Rutin sinir iletim calismlarinin sinirlari Hatice TANKISI

Rutin sinir iletim çalıșmalarının sınırları

Hatice Tankiși, Associate professor, MD, PhdNörofizyoloji Departmanı, Aarhus Üniversite Hastanesi

VII. Korkut Yaltkaya Neurofizyoloji Sempozyumu, 21-23 Aralık, 2012, Antalya, Türkiye

Rutin sinir iletim çalıșmaları Çok eski bir teknik fakat hala en sık kullanılanı

1950, DISA A/S (Denmark)Keypoint® G4 Workstation

PC-BASE EMG SİSTEMLERI

Süre/sinir iletim hızı Amplitüd Geç yanıtlar (F-dalgası, H-refleksi) Temporal dispersion İletim bloğu Aksiyon potansiyellerinin süre ve formu

Rutin sinir iletim çalıșmaları

Supramaksimal uyarı kullanılır

Kalın miyelinli lif fonksiyonunu gösterir

Maksimal yanıtın amplitüd ve süresinin ölçümü ile akson sayısı ve saltatory iletim hakkında bilgi verir


Demiyelinizasyon

Aksonal kayıp


CMAP Amplitude

Median Ulnar Peroneal Tibialis

Mea

n de

crea

se in

CM

AP

am

p. in

SD

s

-5

-4

-3

-2

-1

0

*

*

*

SNAP Amplitude

Median dig I Median dig III Ulnar Sural

Mea

n de

crea

se in

SN

AP

am

p. in

SD

s

-8

-7

-6

-5

-4

-3

-2

-1

* *

Tankisi et al, Clin Neurophsiol 2007

● Demyelin □ Axonal *p<0.05,

53 aksonal PNP

144 duyu ve 145 motor sinir

45 demyelinizan PNP

112 duyu ve 132 motor sinir

Aksonal ve demiyelinizan PNP lerde amplitüd düșüklüğü

Tankisi et al. Clin Neurophysiol, 2007

İletim hızı ve amplitüd arasındaki ilișki

BKAP süresi ve amplitüdü arasındaki ilișki


BKAP süresi


Axonal loss

Demyelination

Near nerve tekniği ile duyu sinir iletim çalıșmaları

Rutin sinir iletim çalıșmalarının sınırlarıRutin sinir iletim çalıșmalarının bilgi vermediğikonular: Denervasyon ve reinnervasyon, nöromuskuler

transmisyon ve kas hastalıkları Motor birim sayısı Miyelinize olmayan C-lifleri ve ince miyelinize Aδ-

lifleri (ısı ve ağrı) Aksonların uyarılabilirliği, membran

potansiyelleri ve iyon kanal fonksiyonu





Elekromiyografi Spontan aktivite MÜP analizi (niceliksel ve niteliksel) Tam kası analizi (niceliksel ve niteliksel), turns

amplitüd analizi gibi Tek lif EMG’si Makro EMG

Denervasyon

Reinnervasyon

Elekromiyografi





MUNE (Motor unit number estimation)Motor birim sayısı bir kası innerve eden ön boynuz hücreleri veya aksonlarin sayısını gösterir Direk olarak motor unit sayısını ölçebilecek bir elektrofizyolojik teknik bulunmamaktadır O yüzden MUNE metodları kullanılmaktadır Daube, 2005

MUNE, alt motor nöron kaybi derecesi ve zamansal gelișimini gösteren en uygun elektrofizyolojik testtir

MUNE, hastalıkların teșhisi, takibi ve prognozunun belirlenmesinde ve ilaç tedavilerine yanıtı değerlendirmede faydalıdır

MUNE, ortalama yüzeysel kaydedilmiș motor unit potansiyelinin (SMUP) maksimal birlesik kas aksiyon potansiyeline (CMAP) bölünmesi temeline dayanır

MUNE (Motor unit number estimation)

Değișik MUNE Metodları MUNE metodları yüzeysel MUP (SMUP) nasıl elde

edildiğine göre değișir Inkremental stimulation Multiple point stimulation (MPS) Adapted MPS (AMPS) Statistiksel metod - submaksimal BKAP deki

değișimler ölçülür Spike triggered averaging –yüzeyel elektrodlarla

kaydedilmiș ve iğne EMG si ile tetiklenmiș ortalama MUP

MUNIX (Motor unit number index) Stimulus yanıt eğrileri/CMAP scan

“Hep ya da hiç” yanıtı

Aarhus’da MUNE deneyimi ALS’de incremental stimulation MUNE ve MUNIX

(Furtula et al, 2012) Polio’da MPS-MUNE ve MUNIX (veriler

değerlendiriliyor, Jan Nielsen) ALS’de MPS-MUNE, MUNIX ve CMAP Scan (PhD

projesi, Barıș İsak) GBS ve CIDP’de MPS-MUNE, MUNIX ve CMAP

Scan (Arastırma yılı projesi, Sansuthan Paramanathan)

Üst motor neuron hastalıklarında MPS-MUNE, MUNIX ve CMAP Scan (Ece Ünlü)

GBS’de CMAP Scan (Median sinir)Sağlıklı kontrol Demyelinizan GBS

Aksonal GBS

0

0,1

0,2

0,3

0,4

0,5

0,6

0,7

0,8

0,9

1

1,1

1,2

1,3

4 5 6 7 8 9 10 11 12Stimulation intensiten (mA)

CMAP

am

plitu

de (m

V)

MPS = 64 Munix = 39

MPS = 48MUNIX = 21

MPS = 256 Munix = 131

0

1

2

3

4

5

6

7

8

9

0 2 4 6 8 10 12 14 16 18 20 22 24

SI (mA)

Amp

(mV)

MPS = 256 Munix = 131

Maksimum BKAP nin %5, %50 ve %95’ini olușturan Sis (S5, S50 ve S95) Absolut SI aralıkları (S95–S5)Rölatif SI aralıkları (S95–S5)/S5)Step yüzdeleri (Blok et al., 2010)

ALS’de CMAP Scan (Median sinir)ALS

Çok etkilenmiș taraf

MPS = 188,46Munix = 150

0

1

2

3

4

5

6

7

8

9

0 2 4 6 8 10 12 14 16 18 20 22 24

SI (mA)

Amp

(mV)

MPS = 256 Munix = 131 Az etkilenmiș taraf

Sağlıklı kontrol





Küçük lif fonksiyonunun belirlenmesi

Büyük boyutlu nociceptiv olmayan afferentlerin elektriksel eșiği küçük boyutlu nociceptive afferenlere göre cok daha düșüktür

Özel teknikler (deneysel bloklar gibi) ya da özel organ uyarımları (kornea, dis eti, glans gibi) kullanılmadıkça, elektriksel uyarım nociceptive sinyalleri engelleyerek büyük affarent lifleri uyarır

Lazer uyarılmıș potansiyeller (LEPs)

Nociceptive yolların fonksiyonunu inceleyen en güvenilir ve kolay elektrofizyolojik yöntem

Radiant-ısı dalgaları seçici olarak yüzeyel derideki serbest sinir uçlarını (Aδ ve C) uyarır (Cruccu and Truini, 2010)

Ana sınırlaması sadece cok az merkezde uygulanıyor olması

neodymium:yttrium–aluminum–perovskite laser (Nd:YAP)

N2-P2 (vertikal kompleks) Cingulate girusun orta parcası

(MCC) Insular ve/vaya frontal

operkulum

N1 Sekonder somatosensoriyel alan

(SII) Posterior insula Pr. SSA (SI) (küçük bileşke) Dikkat ve algılamadan N2-P2 ye

göre daha az etkilenir Bipolar montajla daha büyük

potansiyeller elde edilir

(Cruccu et al, Clin Neurophysiol 2008)


Healthy subject

Patient 1

Patient 2

Erken küçük lif nöropatilerinin teșhisi zor olabilir

Yaklașık ½-1 saat sürebilir Habituasyon problem

Multisinaptik yollar hakkında bilgi verir PNS afferent Uzun spino- talamik yollar Talamo-kortikal yollar


Contact heat-evoked potansiyeller (CHEPs)

Hâlâ klinik geçerliliği gerekmekte olan yeni bir yöntem

Lazere göre daha büyük bir alan uyarılıyor

Iannetti et al, Physiol 2006

İğne deri biopsisi Aδ ve C sinir lifleri sayısal

olarak belirlenir ve intra-epidermal sinir lifleri (IENF) yoğunluğu ölçülür

Santral ağrıda ve demyelinizan nöropatilerde kullanılamaz

Sadece çok az sayıdaki merkezde uygulanabilir

Casanova-Molla et al, Pain 2011

Kvantitativ duyu testleri ve mikronöronografi

Kvantitativ duyu testi: Kontrollü dıș uyarımlara

karșı algılamayı test eder

Nöropatik olmayan ağrı durumlarında da değișiklikler gösterir

Zaman alıcı bir yöntem

Mikronöronografi: Miyelinize olmayan afferent

ve efferent nöronal trafiği incelemede önemli bir yöntem





Periferal sinirlerin elektriksel uyarimlarla test edilmesi

(Bostock)Sinir eksitabilite çalıșmaları: Submaksimal uyarı

kullanılır Özel uyarı yanıtlarını

ölçerek:

→ Aksonların uyarılabilirliği → Membran potansiyelleri → İyon kanal fonksiyonu

Sinir iletim çalıșmaları: Supramaksimal uyarı

kullanılır Maksimal yanıta karșı

amplitüd ve süre ölçümü ile:

→ Akson sayısı → İletim hızı

Sabrınız ve ilginiz için teșekkürler

Küçük lif fonksiyonunun belirlenmesi

Büyük boyutlu nociceptiv olmayan afferentlerin elektriksel eșiği küçük boyutlu nociceptive afferenlere göre cok daha düșüktür

Özel teknikler (deneysel bloklar gibi) ya da özel organ uyarımları (kornea, dis eti, glans gibi) kullanılmadıkça, elektriksel uyarım nociceptive sinyalleri engelleyerek büyük affarent lifleri uyarır

Stimulus Response Curve/CMAP Scan

Blok et al., 2010The Sis that elicited 5%, 50%, and 95% of the maximum CMAP (S5, S50, and S95) The absolute SI range (S95–S5), The relative SI range (S95–S5)/S5)Step percentage (sum of the step sizes of all steps relative to the maximum CMAP amplitude)

Microneurography Particularly important to

investigate efferent and afferent neural traffic in unmyelinated C fibers

Recordings of efferent discharges provide direct information about neural control of autonomic effector organs including blood vessels and sweat glands

Recordings of afferent discharges from muscle mechanoreceptors have been used to understand the mechanisms of motor control

Microneurography Particularly important to

investigate efferent and afferent neural traffic in unmyelinated C fibers

Recording of efferent discharges in postganglionic sympathetic C efferent fibers innervating muscle and skin provides direct information about neural control of autonomic effector organs including blood vessels and sweat glands

Recordings of afferent discharges from muscle mechanoreceptors have been used to understand the mechanisms of motor control

Recordings of discharges in myelinated afferent fibers from skin mechanoreceptors have provided not only objective information about mechanoreceptive cutaneous sensation but also the roles of these signals in fine motor control.

Unmyelinated mechanoreceptive afferent discharges from hairy skin seem to be important to convey cutaneous sensation to the central structures related to emotion.

Recordings of afferent discharges in thin myelinated and unmyelinated fibers from nociceptors in muscle and skin have been used to provide information concerning pain.

Recordings of afferent discharges of different types of cutaneous C-nociceptors identified by marking method have become an important tool to reveal the neural mechanisms of cutaneous sensations such as an itch.

No direct microneurographic evidence has been so far proved regarding the effects of sympathoexcitation on sensitization of muscle and skin sensory receptors at least in healthy humans

Microneurography

Microneurography Microneurography provides useful peripheral neural

information concerning autonomic, motor and sensory functions in humans.

This method is a particularly important tool to analyze directly neural mechanisms underlying autonomic functions under normal and abnormal conditions.

Sympathetic microneurography has achieved an stable position in human autonomic testing.

By using this method, the detailed neural mechanisms underlying autonomic dysfunctions often encountered in neurological diseases such as orthostatic hypotension, sleep apnea, and sweat disturbances have been elucidated in detail as well as in cardio- and renovascular impairment.

Microneurography Microneurography also provides valuable information

concerning peripheral afferent mechanisms of motor control.

This technique provides an invaluable approach to the peripheral mechanisms involved in sensory functions of various modalities by identifying objective signals traveling in sensory afferent nerves.

In the future this method may be more and more employed in combination with other parameters of clinically neurophysiological, psychological/psychophysical, and neuroradiological methods, including functional magnetic resonance imaging and positron emission tomography, as a key approach to the central mechanisms of information processing of peripheral neural signals.

DISA 1500, Digital EMG System 1976 In 1950, DISA A/S (Denmark)

introduced a three channel EMG system capable of displaying and recording waveforms from each channel.

Nicolet Viking Microprocessor controlled EMG System, 1985

PC-BASE EMG SYSTEMS: 1993

MICROPROCESSOR-CONTROLLED EMG SYSTEMS: 1982-1993 PC-BASE EMG SYSTEMS: 1993–2001 HANDHELD & WIRELESS EMG SYSTEMS: 2001-PRESENT DAY

Nicolet Viking EMG System, 1985

Routine nerve conduction studies Use supramaximal stimuli Measure large myelinated

fibre function Show functional changes in

conduction velocity which may not persist with time

Measure amplitude and latency/conduction velocity of maximal response

Assess number of axons and saltatory conduction

Correlation between SNAP amplitude and sensory CV

○ Demyelin.● Axonal❃

Correlation (p<0.05)

Median (digit I) Median (digit III)

Sural Ulnar

Decrease in CV (SD)

Decr

ease

in S

NAP

ampl

itude

(SD)

**

**

*


MUNE (Motor unit number estimation)Motor unit number refers to the number of anterior horn cells or axons innervating and controlling a single muscle. Motor unit number is a critical measure in any disease involving injury or death of motor neurons or motor axons. There is no electrophysiologic technique that allows for simple direct measurement of motor unit number. By providing an accurate estimate of motor unit number, MUNE provides insight into the underlying disorder, its distribution and severity.

MUNIX and IS MUNE in control subjects and ALS patients 48 control subjects and

14 ALS patients Retest on 14 control

subjects and follow-up on 6 ALS patients

(Furtula et al, 2012 in press)

Sensitivity: MUNIX: 0.77 IS MUNE: 0,31

MUNIX and IS MUNE in controls subjects and ALS patients

Individual values of CMAP, MUNIX and IS of 6 patients at inclusion and during follow-up.

Validity of MUNIX and IS MUNE in ALS patients

(Furtula et al, 2012 in press)

CMAP amplitude and MUNIX decreased in follow-up but IS MUNE did not decrease significantly

MUNIX and IS MUNE in controls subjects and ALS patients

Conclusion: MUNIX is a useful MUNE indicator to assess

progression of LMN affection MUNIX has lower intrasubject variability than IS MUNIX has a better sensitivity than IS

MPS and MUNIX in control subjects and polio patients

8 controls and 8 patients with history of polio

MPS MUNE and MUNIX MUAP duration, peak ratio

analysis and force measurement

patient control

MPSMUN: 1,00 mps

3,02,01,00,0

MPS

MUNE

400

300

200

100

0

MPSMUN: 2,00 munix

3,02,01,00,0

MUNIX

500

400

300

200

100

0

patient control


No significant correlation was found between QEMG changes and MPS MUNE and MUNIX in m. APB MUAP Duration

20151050

MP

S M

UN

E

120

100

80

60

40

20

0

Peak-ratio (nr/sec.pr.uV)

1,0,8,6,4,20,0

MP

S M

UN

E

120

100

80

60

40

20

0

Peak-ratio (nr/sec pr. uV)

1,0,8,6,4,20,0

MU

NIX

160

140

120

100

80

60

40

20

0

MUAP Duration

20151050

MU

NIX

160

140

120

100

80

60

40

20

0

p=0,101

p=0,111p=0,056

p=0,779


Conclusion: MPS MUNE and MUNIX are not well

correlated with QEMG methods probably due to they measure different parameters

MUNE can be a supplement for QEMG

Assesment of small-fiber function Large-size, non-nociceptive afferents (i.e., those that

do not carry pain) have a lower electrical threshold than small-size, nociceptive afferents.

Unless special techniques are used, i.e., experimental blocks or stimulation of special organs (cornea, tooth pulp, glans), electrical stimuli unavoidably also excite large afferents, thus hindering nociceptive signals.

Hence standard neurophysiological responses to electrical stimuli, such as nerve conduction studies and somatosensory- evoked potentials (SEPs), can identify, locate, and quantify damage along the peripheral or central sensorypathways, but they do not assess nociceptive pathway function.

For many years researchers have tried numerous techniques for selectively activating pain afferents.

Laser evoked potentials (LEPs) The most reliable and widely

accepted diagnostic tools for assessing nociceptive pathway function are laser evoked potentials (LEPs) and skin biopsy

The currently preferred approach uses laser stimulators to deliver radiant-heat pulses that selectively excite the free nerve endings (Ad and C) in the superficial skin layers.

Consensus from over 200 studies now confirms that late laser-evoked potentials (Ad-LEPs) are nociceptive responses.

LEPs are the easiest and most reliable neurophysiological tools for assessing nociceptive pathway function and are diagnostically useful in peripheral and central neuropathic pain.

In clinical practice, their main limitation is that they are currently available in too few centres.

Ultralate LEPs (related to C-fibre activation) are technically more difficult to record, and few studies have assessed their usefulness.

Laser evoked potentials (LEPs)

Contact heat-evoked potentials (CHEPs)

A recent development that still need clinical validation

The thermode for contact heat stimulation activates a larger surface area than the laser stimulation

CHEPs may be considered a robust technique for the evaluation of patients with sensory neuropathy, whereas LEPs might be more sensitive than CHEPs to the loss of IENF

Iannetti et al, Physiol 2006

Quantitative sensory testing Analyses perception in response to external stimuli of controlled intensity Detection and pain thresholds are determined by applying stimuli to the

skin in an ascending and descending order of magnitude. Mechanical sensitivity for tactile stimuli is measured with plastic filaments

that produce graded pressures, such as the von Frey hairs, pinprick sensation with weighted needles, and vibration sensitivity with an electronic vibrameter. Thermal perception and thermal pain are measured using a thermode, or other device that operates on the thermoelectric effect. QST has been used for the early diagnosis and follow-up of small-fibre neuropathy that cannot be assessed by standard NCS, and has proved useful in the early diagnosis of diabetic neuropathy.

QST is also especially suitable for quantifying mechanical and thermal allodynia and hyperalgesia in painful neuropathic syndromes, and has been used in pharmacological trials to assess treatment efficacy on provoked pains [2].

QST abnormalities, however, cannot provide conclusive evidence of neuropathic pain, because QST shows changes also in non-neuropathic pain states, such as rheumatoid arthritis and inflammatory arthromyalgias. QST is time-consuming and thus difficult to use in clinical practice [2].

Microneurography is particularly important to investigate efferent and afferent neural traffic in unmyelinated C fibers.

The recording of efferent discharges in postganglionic sympathetic C efferent fibers innervating muscle and skin (muscle sympathetic nerve activity; MSNA and skin sympathetic nerve activity; SSNA) provides direct information about neural control of autonomic effector organs including blood vessels and sweat glands.

Sympathetic microneurography has become a potent tool to reveal neural functions and dysfunctions concerning blood pressure control and thermoregulation.

This recording has been used not only in wake conditions but also in sleep to investigate changes in sympathetic neural traffic during sleep and sleep-related events such as sleep apnea. The same recording was also successfully carried out by astronauts during spaceflight.

Recordings of afferent discharges from muscle mechanoreceptors have been used to understand the mechanisms of motor control.

Muscle spindle afferent information is particularly important for the control of fine precise movements.

It may also play important roles to predict behavior outcomes during learning of a motor task.

Microneurography

Correlation between CV and CMAP amplitude

Median Peroneal

Tibial Ulnar

**

*

**

Decrease in CV (SD)

Decr

ease

in C

MAP

am

plitu

de (S

D)

○ Demyelin.

● Axonal❃Correlatio

n (p<0.05)


Cutaneous silent period (CSP)

CSPElectric stimulation

CSPLaser stimulation

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Rutin sinir iletim calismlarinin sinirlari Hatice TANKISI