LA SAPIENZA UNIVERSITY

Clinical Neurophysiology of PainG. CRUCCU, G.D. IANNETTI, A. TRUINIEFNS Panel Neuropathic Pain, ViennaDept. Neurological Sciences, Rome

1. Scales and Questionnaires

3. QST (quantitative sensory testing)

4. Neurophysiological Methods

5. Functional Neuroimaging

2. Clinical Examination

6. Biopsy

EFNS Guidelines on Pain EFNS Guidelines on Pain Assessment (2004)Assessment (2004)

Standard electrodiagnostics

Standard neurophysiological tests (NCS, SEP)• are useful to demonstrate, quantify and localise a lesion along the sensory pathways • cannot assess small-fibre funcion

NCS SEP

Serra Marchettini

Ochoa 1998

Torebjoerk & Ochoa l990

Microneurography

Although it has provided important pathophysiological information, microneurography is time consuming and difficult, requiring both an expert investigator and a collaborative patient; hence it is unsuitable for clinical applications (Good Practice Point)

the R1 Blink Reflex and the SP1 Masseter Inhibitory Reflex, although non-nociceptive, have great diagnostic value in differentiating Classical from Symptomatic Trigeminal Neuralgia (level A evidence).

(Cruccu et al, (Cruccu et al, Neurology Neurology 2006)2006)

Blink Reflex: Aβ

Masseter Inhibitory Reflex: Aβ

Trigeminal Reflexes

Trigeminal Trigeminal Reflexes in Pain Reflexes in Pain

associated to associated to Multiple Sclerosis Multiple Sclerosis

(Cruccu et al, (Cruccu et al, Pain Pain 2009)2009)

Ons

et A

ge

Bila

tera

l

Uni

late

ral

Sens

ory

defic

it

Nor

mal

sen

sitiv

ity

Abn

orm

al T

R

Nor

mal

TR

0

25

50

75

100 CTNSTN

**

* * **

norm

aliz

ed fr

eque

ncy

(%)

or o

nset

age

(yea

rs)

Response to treatment and involvement of first trigeminal division are similar in the two populations. Onset age is lower in CTN than STN (P <0.0001). Bilateral neuralgia and sensory deficits only occur in STN (P <0.001). Trigeminal reflexes (TR) are abnormal in STN (87%) and normal in CTN (94%) (P <0.0001). Data from 10 trials (Class I-III) in 628 patients.

Differential Differential diagnosis diagnosis

between CTN between CTN and STNand STN

(from the AAN-(from the AAN-EFNS guidelines on EFNS guidelines on

trigeminal trigeminal neuralgia 2008)neuralgia 2008)

Cutaneous Silent Period

(Truini et al Muscle Nerve 2008)

CSP LEP

Nociceptive Reflexes

Nociceptive reflexes, such as the RIII flexion reflex, the cutanous silent period and the corneal reflex, have little diagnostic value (grade C statement). But the RIII flexion reflex appears to be the most reliable tool in assessing treatment effects (grade B recommendation).

(Garcia-Larrea et al, (Garcia-Larrea et al, Arch Med ResArch Med Res 2000) 2000)

Lower limbRIII flexion

reflex

Laser Evoked Potentials (LEPs)Laser Evoked Potentials (LEPs)

Laser stimulators raise very quickly the temperature Laser stimulators raise very quickly the temperature in the in the superficial layers of the skin, superficial layers of the skin, selectively excite free nerve selectively excite free nerve endings (mostly Aendings (mostly A and C nociceptors) and provide a and C nociceptors) and provide a synchronous afferent volley that is easily recorded from the synchronous afferent volley that is easily recorded from the scalp (over 200 studies have been published, including several scalp (over 200 studies have been published, including several top Class)top Class)

Signals and generators

Garcia-Larrea et al 2003 Truini et al 2003

LEPs in central neuropathic pain and nonorganic pain

Garcia-Larrea et al Brain 2002

In central neuropathic pain (spinal, brainstem, thalamo-In central neuropathic pain (spinal, brainstem, thalamo-cortical) LEPs are suppressed after stimulation of the cortical) LEPs are suppressed after stimulation of the painful territory, even if the laser pulses evoke painful territory, even if the laser pulses evoke hyperalgesia, and may distinguish neuropathic from non-hyperalgesia, and may distinguish neuropathic from non-organic painorganic pain

Spinal pathway conduction of A and C inputs

(Iannetti et al (Iannetti et al J NeurophysiolJ Neurophysiol. 2003). 2003)

Trigeminal Trigeminal C-LEPsC-LEPs

(Cruccu et al, (Cruccu et al, Brain Brain 2003)2003)

Because of the short conduction distance and a high receptor density, the trigeminal territory is even more advantageous for eliciting (with low-intensity large-spot pulses) “ultralate” LEPs (N2 latency about 280 ms), mediated by unmyelinated C afferents (conduction velocity 1.2 m/s).

highest density of C receptors

Trigeminal C LEPsTrigeminal C LEPs

(Cruccu et al, (Cruccu et al, Brain Brain 2003)2003)

Patients with trigeminal neuropathy:

axonal loss of all myelinated fibre groups

unmyelinated fibres spared Aδ-LEPs absent C-LEPs normal

C-LEPs in patients:Trigeminal Laser evoked potentials in

Wallenberg syndrome

(Cruccu et al (Cruccu et al BrainBrain 2003) 2003)

General results of

LEP studies in

peripheral neuropathic

pain

Truini et al NSL 2004

LEP abnormalities (%) Disease normal delay absence

n LEP type References

73 21 6 52 T 1Agostino et al 2000

[1] Diabetic

neuropathy 38 2 60 45 H-F

2Agostino et al 2000

[3]

Postherpetic neuralgia 35 0 65 40 V 2Truini et al 2003 [20]

Small fibre neuropathy 0 30 70 10 H-F 2Truini et al 2004 [21]

Essential trigeminal neuralgia

49 35 16 47 T 1Cruccu et al 2001 [10]

Symptomatic trigeminal neuralgia

0 64 36 20 T 1Cruccu et al 2001 [10]

13 50 37 30 H-F Kakigi et al 1992 [13] Various

neuropathies 60 0 40 5 H-F 3Signle case reports

total abnormality frequency 68 % 251 all

Specificity/Sensitivity of LEPs vs. SEPs

(Garcia-Larrea and Cruccu, in preparation)(Garcia-Larrea and Cruccu, in preparation)Data from 28 studies in 441 patients

Pain in Carpal Tunnel Syndrome

(Truini et al, (Truini et al, Pain Pain 2009)2009)

PHNPHN

Correl. Correl. Pain vs. Pain vs. R1 R1 AA-LEP -LEP C-LEPC-LEPresponsesresponses

SignificantSignificantat least at least P<0.01P<0.01(Truini et al Pain (Truini et al Pain 2008)2008)

LEPs assessing response to treatment

(Truini et al, (Truini et al, Eur J Pain Eur J Pain 2009)2009)

(Iannetti et al, J Physiol, 2007)(Iannetti et al, J Physiol, 2007)

CHEPs CHEPs vs. LEPsvs. LEPs

0 1 2 3 4 sec

Myelinated-fibre NeuropathyMyelinated-fibre Neuropathy

(Truini et al, Pain 2007)(Truini et al, Pain 2007)

Author Group Group Controlsyear A/n A/n A/nLefaucheur broad SF + SF spared2004 18/20 8/25Atherton broad 24/41 SN-IEFN 0/9 <0.0022007 reduced reduced corr <0.001Schestatsky narrow PD-CP PD2007 enhanced normalObermann broad TN ATN2007 delayed enhanced

Schestatsky 200914 meralgia paresthetica and 14 controlsCHEPs narrow ns ns clinical /NCSreduced in amplitude

diff contr<0.001

IV

Obermann 19 HIV 9 controls narrow 11/19 0/9 <0.01 III2008 reducedChao narrow SN-CHEP SN-IEFN diff contr <0.00012008 reduced reduced corr <0.0001Devigili narrow ns ns IV2008Truini broad 22/41 4\412008Truini 70 CTS broad y y painful hand painless <0.01 96% 29%2009 76 hands with pain and 14/48 1/27de Tommaso 34 CTS and 23 narrow ? ns III2009

Truini broad 27/41 12\412008

I

clinical /NCS

ns 100%clinical/ laborat.

Adelta LEP

Adelta LEP clinical /NCS

I

I

54%

clinical <0.005 71% 66%41 PHN Ophthalmic y yC-LEP

clinical <0.001 91%41 PHN Ophthalmic y yAdelta LEP

25 painful neuropathy and 25 controls

ns ns

41 sensory neuropathy and 9 controls

ns y

CHEPs /IENF

CHEPs /IENF

PREP /IENF y

IV

clinical /NCS

100% 59%

Adelta-LEP clinical

Class

I68%

IV

IV

clinical /NCS

clinical

58%

18 PDN and 9 controls ns ns

24 TN and 18 ATN ns nsPREP <0.05

Method Signif. Specif.

IV

90%clinicalAdelta-LEP y y <0.0002

10 painful neuropathy and 18 controls

Adelta LEP /IENF

clinical /NCS

Sensit.Ref. Standard

Patients Blind Prosp.Spectrum

45 sensory neuropathy

Evidence Table LEPsEvidence Table LEPs

Andrea Truini

Giandomenico Iannetti

Giorgio Cruccu

THANKS FOR YOUR

ATTENTION