I POTENZIALI EVOCATI LASER (LEPs) NELL ANALISI DEL DOLORE NEUROPATICO LASER EVOKED POTENTIALS (LEPs) IN NEUROPATHIC PAIN ASSESSMENT Ferdinando Sartucci 1,2,3 1 Dipartimento di Medicina Clinica e Sperimentale, Unità di Neurofisiopatologia Universitaria, Università di Pisa, Pisa; 2 DAI di Specialità Mediche, Azienda Ospedaliero-Universitaria Pisana (AOUP), Pisa; 3 Istituto di Neuroscienze, CNR, Pisa.
Neuropathic pain SOMATOSENSORY AFFERENT PATHWAY Neuropathic pain is pain arising as a direct consequence of a lesion or disease affecting the somatosensory system (Treede et al., Neurology 2008) 2
Neuropathic pain epidemiology Author Methods Sample Pain Prevalence Toth, 2009 Perez, 2009 Bouhassira, 2008 telephonic use of DN4 observational study in primary care postal survey, DN4 1239 35% 18% 7220 31% 11% 23.712 31.7% 6.9% Neuropathic pain prevalence 3
Peroneal mononeuropathy L5- radiculopathy Clinical diagnosis Saphenous mononeuropathy Myelopathy Herpes Zoster L3- radiculopathy Brachial plexopathy Polyneuropathy Amiotrophy Fibromyalgia 4
Grading system (Treede et al., Neurology 2008) 5
Standard neurophysiological testing Trigeminal reflexes (A -fibre mediated) A -fibres C-fibres A -fibres NCS (A -fibre mediated) Somatosensory evoked potentials (A -fibre mediated) 6
Differential diagnosis between CTN and STN Trigeminal reflexes in STN % 100 75 50 25 0 Findings in 120 patients CTN STN Normal trigeminal reflexes Abnormal trigeminal reflexes Abnormal trigeminal reflexes are strongly associated with symptomatic trigeminal neuralgia (STN). We found a sensitivity of 96% (95% CI: 80 to 99) and a specificity of 93% (95% CI: 86 to 96), and positive and negative predictive values of 0.77 and 0.99, respectively. 7
Selective activation Aδ- and C-fibre mechano-heat nociceptors Aδ- and C-nerve terminals of the skin Increase of the skin temperature after a CO 2 -laser simuli Laser pulse ms 8
LEP: Cortical areas involved and scalp recording Caudal region of the anterior cingulate gyrus Operculoinsular cortex 9
A -Laser evoked potentials N1 N2 P2 Moisset and Bouhassira, Neuroimage 2007 10
Ultralate laser evoked potentials related to C afferents Laser evoked potentials C-LEPs Standard laser stimuli evoking double sensation Low intensity laser stimuli evoking thermal sensation Aδ-LEPs C-LEPs (Cruccu et al, Brain 2003) Bromm and Treede, 1983 11
Spinal pathway conduction of A and C inputs (Iannetti et al 2003) 12
Age and drug influences Age-amplitude correlation Attenuated LEPs after tramadol Truini A., Panuccio G., Galeotti F., Maluccio MR., Sartucci F., Avoli M., Cruccu G.: Laserevoked potentials as a tool for assessing the efficacy of antinociceptive drugs. Eur. J Pain. 14(2):222-5,2010 13
Painful Neuropathy (Truini et al., Pain 2010) 14
Postherpetic neuralgia V1 skin biopsy in normal subject Normal Side Affected Side Green: PGP 9.5 Red: Collagen IV V1 skin biopsy in PHN patient A -LEP amplitude ( V) 25 20 15 10 5 0 C-LEP amplitude ( V) 15 10 5 0 0 5 10 Constant Pain (NRS 11 points) 0 5 10 Constant Pain (NRS 11 points) (Truini et al, Pain 2008) 15
Other Neurophysiological techniques Contact heat evoked potentials Concentric electrode-related responses Truini et al., Pain 2007 Cruccu and Truini, CLINPH 2009 16
Brain Res., F. Sartucci et al., 769, 362-366, 1997 17
Contact heat evoked potentials (CHEPs) (From studies by Greffrath, Anand) 18
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Methods Laser stimulation of the forearm. Intensity: 102-152 mj/mm2, stimulus duration: 10 ms, diameter: 5 mm. 5 ms pulse interval. Interstimulus interval: 10-15 sec. 20 trials Contact heat stimulation of the forearm. 51 C. 5 ms pulse interval. Interstimulus interval: 10-15 sec. 20 trials Concentric electrode stimulation of the forearm. Triple pulse stimulation, 5 ms pulse interval. Interstimulus interval: 10-15 sec. 20 trials Two levels of intensity used: low, pinprick stimulation (0.9-1.2 ma, 1.5 X PTh), high, electrical sensation stimulation (2.4-3.6 ma, 2.5 X PTh) 20
New tools and other methods 21
NEUROPATHIES WITH PROMINENT SMALL FIBER INVOLVEMENT Small fiber involvement testing: Sympathetic Skin Responses L. Sagliocco, F. Sartucci et al., Clinical Autonomic Research, 1999. 22
Results: LEP amplitudes and latencies Figure 2 LEPs grand averaging: traces were recorded at baseline (T0, black) and immediately after cerebellar polarization (T1, red) due to sham (left column), anodal (middle) and cathodal (right) tcdcs. B. Histograms showing LEPs variables (mean±s.d) after sham (white), anodal (black) or cathodal (grey) tcdcs with respect to baseline. Top panels: changes in N1 variables (amplitude and latency) over time; bottom panels: changes in N2/P2 complex ( p < 0.001; p < 0.0001). Bocci et al., Restor Neurol Neurosci 2015 23
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PARAMETRI NEUROFISIOLOGICI (Protocollo S.D. Neurofisiopatologia Universitaria, Pisa) LEP - Potenziali evocati laser Il complesso N2/P2 riflette l attività della corteccia cingolata, insulare e dell opercolo frontale L onda N1 riflette l attività della porzione superiore della scissura silviana, S1 e S2 neodymium: yttrium aluminium perovskite Nd: YAP laser (λ = 1.34 μm) (Lenz et al., 1998; Garcia-Larrea et al., 2003; Tsuji et al., 2006) 25
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Mielopatie Iannetti et al J Neurol Neurosurg Psychiat 2001 28
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Conclusion Standard neurophysiological responses to electrical stimuli, such as nerve conduction studies and somatosensory-evoked potentials, are useful to demonstrate, locate, and quantify damage along the peripheral or central sensory pathways. But they do not assess function of nociceptive pathways. LEPs are easy to record and can be obtained following stimulation of any dermatomal areas They are more altered in spontaneous constant pain than in iperalgesia or allodynia LEPs are the easiest and most reliable neurophysiological method of assessing function of nociceptive pathways. Late LEPs (which assess A-delta pathways) are diagnostically useful in peripheral and central neuropathic pains. Normal or facilitated LEPs suggest nociceptive pathways integrity and not support a neuropathic pain In selected context (pain sine material, non-organic anesthesia); increased in amplitude LEPs suggest a psychogenic basis Punch skin biopsy is easy to perform, is minimally invasive, and most suitable for follow-up. Punch skin biopsy is a minimally invasive tool for detecting small fibre involvement. More study with C-LEPs are necessary to determine amyelinic role in pain physiopathogenesis 32
Spesso il piacere è un ospite passeggero, ma il dolore ci stringe in un crudele abbraccio John Keats Thanks to: Tommaso Bocci Davide Barloscio Michelangelo Bartolotta Michela Santin Department of Clinical and Experimental Medicine, University of Pisa, Uniti of Clinical Neurophysiology Massimiliano Valeriani Division of Neurology, Ospedale Bambino Gesu, IRCCS, Rome Center for Sensory-Motor Interaction, Aalborg University, Aalborg, Denmark Giuliano De Carolis Pain Therapy Unit, Azienda Ospedaliera Universitaria Pisana, Pisa Enrica Santarcangelo Institute of Physiology, University of Pisa Giancarlo Carli Department of Medicine, Surgery and Neuroscience, University of Siena Alberto Priori Department of Neurological Sciences, University of Milan, Fondazione IRCCS Ospedale Maggiore Policlinico, Milan 33