Electrophysiology in diagnosis and management of neuropathic pain

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Neuropathic pain

Electrophysiology in diagnosis and management of neuropathic pain L. Garcia-Larrea a,b,*, K. Hagiwara a,c a

Inserm U1028, CNRS, UMR5292, central integration of pain (NeuroPain) Lab – Lyon neuroscience research center, universite´ Claude Bernard, 69677 Bron, France b Centre d’e´valuation et de traitement de la douleur, hoˆpital neurologique, 69000 Lyon, France c Department of Clinical Neurophysiology, Neurological Institute, Faculty of Medicine, Graduate School of Medical Science, Kyushu University, Fukuoka, 812-8582, Japan

info article

abstract

Article history:

Electrophysiological techniques demonstrate abnormalities in somatosensory transmission,

Received 7 September 2018

hence providing objective evidence of ‘somatosensory lesion or disease’ which is crucial to the

Accepted 24 September 2018

diagnosis of neuropathic pain (NP). Since most instances of NP result from damage to thermo-

Available online xxx

nociceptive pathways (thin fibres and spino-thalamo-cortical systems), specific activation of

Keywords:

contact heat stimuli, and in a near future probably also with contact cold and intra-epidermal

these is critical to ensure diagnostic accuracy. This is currently achieved using laser pulses or Neuropathic pain

low-intensity currents. Standard electrical stimuli, although of lesser diagnostic yield, are useful

Evoked potentials

when large and small fibres are affected together. Nociceptive evoked potentials to laser (LEPs)

Laser-Evoked Potentials

and contact heat (CHEPs) have shown adequate sensitivity and specificity to be of clinical use in

Allodynia

the differential diagnosis of NP, in conditions involving Ad of C-fibres and spino-thalamo-

Malingering

cortical pathways. LEPs have also a role in the detection of patients at risk of developing central

Diagnosis

post-stroke pain after brainstem, thalamic or cortical injury. Cognitive cortical responses and autonomic reactions (sympathetic skin responses) reflect pain-related arousal and can document objectively positive symptoms such as allodynia and hyperalgesia. They are of help in the differential diagnosis of somatisation disorders, by discriminating conscious simulation (malingering) from conversive sensory loss. The electrophysiological approach to patients suspected, or at risk, of NP is a cost-effective procedure that should never be absent in the diagnostic armamentarium of pain clinics. # 2018 Elsevier Masson SAS. All rights reserved.

1. The need of biomarkers for the definite diagnosis of neuropathic pain Pain by excess of nociception (‘‘nociceptive pain’’) is transmitted by an intact nervous system following stimulation of

nociceptors, while ‘‘neuropathic pain’’ (NP), is transmitted by an altered or diseased somatosensory system. Establishing a formal definition, clear-cut diagnostic criteria, and unequivocal boundaries for NP has been the subject of substantial controversy during the past 30 years. The current definition from the International Association for the Study of pain (IASP)

* Corresponding author. CETD, hoˆpital neurologique, 59, boulevard Pinel, 69003 Lyon, France. E-mail address: [email protected] (L. Garcia-Larrea). https://doi.org/10.1016/j.neurol.2018.09.015 0035-3787/# 2018 Elsevier Masson SAS. All rights reserved.

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is ‘‘pain resulting as a direct consequence of a lesion or a disease of somatosensory systems’’ [1,2]. With respect to previous definitions, this one underscores the crucial importance of somatosensory systems (rather than simply the ‘‘nervous system’’) and eliminates the notion of ‘‘dysfunction’’, which was problematic in previous proposals because of its inherent ambiguity. Because of the lack of a specific diagnostic tool for NP, a grading diagnostic system of ‘possible’, ‘probable’ and ‘definite’ NP was proposed, which establishes levels of certitude as to ‘‘how likely a given pain condition is neuropathic in nature’’. Thus, pain with a neuro-anatomically plausible distribution and history consistent with somatosensory lesion or disease is considered as ‘‘possible NP’’. If sensory symptoms, positive or negative, are described within the distribution of the pain, the diagnostic level increases to ‘‘probable NP’’. Finally, if the somatosensory involvement is confirmed by objective diagnostic tests the patient can be diagnosed as having ‘‘definite NP’’ [1,3]. Since a definite diagnosis of NP can only be posited when reasonable proof of lesion or disease has been produced, the diagnostic workup of NP should seek objective biomarkers for this.

2.

Images are not enough

In many cases, imaging is sufficient to demonstrate lesions that can be held responsible for somatosensory abnormalities; however, images can be equivocal as to their responsibility for the observed functional symptoms, including pain (e.g., [4]), and they may be notoriously insufficient to determine whether a given patient suffers from, or is susceptible to develop NP. Dissociation between radiological images and sensory signs is not uncommon in central pathology such as multiple sclerosis [5,6]; images can be also equivocal in spinal and root pathology, especially in case of intraforaminal lesions (e.g., [7–10]) and are of little help to ascertain symptoms in peripheral neuropathies. Predicting NP development on the basis of images alone is also problematic. For instance, while lateral medullary lesions (Wallenberg’s syndrome) can induce NP in 25–50% of cases [11,12], whether or not a given patient will develop pain after this type of lesion cannot be established based on computed tomography (CT), magnetic resonance imaging (MRI) or angiographic data. Quantitative sensory testing (QST) uses precisely graded and reproducible stimuli to estimate sensory and nociceptive thresholds, and is a powerful method to follow-up somatosensory disturbances of various modalities. QST, however, is not an objective test since it relies on the patient’s subjective report, which is subject to dissimulation or malingering [13,14]. The electrophysiological recording of neural responses, on the other hand, can assess and quantify somatosensory deficits to a variety of peripheral stimuli (electrical, thermal or tactile). Since stimuli can be applied precisely to the painful territory, electrophysiological techniques are ideally suited to provide the proof of ‘somatosensory lesion or disease’ in the painful territory, which is required for a definite diagnosis of NP. The main goal of these techniques will be to support, clarify, and quantify the

patient’s subjective report of somatosensory dysfunction (thus substantiating NP diagnosis), or, alternatively, to contradict such report if it appears incompatible with the objective data.

3. Different techniques to assess different systems Standard sensory electrophysiological examination is widely available and comprises essentially nerve conduction studies (NCS) and somatosensory evoked potentials (SEPs) to nonnoxious electrical stimulation. These techniques explore nonnociceptive pathways, namely large myelinated (Ab) fibres in the periphery, and the dorsal column–medial lemniscus system (DCML-system) at central level [15]. Further to these procedures, the specific assessment of thermo-algesic systems (fibres Ad and C in the periphery, spinothalamic tract (STT) system at central level) is essential in the diagnostic workup of NP. Evoked potentials to radiant laser pulses (laserEPs, or LEPs) or contact heat thermodes (CHEPs) are the most commonly employed techniques to explore specifically the nociceptive transmission system [15–17]. Also, intraepidermal low-intensity currents have been shown to activate selectively Ad fibres at non-noxious levels [18–21], and might become clinically useful in a near future (Fig. 1), as could also be the case for responses to cold stimuli using thermodes with steep temperature ramps [22]. Lower limb nociceptive (‘‘RIII’’) flexion reflexes allow objective assessment of pain thresholds [23,24], but they are seldom used in clinical routine. Other techniques such as microneurography, which allows investigating either large or thin fibres by introducing a needle within the nerve itself, are not of current clinical use but are important in pathophysiological NP research [25]. Table 1 summarises a number of techniques, most of them well standardised in most hospitals, indicating the subtype of somatic system that is tested at peripheral and central level, according to the type of stimulus that is applied. The interpretation of electrophysiological results for NP diagnosis greatly benefits from the concomitant analysis of subjective sensory/pain thresholds, reaction times, and sympathetic skin responses. The electrophysiological investigation of a pain patient should always be performed together with a clinical somatosensory exam, which will indicate the territory to be stimulated and the optimal stimulation modalities. The stimulation should always concern the painful territory, results being compared with a non-affected region, whenever possible its contralateral homologue [15]. When stimulating at slow paces, motor reaction times and sympathetic skin responses (SSR) can be recorded using a single bipolar montage between the palm and the dorsum of the hand. SSRs to noxious stimuli are autonomic reactions reflecting pain-related arousal [26], which in healthy subjects correlates with both subjective intensity ratings and amplitude of cortical responses [27,28]. SSRs are therefore useful to document objectively the existence of abnormal pain percepts (see section 7). Dissociation between autonomic responses and verbal reports has also diagnostic relevance in patients suspected of conversion disorder or malingering (see section 8).

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Fig. 1 – Scalp evoked potentials and sympathetic skin responses (SSRs) to nociceptive laser and non-nociceptive intraepidermal stimulations in a healthy subject. Latency times are measured at vertex (Cz) potential peaks (indicated by triangles). In both cases, latency times are consistent with Ad peripheral activation, noxious for laser but non-noxious for intraepidermal. Latency differences between responses to the two modalities is 25.4 ms, which is compatible with the heat transduction time needed for laser. Sympathetic skin responses (SSR) to the intra-epidermal electrical stimulation are diminished owing to its non-painful nature, which elicits diminished arousal reactions relative to laser (see section 7).

Table 1 – Summary of the principal types of non-invasive peripheral stimulation used for electrophysiological pain studies, along with the transmission systems activated at peripheral and central level, and the main types of clinical tests. Stimulus Electrical transcutaneous (non-noxious) Tactile, air puff Electrical transcutaneous (noxious) Electrical (intraepidermal) LASER (CO2, YAP, YAG) Contact heat/cold

Peripheral activation

Central activation

Common tests

Ab Ab Ab, Ad, C (unselective) Ada Ad, C Ad

DC system DC system DC + STT systems STT system STT system STT system

NCV, SEPs, Blink t-SEPs Nociceptive (RIII) reflex IE-SEPs Laser-EPs, nociceptive SSR CHEPs

DC-system: dorsal columns/medial lemniscus; STT: spinothalamic. Intraepidermal currents are selective for Ad fibres only for stimuli of low intensity (< 0.25 mA).

a

4.

Exploring non-nociceptive pathways

Considerable evidence has accumulated showing that NP is most especially associated with lesions of temperature and pain pathways at peripheral [29,30], spinal [31] or supraspinal levels [32–34]. Conversely, the specific involvement of large fibres and/or the DCML system is not crucial for most cases of NP [32,35]. Although NCS and SEPs do not explore specifically

the pain/temperature systems, their study remains of considerable importance in the evaluation of pain patients. For instance, large and thin peripheral fibres are mixed in nerves, plexuses and spinal roots, and segregate only at the dorsal root entry zone [36]; therefore, peripheral lesions, in particular traumatic or metabolic, tend to affect both large and thin fibres indistinctly. Also, some specific features of NP, in particular paroxysmal discharges, might be specifically linked to a

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Fig. 2 – Somatosensory evoked potentials to electrical non-noxious stimulation of median nerves in a patient with pain and dysesthesiae in the radial aspect of right forearm with non-systematised root distribution, following a car accident. Plexus responses distal to dorsal ganglion are normal bilaterally (upper traces) while responses from dorsal horn, caudal brainstem and cortex (2nd–4th rows) are clearly abnormal to right median-nerve stimulation. These results show axonal loss and abnormal transmission time between spinal ganglion and the spinal cord at a C6-C7 level on the right side. Although standard SEPs only reflect conduction in large non-nociceptive fibres, these results demonstrate impairment of dorsal roots and/or the dorsal root entry zone over a territory consistent with pain distribution, and therefore substantiate the diagnosis of neuropathic pain (Reproduced from Garcia-Larrea Neurophysiol Clin 2012, by permission).

functional impairment of large Ab fibres, and therefore can be associated with abnormalities in standard NCS and SEPs [29,37,38]. Examples of association between paroxysmal pain and dysfunction of large myelinated fibres are found in classical trigeminal neuralgia, linked to segmental demyelination at the root-brainstem entry zone, and the ‘Lhermitte’s sign’, closely associated with demyelination of spinal dorsal columns. The use of SEPs to assess DCML function has significant predictive value as to the efficacy of spinal-cord stimulation (SCS) [39]. Last and not least, one important localising sign is given by the proximal or distal location of the somatosensory lesion relative to the dorsal root ganglion (DRG). A proximal lesion (between DRG and the spinal cord) allows axonal flux to remain normal in the peripheral nerves distal to DRG, and therefore preserves the amplitude of peripheral potentials. Conversely, lesions that are distal to DRG (neuropathies, plexopathies or ganglionopathies) reduce distal axonal flux and alter considerably NCS results. This may have important consequences, both diagnostic and therapeutic, as illustrated by the distinction between plexus and root lesion in Fig. 2.

Given the above considerations, and the fact that standard NCS and SEP studies are readily obtainable in most neurophysiological departments, it follows that a standard electrophysiological assessment with NCS/SEPs should remain a first-line approach in case of suspected NP, in parallel to more selective examinations of the pain and temperature pathways.

5. Is this neuropathic pain? Electrophysiology to assist diagnosis Despite their value as described above, standard exams such as NCS or SEPs will remain normal in those patients with pure or predominant thin fibre or spinothalamic system (STS) involvement, which are the most likely to induce NP. This includes small-fibre neuropathies and a wide array of spinal, brainstem, thalamic and cortical lesions or diseases [17,31,33,34]. The study of thermo-algesic pathways using appropriate stimuli is therefore a crucial step for diagnosis of NP in these patients, and the most useful test to demonstrate such lesions in thin fibres or STS pathways are laser-evoked

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Fig. 3 – This 65 y woman underwent a minor head trauma (temporal concussion without loss of consciousness) and a CTscan performed in the emergency room was considered normal at supratentorial level. Four weeks later, she developed burning pain in the right upper limb, which was not considered neuropathic despite a new CT-scan that showed an asymmetry at midbrain level (June 2006). Standard SEPs were normal. While malingering was being seriously considered, laser-EPs demonstrated significant abnormalities of conduction in pain-temperature pathways after stimulation of the painful right hand (bottom left) but remained normal to stimulation of the non-painful side (top left). A gradient-echo (T2*) MRI showed a hypo-signal image in the posterior left midbrain, suggesting a haemorrhagic sequel. This small midbrain lesion impinged with spinothalamic conduction and was responsible of the neuropathic pain (Modified from Garcia-Larrea Neurophysiol Clin 2012, with permission).

potentials (laser-EPs) and contact-heat evoked potentials (CHEPs) [15,16,40–43]. Significant abnormality of laser-EPs or CHEPs to stimulation of a painful territory should be considered as an electrophysiological signature of NP. At central level, specific or predominant alteration of nociceptive responses is characteristic of syringomyelia [44,45], lateral brainstem syndromes [46,47], thalamic painful syndrome [35] and operculo-insular stroke [34]. The exquisite sensitivity of laser-LEPs to thin-fibre and STT impairments allows the detection of minute lesions otherwise undetected, and gives to these techniques medico-legal value in a number of European countries. An illustrative case is presented in Fig. 3. The type of electrophysiological abnormality will depend both on the lesion site and on the mechanisms of the

pain. Ischemic necrosis interrupting transmission where the STT occupies a small volume (e.g., brainstem lesions) will entail profound LEP/CHEP abnormalities, whereas slowly progressive lesions that tend to distort structures without much axonal loss (e.g., spinal tumours or syringomyelia) tend to produce less impressive abnormalities, which can be reversible if the compression is corrected (Fig. 4). Dissociations between DCML and STS involvement may have implications for the development of central pain. For instance, thalamic lesions that alter the laser-EPs have a great potentiality to develop thalamic pain, while lesions affecting exclusively the ventro-postero-lateral nucleus and sparing the STS terminals rarely entail neuropathic pain [35,48].

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Fig. 4 – Pre- and post-operative LEPs in a patient with neuropathic pain following post-traumatic syringomyelia. Lesions entailing slow compression of spinothalamic axons, such as syringomyelia and other central spinal lesions, tend to distort responses but may entail little axonal loss, and abnormalities can therefore revert in case of decompression, as was the case in this patient, in whom the pain also subsided in parallel with recovery of spinothalamic-related LEPs. A similar example of recovery of LEPs after decompression from syringomyelia can be seen in reference [45].

In peripheral neuropathies, frank amplitude reduction of laser-EPs has been correlated with the intensity of constant burning pain, whereas their partial preservation was associated with provoked pain [37,49]. Also in central pain syndromes, continuous pain was more frequent in case of complete obliteration of laser-EPs, while the prevalence of evoked pains (hyperalgesia, allodynia) increased when laser-EP alteration was only partial [41,50–52]. These data have been confirmed by independent studies using psychophysical testing, which showed that thermal thresholds are more severely affected in patients with ongoing burning pain than in those with allodynia or hyperalgesia [53]. Preserved somatosensory transmission after stimulation of a painful territory tends to exclude the diagnosis of NP, or at least empowers a reasonable doubt. Before excluding a somatosensory lesion, however, it is important to ascertain that responses have been recorded to stimulation of all the different types of fibres (Ab, Ad and C) (Fig. 5). Non-neuropathic syndromes with chronic pain such as fibromyalgia, chronic myofascial pain, chronic fatigue syndrome, tension headache and migraine, typically show normal (or even enhanced) central somatosensory responses, thereby underscoring their pathophysiological differences relative to NP. A deficit of habituation to repeated series of noxious stimuli has been described in some of these conditions, notably migraine and fibromyalgia [54,55]. This may imply dysfunction in pain control descending mechanisms [56] and/or central sensitisation of ascending somatic signals [57]. Unfortunately, mechanistic biomarkers of central sensitisation are scarce, and their predictive value remains subject of controversy. While

biomarkers make sense if they are linked to patient-relevant outcomes [58], the specificity of some sensitisation markers such as lack of habituation has been questioned, since they may be identified in both non-neuropathic pain such as migraine [54] and in neuropathic pain syndromes [59].

6. Will pain develop in this patient? Electrophysiology to assist prevention/prognosis In a number of cases, electrophysiological studies can provide prognostic information as to the likelihood of development of NP. The capacity of intraoperative monitoring of sensory (and motor) potentials to detect impending neural lesions that can lead to postoperative NP has been documented in many surgical settings including thoracotomy [60], rhizotomy [61], scapular-shoulder arthrodesis [62], carotid endarterectomy [63] and resection of spinal cord tumours [64]. Electrophysiological markers can help to estimate the probability that NP may develop in patients with stroke, spinal injury or multiple sclerosis. Thus, the overall incidence of central post-stroke pain increases from 8–10% in the whole population [65,66] to almost 20% in patients with somatosensory involvement [67], and may reach 50% in case of specific STT involvement as in Wallenberg syndrome [11,12]. Combining anatomical and physiological indices of prediction may be a powerful, yet reasonably simple way to detect patients at risk. A recent study of 42 consecutive patients with thalamic stroke showed that involvement of STS afferents to the posterior thalamus, as assessed by the combined study of

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Fig. 5 – Post-thoracotomy pain with selective LEP abnormality to stimulation of C fibres. In the upper part of the figure, standard laser stimulation using high energy laser pulses with small spot size (Nd:YAP; 80 mJ/mm2, 4 mm spot) yields normal and symmetrical responses from the painful and non-affected territories. In the lower panel, selective stimulation of C-warmth fibres using lower energy densities and a larger spot size (30 mJ/mm2, 20 mm spot diameter) yielded significantly attenuated C-LEPs (left) and sympathetic skin responses (right) to stimulation of the painful region exclusively. Please note that the time bases are different for Ad and C-fibre responses.

laser-EPs and MRI, could classify central thalamic pain patients with 93% sensitivity and 87% positive predictive value [35]. Also, it was recently reported that subacute spinal cord injury entails cortical changes that precede the onset of neuropathic pain, which might be used to discriminate patients at risk [68,69]. Although all these data are recent and need replication, they suggest that sorting out of patients at different risks of developing NP after a neural lesion may be achievable, even at the individual level, by combining anatomical and functional investigation of sensory systems.

7.

Objective indices of pain

Electrophysiological techniques provide objective information on somatosensory transmission, but they do not reflect the pain itself. So far, neither electrophysiology nor functional imaging have been able to devise clinical tests that detect activities unmistakably associated with ongoing NP. Some exceptions might apply to invasive tests such as microneurography [70,71], but these techniques are not yet applied in clinical routine.

It is however possible to document the existence of provoked pain sensations using pain-related autonomic reactivity markers, such as pupillary dilation [72] or skin sympathetic responses (SSR) [26]. The latter technique is particularly attractive in clinical settings due to the easiness of its implementation, which does not need sophisticated equipment and can be performed in parallel with evoked potentials. SSRs to noxious stimuli (pain SSR) reflect the arousal reaction triggered by an abrupt painful sensation. They are easily obtained in both healthy subjects and patients and can be evaluated after very few stimuli, hence avoiding habituation [26,73]. The SSR is enhanced by increasing stimulus intensity, and its amplitude was found associated with the magnitude of the ‘pain matrix’ activation in fMRI [27]. Abnormally enhanced SSRs to innocuous stimuli can therefore be useful as objective hallmarks of allodynia in patients with NP [74]. This technique has also limitations: since the absolute amplitude of the SSR is highly variable across subjects, responses to stimulation of a painful territory must rely on comparison against stimulation of a non-painful region. Also, interpretation of the SSR implies that the efferent autonomic branch of the reflex remains intact, and therefore

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Fig. 6 – Dissociation between verbal reports of anaesthesia and objective signs of preserved perception. This 35 year-old man presented with painful dysesthesiae and ‘electric discharges’ in the right side of the body, associated with multimodal sensory deficit for thermal, noxious and vibratory stimuli. Asthenia and sphincter troubles followed shortly, and a tentative diagnosis of multiple sclerosis was presumed, although T2-MRI was not confirmative. Sensory deficit did not respond to corticosteroids and immunotherapy (azathiopirine, interferon) and pain was unresponsive to gabapentin, venlafaxine and clonazepam. Suspicion was raised of a somatoform condition after CSF analysis, visual and somatosensory potentials and a second MRI were found normal after despite two years of unchanged symptoms. A. Upper left panel the voluntary motor responses (EMG signals) which are normal to stimulation of the normal side (black traces) but absent to stimulation of the ‘anaesthetic’ side (red traces). In contrast with this, the lower right panel (B) show enhanced autonomic responses to laser stimulation of the ‘anaesthetic’ right side, despite a verbal response indicating lack of sensation. C. Evoked potentials to laser stimuli show the persistence of sensory responses, identical to left and right stimulation, and the presence of a cognitive response late response (‘‘P3’’) to stimulation of the supposedly right side (right traces), indicating the persistence of a conscious perception of the right-sided stimulus despite verbal reports of anaesthesia. This pattern of responses is consistent with conscious simulation.

usefulness cannot be granted in patients with severe autonomic dysfunction.

8. Pain sine materia: from malingering to conversion NP syndromes can be imitated, either voluntarily [14] or unconsciously in the context of conversion disorders [75]. Conversion sensory symptoms can be also associated with actual neural injury [4]. All these cases represent a serious challenge for diagnosis and treatment, as, by definition, a grading of ‘probable NP’ can be attributed on the basis of purely subjective symptoms [3], and semi-objective approaches such as QST can be voluntarily biased [13,14]. The use of

electrophysiology in patients with pain suspected to be of nonorganic origin is therefore relevant; it is based on the assessment of sensory transmission, but also of pain-related autonomic arousal, and in some instances cognitive processes linked to conscious perception. A typical diagnostic challenge appears in patients complaining of pain with neurological or ‘near-neurological’ distribution, and alleged thermo-algesic hypoesthesia within the distribution of the pain (i.e. ‘‘probable NP’’) but in whom normal neuroimaging and electrophysiological exams entail reasonable doubt about the reality of an organic cause. After eliminating rare NP syndromes where no sensory transmission changes are demonstrated, such as erythromelalgia [76,77] or ‘‘irritable nociceptor’’ syndromes [78], a differential diagnosis between deliberate deception (malingering) and

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unconscious somatoform (conversion) disorder may be at stake. Searching for possible dissociations between verbal reports of sensory loss and objective signs of preserved perception is a useful approach to this problem, since such dissociation will support a diagnosis of conscious simulation. Autonomic reactions in patients with alleged hypoesthesia will explore whether such hypoesthesia is ‘‘real’’ – in the sense that it is accompanied by reduction or absence of autonomic reactions to pain (e.g., [73]). Indeed, normal autonomic arousal to the stimulation of a supposedly numb or anesthetized region suggests that the stimulus was perceived as noxious, hence contradicting the verbal reports (Fig. 6). Cognitive cortical responses can also be used to explore cases of suspected non-organic hypoesthesia. Long-latency responses (‘‘P300’’ or ‘‘P3b’’) are indices of conscious stimulus recognition, elicited by stimuli that are consciously recognised as ‘targets’ [79,80]. In healthy subjects these responses cannot be purposely blocked, since conscious efforts to pretend a lack of perception tend to enhance, rather than reduce, such responses [81]. This particular behaviour has prompted the use of these responses in brain-computer devices for patients unable to speak [82,83] and also as a forensic aid as ‘crime detectors’ [84,85]. In the field of sensory assessment, the P300 has been reported to disentangle simulated hypoesthesia from genuine unconscious conversion [86]. As in the case of autonomic reactions, the use of P300 recordings here relies on the fact that discordance between verbal reports and cortical reactions of awareness supports voluntary deception, which can range from simple malingering to somatic symptom disorder [87] (Fig. 6). Lastly, some patients with ‘medically unexplained’ hypoesthesia may demonstrate genuine absence of vegetative reactions or cognitive signs of stimulus awareness in the affected territory, despite normal sensory transmission. This of course does not support the hypothesis of malingering, but rather substantiates the patient’s claims of abnormal sensory feelings. In these cases, the patient’s condition may reflect a high-order disorder where normal sensory transmission up to the primary sensory cortices fails to translate into conscious awareness or autonomic reactions. Lack of vegetative responses to relevant stimuli has been described in neuropsychiatric syndromes of sensory delusion, such as Capgras syndrome, whereby patients do not recognise close relatives and fail to evoke enhanced vegetative reactions to them [88,89]. A high-order dysfunction entailing functional disconnection between sensory and limbic cortices is postulated in these cases, which are not without reminding of the concept of ‘‘La belle indiffe´rence’’ put forward by Sigmund Freud more than one century ago [90].

9.

Conclusions

Electrophysiological techniques can provide objective evidence of ‘somatosensory lesion or disease’ which is crucial to the diagnosis of neuropathic pain (NP). Evoked potentials to laser and contact heat have adequate sensitivity and specificity to be of clinical use in the differential diagnosis of NP. Electrophysiology may also have a role in the detection

9

of patients at risk of developing central pain after spinal, brainstem, thalamic or cortical injury. Cognitive cortical responses and autonomic reactions reflecting arousal can document positive NP symptoms such as allodynia and hyperalgesia, and are of help in the differential diagnosis of somatisation disorders. The electrophysiological approach to patients suspected, or at risk, of NP is a cost-effective procedure that should never be absent of the diagnostic armamentarium in pain clinics.

Disclosure of interest The authors declare that they have no competing interest.

Acknowledgements This work received financial support from the Socie´te´ Franc¸aise d’Evaluation et Traitement de la Douleur (SFETD) (Translational Research Grant 2012-14), the LABEX (Laboratory of Excellence) ‘‘CORTEX’’, ANR-11-LABX-0042, ANR-11-IDEX0007, and the APICIL Foundation.

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