Clinical Neurophysiology testing in neuropathic pain Why? How? When?
Luis Garcia-Larrea Central intégration of pain Unit U879 Inserm – UCB Lyon Hôpital Neurologique Lyon, France
Pain
nociceptive
neuropathic
Neuropathic pain: definition from the IASP « Pain resulting as a direct cause of a lesion or a dysfunction of the nervous system » Proposition of change (IASP SIG 2007) : « Pain resulting as a direct consequence of a lesion or a disease of somatosensory systems »
We need markers
20 year-old man : morning fatigue, occasional enuresis, pain & soreness of left thumb on awakening
Nocturnal (morpheic) epilepsy
Images are not enough Pain
No pain
?
?
On a population basis, clinical neurophysiology helps to: Support pathophysiological mechanisms Establish anatomo-functional relationships Distinguish population subtypes Derive norms that can be applied later to individuals
On an individual basis, clinical neurophysiology helps to: Lend objective basis to a subjective complain Clarify its pathophysiology: classify (or not) as neuropathic pain Quantify the abnormality and allow follow-up …or contradict the patient’s report!
Do not confound different modalities of clinical use 1- Diagnostic 2- Physiopathology – epidemiology
Patient A: normal
Group A: controls Patient B: abnormal
Group B: patients
Instances of persistent pain where CN may be useful
• pain with obvious neuropathic (somatosensory) lesion • pain of possible neuropathic origin • pain without obvious organic reason (sine materia) • neuropathic lesions potentially causing neuropathic pain
Techniques of clinical neurophysiology in chronic pain patients
• electroneurography •standard •microneurography • nociceptive reflexes • somatosensory evoked potentials • electrical stimulus (SEPs) • laser stimulus (LEPs) • contact-heat stimulus (CHEPs) • transcranial electromagnetic stimulation • rTMS • TDCS
Somatosensory evoked potentials • Aβ-mediated • electrical stimulus (SEPs) • tactile stimulus (t-SEPs) • air puff (a-SEPs) • Aδ-mediated • laser stimulus (LEPs) • contact-heat stimulus (CHEPs) • concentric electrode (c-SEPs) (?) • C-fibre mediated • laser stimulus (C-LEPs)
Neuropathic pain is most often associated with lesions in pain / temperature pathways
• peripheral neuropathic pain (Mendell and Sahenk, N Eng J Med 2003) • spinal cord neuropathic pain (Defrin et al, Pain 2001) • central post stroke pain (Boivie, Pain 1989)
Localisation of most frequent lesions associated to neuropathic pain
Most (if not all) of these lesions can be detected by laser-evoked potentials, while only a small fraction is detected by standard SEPs
Modified from Treede et al, Neurophysiol Clin 2003, 6: 303-14
1. pain with obvious neuropathic (somatosensory) lesion
M. Ama… L3P0048. Lateral medullary infarct. Neuropathic pain FP1*
REOG*
FP2*
F7*
F3*
FZ*
F4*
F8*
FT7*
FC3*
FCZ*
FC4*
FT8*
T3*
C3*
C4*
T4*
TP7*
CP3*
CP4*
TP8*
T5*
P3*
P4*
T6*
O2*
A2 (TP10)*
CZ*
CPZ*
PZ* A1 (TP9)*
O1*
FP1*
REOG*
FP2*
F7*
F3*
FZ*
F4*
F8*
FT7*
FC3*
FCZ*
FC4*
FT8*
T3*
C3*
C4*
T4*
TP7*
CP3*
CP4*
TP8*
P4*
T6*
O2*
A2 (TP10)*
CZ*
CPZ* T5*
P3* PZ*
A1 (TP9)*
O1*
Male, 30 year-old. Testicular carcinoma orchiectomy plus chemotherapy 6 months later : Pain irradiating down the left leg fluctuating paresthesiae, outer face of left leg and dorsolateral foot global hypesthesia left foot Urologist : metastatic (lymphatic) dissemination on retroperitoneal space and invasion of lumbsacral plexus. Difficult to tag even with high resolution MRI. Neurophysiologist : nerve conduction study of superficial peroneal nerves (pure sensory branches innervating dorsal feet). Normal and symmetrical amplitude.
Conclusion : Lesion must be proximal to sensory ganglion. No plexular invasion Plexular metastasis immediate run of chemotherapy Probable root compression Brief period of rest, then progressive rehabilitation. Symptoms subsided Electrophysiological study of value to determine management
Vertebral fracture T5, paraparesis. Post-traumatic syringomyelia 5 years later, pain in left arm FP1*
EOG*
FP2*
F7*
F3*
FZ*
F4*
F8*
FT7*
FC3*
FCZ*
FC4*
FT8*
T3*
C3*
CZ*
C4*
T4*
TP8*
TP7*
CP3*
PZ*
CP4*
TP8*
P4*
T6*
T5*
P3*
PZ*
P4*
T6*
O2*
TP10*
TP9*
O1*
O2*
TP10*
FP1*
EOG*
FP2*
F7*
F3*
FZ*
F4*
F8*
FT7*
FC3*
FCZ*
FC4*
FT8*
T3*
C3*
CZ*
C4*
T4*
TP7*
CP3*
CPZ*
CP4*
T5*
P3*
PZ*
O1*
TP9*
5.000µV 0.15S
0.00
0.25
0.50
0.75
1.00
1.25
1.50
0.00
0.25
0.50
0.75
1.00
1.25
1.50
S
Stim left hand (painful)
Stim right hand
P1*
FP2*
FP1*
F7*
F3*
FZ*
F4*
F8*
FT7*
FC3*
FCZ*
FC4*
FT8*
T3*
C3*
CZ*
C4*
T4*
CP3*
TP7*
CP4*
CPZ*
P3*
TP8*
F3*
FZ*
F4*
F8*
FT7*
FC3*
FCZ*
FC4*
FT8*
T3*
C3*
CZ*
C4*
T4*
TP7*
CP3*
CP4*
TP8*
P4*
T6*
O2*
A2 (TP10)*
CPZ*
P3*
PZ* A1 (TP9)*
FP2*
F7*
T6*
P4*
REOG*
PZ* O2*
O1*
A2 (TP10)*
A1 (TP9)*
O1*
?
FZFZ-
CZCZ-
CPZPZ-
+
+ -0.10
0.00
0.10
0.20
0.30
0.40
0.50
0.60
0.70
Postop: stim left hand
0.80
0.90
-0.10
0.00
0.10
0.20
0.30
0.40
0.50
0.60
0.70
0.80
0.90
Postop: stim right hand : now painful !
Syringomyelia C6-T1: selective abnormality to C-fibre stimulation A-delta mode
C-warmth mode
RT(EMG)
RT(EMG)
FZ*
FZ*
FCZ*
FCZ*
FCZ*
CZ*
CZ*
CZ*
CZ*
CPZ*
CPZ*
CPZ*
CPZ*
PZ*
PZ*
PZ*
PZ*
RT(EMG)
RT(EMG)
FZ*
FZ*
FCZ*
0
L3P275
900ms
0
900ms
0
1800ms
0
1800ms
Peripheral / radicular lesions
Cruccu & Garcia-Larrea, Clin Neurophysiol Suppl., 2004
In patients with “obvious” neuropathic pain • • • •
confirm objectively ss transmission abnormalities change pathophysiological orientation(and ttt) uncover other lesions quantify / qualify clinical impairment
2. Is this pain neuropathic ?
70y-old woman, minor cranial trauma (mandibular fracture, no loss of consciousness) transient diplopia (IV) CT-scan considered normal (except subdural hygroma) 8 dyas later, burning pain in left foot, claims loss of heat sensation on left hand
R
L June 2006
August 2006
right hand stimulation
left hand stimulation Fz Cz
Man, 50 y, sudden onset of left burning pain and thermal hypoesthesia. No other symptoms or signs Neurologist: « consider malingering » CO2-laser EPs to upper and lower limb stimulation L
R Left UL Right UL
Left LL Right LL
Mme Sorr…, 44a, A3P0096. Cervico-brachial pain during effort – cervical manipulation : vertigo, sensation of a cold left leg, then burning pain in left side of the body..Thermo-algesic hypaesthesia with C6 level. Normal brain and spinal MRI
F7*
FP1*
Motor response (rectified) REOG*
F3*
FZ*
FP2*
F4*
F8*
FCZ*
FT7*
FC3*
FCZ*
FC4*
FT8*
T3*
C3*
CZ*
C4*
T4*
TP7*
CP3*
CPZ*
CP4*
TP8*
CZ*
CPZ*
T5*
P3*
PZ*
P4*
T6*
0
O1*
Red: stim L3 right Noir: stim L3 left (painful)
O2*
900ms
Nociceptive spinal reflexes
Recording: Biceps femoris
Stimulation : ankle & popliteal fossa (Tibial nerve, 1 ms shocks) Ertekin et al. J Neurol Neurosurg Psychiatry. 1975, 38:959-65. Conduction velocity along human nociceptive reflex afferent nerve fibres • fastest reflex conduction velocity along the posterior tibial nerve 10-25 m/s • A-delta group of cutaneous afferent nerve fibres
Nociceptive spinal reflexes RIII reflex
0
80
160
240
320
400ms
% of initial RIII amplitude (top) – VAS (bottom)
Reflex magnitude uV8 x sec 10 100%
RIII threshold ~ pain threshold
6 4 2
RIII
0
0
0Mental task
30
60 min
40 mA stim intensity Willer et al, Pain 1977
Nociceptive reflexes to confirm neuropathic allodynia
Allodynic side Normal side 3 mA
7 mA
4 mA
8 mA 4.5 mA
17 mA 7 mA
Algo_632
Neurophysiological techniques detect abnormalities in somatosensory transmission • In both lemniscal and spinothalamic pathways • Even due to minute lesions
Abnormal somatosensory responses to stimulation of a painful region are the neurophysiological signature of neuropathic pain Medico-legal value
3. pain without obvious somatosensory reason (pseudo-neuropathic pain)
Garcia-Larrea et al., Brain 2002, 125(12)
Pain sine materia (mainly fibromyalgia) : average of 12 patients Normal side
Painful side
Garcia-Larrea et al, 2002
1) Absence of abnormalities of somatosensory transmission indicates that that pain in fibromyalgia is not neuropathic 2) However, other neurophysiological abnormalities can be associated to fibromyalgic pain
Widespread pain in fibromyalgia is related to a deficit of endogenous pain inhibition. Julien N, Goffaux P, Arsenault P, Marchand S. Pain 2005;114(1-2):295-302.
…when the patient lies…
Male, 35 a. 2006 : multiple sensory symptoms right side, subacute onset Right hypaesthesia, selective for thermal and vibration senses Painful dysesthesiae + « electric discharges » right side of the body Genital & sphincter trouble, asthenia Initial dx: Mumtiple Sclerosis (ttt Corticoids, Interferon, Imurel) + specific treatment for his ‘neuropathic pain’ : Neurontin, Effexor, Rivotril
But… CSF, VEP, SEP normal 2 brain MRI (T1 – T2) normal 2008 : revision of initial diagnosis and suspected somatoform trouble
35 a, douleurs & déficit thermoalgique hémicorps droit. Potentiels évoqués par laser Nd:YAP Motor response FP1*
F7*
F3*
FT7*
FC3*
REOG*
P1
FP2*
FZ*
FCZ*
F4*
N2
P1
Stim main droite: VAS 0-1 Stim main gauche: VAS 4 F8*
FC4*
FT8*
C4*
T4*
P2
T3*
N1 TP7*
C3*
N1 CP3*
T5*
P3*
O1*
L3P218
CZ*
CPZ*
CP4*
TP8*
PZ*
P4*
T6*
O2*
29 y; …lombotomy (pyélo-ureteral dysfucntion). Pain and thermoalgesic anesthesia L1 G
Stim L1 G, VAS 4/10
Stim L1 D, VAS 0/10 FP1*
FP 1*
REOG*
REOG*
FP2*
FP 2*
F7*
F3*
FZ*
F4*
F8*
FT7*
FC3*
FCZ*
FC4*
FT8*
T3*
C3*
C4*
T4*
CP 4*
TP 8*
F7*
F3*
FZ*
F4*
F8*
FT7*
FC3*
FCZ*
FC4*
FT8*
T3*
C3*
C4*
T4*
CP4*
TP8*
P4*
T6*
O2*
A2 (TP10)*
CZ*
CZ*
CP3*
TP7* CP 3*
TP 7*
CPZ* CP Z*
P 3*
T5*
P3*
T5*
T6*
P 4*
PZ* P Z*
A1 (TP9)* A1 (TP9)*
O2*
O1*
O1*
A2 (TP 10)*
FZFZCZCZPZPZ-
-0.10
0.00
0.10
0.20
0.30
0.40 S
0.50
0.60
0.70
0.80
0.90
-0.10
0.00
0.10
0.20
0.30
0.40 S
0.50
0.60
0.70
0.80
0.90
29 y - Lombotomy (pyelo-ureteral dysfunction). Pain & thermoalgesic anaesthesia L1 left
Stim L1 right, VAS 4/10
Stim L1 left, VAS 0/10 FP1*
FP 1*
REOG*
REOG*
FP2*
FP 2*
F7*
F3*
FZ*
F4*
F8*
FT7*
FC3*
FCZ*
FC4*
FT8*
T3*
C3*
C4*
T4*
CP 4*
TP 8*
F7*
F3*
FZ*
F4*
F8*
FT7*
FC3*
FCZ*
FC4*
FT8*
T3*
C3*
C4*
T4*
CP4*
TP8*
P4*
T6*
O2*
A2 (TP10)*
CZ*
CZ*
CP3*
TP7* CP 3*
TP 7*
CPZ* CP Z*
P 3*
T5*
P 4*
T6*
P3*
T5*
PZ* P Z*
A1 (TP9)* A1 (TP9)*
O1*
O2*
O1*
A2 (TP 10)*
FZ-
CZPZ-
-0.10 0.00 0.10 0.20 0.30 0.40 0.50 0.60 0.70 0.80 0.90 S
FZCZPZ-
-0.10 0.00 0.10 0.20 0.30 0.40 0.50 0.60 0.70 0.80 0.90 S
Can be sure that the patient actually perceived the stimulation ?
Normal side Anesthetic side
LEP-P2 Cognitive N2
CZ LEP-N2 Cognitive P3 -0.10 0.00 0.10 0.20 0.30 0.40 0.50 0.60 0.70 0.80 S
0.90
Cognitive responses provide hints that the stimulus not only reached the sensory cortex, but also that it most probably reached consciousness !
Conversion anesthesia can produce an absence of cognitive P3
Left hemianesthesia, normal neuroradio + neurophysio, 5 years evolution non-target
400ms
target
400ms
But this cannot be done vountarily
Affected side
normal side frequent
frequent
rare
rare
Modified from Lorenz et al NeuroReport 1998
EMG Standard LEPs -> Red Deliberate lie : « do not feel the stimulus » -> Green
FZ
« Lie experiment » results in :
FCZ
• Absence of motor response to stimuli • Ehancement of a centroparietal « P3 »
CZ
CPZ
PZ L3P226- Nemo…
FP1*
F7*
REOG*
F3*
Sympathetic skinFC3* FT7* response (2-10 sec) T3*
FP2*
Motor response «reaction time» (250-300ms)
FZ*
F4*
F8*
FCZ*
FC4*
FT8*
C4*
T4*
CP4*
TP8*
P4*
T6*
O2*
A2 (TP10)*
C3* CZ*
TP7*
CP3* CPZ*
T5*
P3* PZ*
A1 (TP9)*
O1*
« early » lateralised response (N1: 150-180 ms)
«Vertex response» (N2-P2: 200 -350 ms)
VAS = 4/10 R/L
Subjective rating
Prie…doul MSG C4 rép augmentées côté douloureux Subject: EEG file: Prieur-C4dr-s1.avg Recorded : 10:18:48 08-Jan-2009 Rate - 500 Hz, HPF - 1 Hz, LPF - 30 Hz, Notch - 50 Hz FP1*
F7*
FT7*
T3*
TP7*
T5*
A1 (TP9)*
Neurosoft, Inc. SCAN 4.2 Printed : 19:17:00 09-Jun-2009 REOG*
FP2*
F3*
FZ*
FC3*
FCZ*
FC4*
FT8*
C3*
CZ*
C4*
T4*
CP3*
CPZ*
CP4*
TP8*
P3*
PZ*
P4*
T6*
O2*
A2 (TP10)*
O1*
F4*
F8*
Les PEL préservés affirment que la volée afférente a été transmise jusqu’aux aires corticales impliquées dans le traitement sensoriel de la douleur Pouvons-nous être sûrs que le patient a réellement perçu la stimulation ?
Motor response FP1*
F7*
F3*
FT7*
FC3*
REOG*
P1
FP2*
FZ*
FCZ*
F4*
N2
P1
Stim main droite: VAS 0 Stim main gauche: VAS 4 F8*
FC4*
FT8*
C4*
T4*
P2
T3*
N1 TP7*
C3*
N1 CP3*
T5*
P3*
O1*
L3P218
CZ*
CPZ*
CP4*
TP8*
PZ*
P4*
T6*
O2*
Motor response REOG*
FCZ
N2 CZ
P2
«P3»
CPZ
PZ
L3P218
0
900ms
Subject: EEG file: Prieur-C4ga-s1RCS.avg Recorded : 10:26:25 08-Jan-2009 Rate - 500 Hz, HPF - 1 Hz, LPF - 30 Hz, Notch - 50 Hz
Neurosoft, Inc. SCAN 4.2 Printed : 13:09:35 05-Oct-2009
Prieur RCS C4 MSG MSD
Electrode:REOG
-750.0 -500.0 -250.0 µV 0.0 250.0 500.0 750.0 -1.0
0.0
1.0
2.0
3.0
4.0 S
5.0
6.0
7.0
8.0
9.0
Subject: EEG file: Prieur-C4dr-s1RCS.avg Recorded : 10:18:48 08-Jan-2009 Rate - 500 Hz, HPF - 1 Hz, LPF - 30 Hz, Notch - 50 Hz
Neurosoft, Inc. SCAN 4.2 Printed : 13:10:56 05-Oct-2009
Electrode:REOG
-750.0 -500.0 -250.0 µV 0.0 250.0 500.0 750.0 -1.0
0.0
1.0
2.0
3.0
4.0 S
5.0
6.0
7.0
8.0
9.0
Prieur PEL C4 G
FP1*
F7*
FT7*
T3*
TP7*
T5*
A1 (TP9)*
REOG*
FP2*
F3*
FZ*
FC3*
FCZ*
FC4*
FT8*
CZ*
C4*
T4*
CP3*
CPZ*
CP4*
TP8*
P3*
PZ*
P4*
T6*
O2*
A2 (TP10)*
C3*
O1*
F4*
F8*
4. Can we predict neuropathic pain ?
Clinical neurophysiology allows to characterise abnormalities in patients who are already in pain. But can we also predict the occurrence of neuropathic pain in patients who have not yet developed painful symptoms ?
1)
Study of patients with potentially pain-inducing lesions, but having or not developed neuropathic pain
2)
Study of patients with pain-inducing anatomical lesions assessed before the (eventual) development of painful symptoms.
LEPs in focal brainstem lesions with / without pain pain (n=8)
no pain (n=11)
REOG*
REOG*
FZ*
FZ*
FCZ*
FCZ*
CZ*
CZ*
CPZ*
CPZ*
PZ*
PZ*
Lateralised (opercular) and vertex responses may be disociated
vertex response -
N2
P2
FCZCZFCZ-
-
spinal lesion
FCZ-
+ -0.10
0.00
0.10
0.20
0.30
0.40
0.50
0.60
0.70
0.80
0.90
0.80
0.90
S
lateralised response -
N1 T3-
T4T4T4-
+ -0.10
0.00
0.10
0.20
0.30
0.40 S
0.50
0.60
0.70
LEPs in focal brainstem lesions __ normal side __ affected side, non painful __ affected side, painful
Valo -10.0 -7.5 -5.0 -2.5 µV 0.0
Szy
2.5 5.0 7.5 10.0 -100.0 0.0
Ama
100.0 200.0 300.0 400.0 500.0 600.0 700.0 800.0 900.0 ms
Do not confound different modalities of clinical use 1- Diagnostic 2- Physiopathology – epidemiology
Patient A: normal
Group A: controls Patient B: abnormal
Group B: patients
Time and Time-Frequency averaging of LEPs Hz
Single-trials
n5
n5
n16
n16
n19
n19
Single-trials
Courtesy Léon Plaghki Time average (n = 30)
Time-frequency-power of time average
Hz
evoked Hz
ms
Average of time-frequency-power (n =30) induced X
TF-SI +3µV Amplitude variation relative to baseline
10Hz
Controls
TF-AV
200ms
-3µV
controls Wall, no pain
TF-SI
Wall-no pain
Wall, pain
TF-AV
Fréquency
TF-SI
Wall-Pain TF-AV
Normal side
Affected side
time Controls Wallenberg – non pain Wallenberg - pain
A pathway toward prediction ? 3.A Controls Non-pain patients Pain patients
AMAX
s
∆T/∆F
3.B
AMAX
1/ [∆T/∆F]
Three simple rules
• Use all the methods at your disposal • As a function of the clinical problem ! • stimulating the affected region !
• Do not stick to one technique • Avoid the city-lamp syndrome • look for the problem where the problem is
Nd:YAP laser, stim left hand (C6)
N2
Cz-nose
P2
T4-nose
N1 P1
Fp1-nose
T4-Fp1 N/P1-bip
0
200
400
600
800ms
Scalp topography of LEPs
N1/P1
‘N2’ 166 ms 181 ms P2
214 ms 242 ms 294 ms
322 ms
Localisation of suprasylvian sources of LEPs in 12 published studies (1993-2003) Y= -42 -> -18
X= 32-38
-18-> -10
40-44
-8 -> 4
46-50
6 -> 14
52-56
150-180 ms
Garcia-Larrea, Frot & Valeriani, Neurophysiol Clin 2003, 6: 279-283
Tal Coordinates X = 43 mm Y = 2 mm Z = 12 mm
Intensity
Frot M et al, 2004
200-350 ms Rolandic Fissure x = +5 mm
(2)
AC-PC
(1)
VAC VPC -200 -150 (1) -100 -50 µV 0 50 100 150 200 -100 150
y = +38mm z = +2mm
400
ms
650
900
-200 -150 (2) -100 -50 µV 0 50 100 150 200 -100 150
y = -12mm z = +43mm
400
650
900
ms
Garcia-Larrea, Frot & Valeriani, Neurophysiol Clin 2003, 6: 279
LEPs in practice •
Detection of lesions in pain / temperature pathways
•
Even very small lesions, if they are « correctly placed »
•
Semiological aspects still crude, need refining, but • Type of abnormality may change with lesion localisation • Type of abnormality may change with type of pain • Are abnormalities predictive?
•
Diagnosis of NP is supported by abnormal LEPs
•
In some cases, LEP may contradict the diagnosis of NP
Attention : LEPs reflect the deficit -not the pain itself!
Lésion plexullaire droite 2 ans auparavant Douleur paroxystique bras droit, topographie changeante … probable douleur neuropathique ? Stim: right median nerve
Stim: left median nerve Brachial plexus (distal to ganglion)
??
Dorsal horn, segmental
??
Brainstem
SI cortex SI cortex
0
10
20
30 ms
0
10
20
30 ms
All this was done with : Caroline Perchet Philippe Convers Michel Magnin Roland Peyron Maud Frot François Mauguière Patrick Mertens Bernard Laurent Carmen Montes …
