a more or less intact pain
pathway, LEP amplitudes are not enhanced [18,30,88]. In a
human surrogate model for hyperalgesia (topical capsaicin),
amplitudes were normal or decreased [84]. The LEP is no
direct measure for spontaneous pain; it may, however, give
hints on the underlying mechanism: spontaneous pain in
combination with reduced LEP amplitudes may derive from
deafferentation, whereas spontaneous pain with normal LEP
may be due to central sensitization (or may be psychogenic).
For the evaluation of hyperalgesia and related pain mecha-
nisms, quantitative sensory testing (QST) is the better tool.
4.4. LEP for screening?
In clinical practice it would be useful to improve assess-
ment of hypoalgesia. Although LEP are sensitive and suitable
for application in any dermatome, they cannot serve as a
screening tool. The recording (and evaluation) of LEP takes
12 h rather than minutes, the device is expensive, and
reimbursement is usually not adequately implemented in the
clinics billing system (LEP testing may be charged as stan-
dard SEP which of course does not cover the effort). There-
fore, in the clinical setting, there has to be a clear indication:
objectify/clarify an STT lesion or involvement of the nocice-
ptive pathway. Additionally, LEP can be an objective mea-
sure for follow-up examinations and allow a differentiation
between neurogenic and psychogenic origin of disturbed
pain perception.
5. Conclusions
Standard SEP are of limited value in patients, who present
with a dissociated sensory loss of pain and temperature
sensitivity and preserved tactile and proprioceptive sensitiv-
ity. The technique of LEP recording allows the assessment of
the functional status of the nociceptive pathways within the
somatosensory system. According to the anatomy of the
nociceptive pathways, this type of a sensory deficit occurs
predominantly with peripheral, spinal, or brainstem lesions.
LEP abnormalities consist of complete absence, amplitude
reductions and/or latency increases. Objective neurophysi-
ological documentation of clinically relevant sensory defi-
cits, detection of subclinical lesions, differentiation of axonal
and demyelinating lesions and differential diagnosis of or-
ganic vs. psychogenic deficit in pain perception are potential
clinical uses of this technique.
Care should be taken to use a defined task for the patients,
because the LEP components that are evaluated clinically are
late components (similar to VEP), and are more sensitive to
attention and other task-related variables than the early com-
ponents of the standard SEP. Small generalized changes in
pain sensitivity are not detectable with LEP, except when
using statistical comparisons between groups of subjects. In
psychiatric patients with altered pain perception, LEP can be
normal, because the pathways are intact. If the dissociated
sensory deficit is localized, however, the within-subject com-
parison of an affected and a healthy control site allows to
judge the integrity of the nociceptive pathways on a single-
case basis as well as follow-up studies to document treatment
efficacy.
Acknowledgements
Supported by the Deutsche Forschungsgemeinschaft
(Tr 236/13-2) and NIH (NS 38493).
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