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Clinical Neurophysiology: New Clinical and Research

Applications

Yew-Long LOHead & Senior Consultant Department of Neurology

National Neuroscience InstituteSingapore General Hospital

EditorShin Yi QUEK

Published by White Cells Series

An imprint under SingHealth Academy, Singapore Health Services Pte Ltd

31 Third Hospital Avenue, #03-03 Bowyer Block C, Singapore 168753

SingHealth Academy Publishing Team:

Quek Shin Yi, Benny Chung, Sukhvinder Kaur, Lee Fengting

Copyright © 2013 Singapore Health Services Pte Ltd.

Photographs on inner book cover by Yew-Long Lo. All other images by Singapore General Hospital.

All rights reserved. No part of this publication may be reproduced, stored in a retrieval system

or transmitted, in any form or by any means, electronic, mechanical, photocopying, recording

or otherwise, without the prior permission of the copyright owner. Request for permission

should be addressed to The Publisher, c/o The Editorial Office, SingHealth Academy, 168 Jalan

Bukit Merah, Tower 3 #06-07, Singapore 150168. Tel: (65)6377-8649, Fax: (65) 6377-4262.

Email: [email protected].

The publisher makes no representation or warranties with respect to the contents of this book,

and specifically disclaims any implied warranties or merchantability or fitness for any particular

purpose, and shall in no event be liable for any loss of profit or any other commercial damage,

including but not limited to special, incidental, consequential, or other damages.

National Library Board, Singapore Cataloguing-in-Publication Data

Clinical neurophysiology : new clinical and research applications / Yew-Long Lo ;

editor, Shin Yi Quek. – Singapore : White Cells Series, c2013.

p. cm.

ISBN : 978-981-07-5154-8

1. Neurophysiology – Research. 2. Nervous system – Diseases – Diagnosis.

3. Electrodiagnosis. I. Shin, Yi Quek, 1987- II. Title.

RC553.C64

616.80465—dc23 OCN824352665

iii

Foreword viiPreface ixAcknowledgements x

Section 1 Nerve Conduction Study 2Chapter 1 Carpal Tunnel Syndrome 4 1.1 Sensory Nerve Conduction Study 4

Chapter 2 Ulnar Neuropathy 10 2.1 Mixed Nerve Conduction Study 10

2.2 Short-Segment Studies 17

2.3 Distal Ulnar Lesions 24

Chapter 3 Brachial Plexopathy 32 3.1 Mixed Nerve Conduction Study 32

3.2 Motor Root Conduction in Brachial Neuritis 39

3.3 Motor Root Conduction in Traumatic Brachial Plexopathy 50

3.4 Pectoral Nerve Conduction Study 55

3.5 Lower Subscapular Nerve 60

Chapter 4 Radial Neuropathy 66 4.1 Posterior Antebrachial Cutaneous Nerve 66

4.2 Posterior Antebrachial Cutaneous Nerve in Radial Neuropathy 71

Chapter 5 Peroneal Neuropathy 78 5.1 Deep Peroneal Sensory Nerve 78

5.2 Superficial Peroneal Sensory Nerve 85

Chapter 6 Polyneuropathy 90 6.1 Laterality Index in Sensorimotor Neuropathy 90

Chapter 7 Meralgia Paraesthetica 96 7.1 Lateral Femoral Cutaneous Nerve 96

7.2 Medial Femoral Cutaneous Nerve 103

Contents

iv

Chapter 8 Cervical Radiculopathy 106 8.1 F Waves 106

Chapter 9 Spinal Cord Disorders 112 9.1 Cutaneous Silent Period 112

9.2 Cervical Whiplash Injury 121

Section 2 Electromyography 138Chapter 10 Myokymia 140Chapter 11 Radiation Injury 148Chapter 12 Laryngeal Electromyography 154Chapter 13 Other Neurological Conditions 164 13.1 Myorhythmia and Interferon 164

13.2 Myorhythmia and Stroke 167

13.3 Bilateral Trapezius Hypertrophy 170

13.4 Adefovir-Associated Myopathy 172

13.5 Orthostatic Tremor 175

Section 3 Neuromuscular Transmission 178Chapter 14 Repetitive Nerve Stimulation 180 14.1 Area Decrement 180

14.2 Effect of Exercise 185

14.3 Repetitive Nerve Stimulation of Hypoglossal Nerve 191

14.4 Repetitive Nerve Stimulation of Long Thoracic Nerve 198

14.5 Presynaptic Neuromuscular Transmission Defect 203

Chapter 15 Single Fibre Electromyography 208

Section 4 Transcranial Magnetic Stimulation 220Chapter 16 Cervical Disorders 222 16.1 Cervical Myelopathy and MRI 222

16.2 Cervical Myelopathy and Screening 240

16.3 Pectoralis Motor Evoked Potentials in Cervical Spondylosis 248

Chapter 17 Anti-GQ1b IgG Disorders 256 17.1 Miller Fisher Syndrome and Corticospinal Dysfunction 256

17.2 Miller Fisher Syndrome and Corticobulbar Dysfunction 265

17.3 Bickerstaff's Brainstem Encephalitis 271

v

Chapter 18 Motor Control 276 18.1 Cortical Silent Period Threshold 276

18.2 Lower Limb Ipsilateral Silent Period 284

18.3 Interhemispheric Inhibitory Motor Control 292

18.4 Motor Imagery 300

18.5 Cortical Excitability in Deception 309

18.6 Cortical Excitability in Vocalisation and Musical Tasks 316

18.7 Cortical Excitability Changes in Acupuncture 322

18.8 Cortical Plasticity Changes in Acupuncture 328

18.9 Cerebellar Motor Control 337

18.10 Neurovascular Coupling: TMS and Near-Infrared

Spectroscopic Imaging (NIRS) 354

Chapter 19 Other Applications Of TMS 368 19.1 Cerebellar Control and Miller Fisher Syndrome 368

19.2 Magnetic Facial Nerve Stimulation 378

19.3 Magnetic Hypoglossal Nerve Stimulation 384

19.4 Migraine and Cortical Excitability 390

19.5 Magnetic Stimulation and Tinnitus 399

19.6 Spinal Magnetic Stimulation and Pain 405

Section 5 Intraoperative Monitoring 412Chapter 20 Somatosensory Evoked Potentials 412

20.1 Intraoperative Monitoring for Spinal Surgery 414

20.2 Preoperative Somatosensory Evoked Potentials 421

Chapter 21 Intraoperative Electromyography 424Chapter 22 Intraoperative Motor Evoked Potentials 428 22.1 Desflurane 428

22.2 Propofol Total Intravenous Anaesthetic Regimens 435

22.3 Ipsilateral Motor Evoked Potentials 443

22.4 Bilateral Motor Evoked Potentials 451

22.5 Cortical Stimulation Position 456

Section 6 Autonomic Function Tests 466Chapter 23 Sudomotor Dysfunction 468Chapter 24 Cardiovascular Dysautonomia 476

vi

Section 7 Ultrasound And Neurophysiology 480Chapter 25 Ultrasound and Radial Neuropathy 482Chapter 26 Ultrasound and Peroneal Neuropathy 492Chapter 27 Ultrasound and Bell's Palsy 498 Appendix A1 –10Bibliography B1–9Common Abbreviations C1Index I1 –4Postscript

vii

It is a pleasure to prepare a foreword for the work by Dr. Yew-Long Lo, whose academic

progress I have witnessed for some time. I have seen many notable contributions he has

made, covering the central and peripheral nervous systems. This book comprises about 500

pages on new applications of Clinical Neurophysiology methods mostly compiled from his

own original papers. Amassing this body of work, he now presents the treatise with added

clinical notes and flowcharts to document the bases of electrophysiologic examination.

The recent advent of technology has seen proliferation of new scientific methods ranging

from molecular biology to neuroimaging. They have helped answer questions on the human

nervous system that researchers have wondered about for a very long period of time.

These methods have gradually found their way into clinical medicine, leading to dramatic

changes in medical practice. Despite such a shift in landscape, Clinical Neurophysiology has

managed to remain relevant to patient care. I welcome Dr. Lo’s effort and enthusiasm to

encourage continued developments of this discipline, which I have followed closely during

the last twenty years.

The field of Clinical Neurophysiology has also made tremendous progress over the

last several decades, and is now a scientific field with far-reaching applications. Its role in

evaluating function, monitoring changes, and, of late, therapeutic modulation of the nervous

system will certainly be enhanced in the years to come. In many ways, this book depicts

the various roles in which Clinical Neurophysiology plays in its contribution to medicine,

both within and beyond the Neurosciences. It describes a well-balanced overview so that

clinicians understand and appreciate their proper use.

Neurologists consider neurophysiologic analyses as an extension of the physical

examination, which, therefore, dictates the overall approach of the study to supplement

clinical findings. These techniques contribute in elucidating topographic localisation

and grading the degree of functional involvement. The book instructs the principles of

electrodiagnosis in a rigorous but unique way, allowing the reader to learn the breadth and

depth of its technology to complement the practice of Neurology.

Foreword

viii

Dr. Lo has successfully covered the topics to discuss the needs of medical practitioners

engaged in Clinical Electrophysiology. It provides a comprehensive analysis of many

frequently posed questions. I recommend this volume highly to anyone interested in clinical

application of electrodiagnostic practice, with the conviction that readers will find many

valuable pointers amongst its pages. I hope it will be widely used by Neurologists who are

active in the field, adding substantially to the education of young colleagues.

Jun Kimura, MD

Professor of Neurology, University of Iowa

Professor Emeritus, Kyoto University

Past President, World Federation of Neurology

ix

When I was first exposed to basic nerve conduction studies as a Neurology trainee,

the ability to record electrical signals in humans fascinated me a great deal. Going through

multiple routines of carpal tunnel syndrome or peripheral neuropathy evaluations, it

soon occurred to me that very much more value can be added to current capabilities of

electrodiagnosis. This book, henceforth, details my journey through Clinical Neurophysiology,

primarily with this objective in mind. Secondarily, the field has empowered the Neurologist

or Neuroscientist towards a deeper understanding of both central and peripheral nervous

system function, pointing them towards clinically relevant research directions.

This book will probably engage more advanced practitioners of the field, but junior

colleagues may also benefit from appreciating the workflow and thought processes

involved in patient management. I have also taken the liberty to include clinical notes for

rationalisation of each technique in the clinical context.

While the book has been divided into collections of materials for each electrodiagnostic

technique, it was felt that practical approaches, based on routine patient encounters, would

be most apt. To this end, the appendices attempt to fill this gap by integrating the presented

material in a logical thought process.

Clinical Neurophysiology is a scientific domain that is highly collaborative, both within

Neurology, Neuroscience, as well as other medical subspecialties. I am hopeful that in this

way, the efforts invested in this publication will benefit a wider audience.

Yew-Long, LO

Head & Senior Consultant

Department of Neurology

National Neuroscience Institute

Singapore General Hospital

Singapore Health Services Pte Ltd

Preface

x

The production of this book has taken over 3 years, from conceptualisation to press. I

am highly indebted to Ms Quek Shin Yi and the SingHealth Academy for seeing the entire

project through. Without the expert editing, art direction, organisation, production and,

most of all, encouragement I received, I would have lost faith midway.

I am grateful for the financial support and patience provided by Transmedic Pte Ltd. It is

our mutual belief that the project will benefit practitioners of Clinical Neurophysiology at

every level.

I am most humbled and inspired by Professor Jun Kimura’s encouraging words of support

in his Foreword for this publication. Professor Kimura has been a role model, champion

and constant source of inspiration for Neurologists and Clinical Neurophysiologists alike.

His humility, passion and approachability are qualities that all of us look to emulate, but will

unlikely achieve.

Although 3 years seem short for a scientific publication, much of the content reflects

some 2 decades of work in this field. The dedication of my collaborators from the

Neurodiagnostic Unit, and my colleagues from the Neurology Department, Singapore

General Hospital has humbled me greatly. Specifically, I thank previous co-authors Drs

Kerry Mills, Pavanni Ratnagopal, Siew Ju See, Prakash Kumar, Eng King Tan, Simon Ting, David

Lau, Stephanie Fook-Chong, Wei Yi Ong, Ling Ling Chan, Sitaram Raman, Jane George, Yew

Meng Chan, Cun Tai Guan and the spine surgery team from the Singapore General Hospital

for their valuable contributions. Obviously, many of my previous publications would not

have materialised without the generous support from the National Medical Research

Council and Ministry of Health, Singapore.

Mostly, I would like to express my sincere gratitude to the patients and healthy control

subjects from which we obtained valuable clinical data. You have contributed greatly towards

the understanding of human nervous system function, which will eventually lead to better

treatment of neurological disorders.

Acknowledgements

xi

If I had omitted any esteemed acquaintance from this seemingly endless list, rest assured

it is purely unintentional. Most certainly, it is consequential of an ever expanding network of

collaborators often encountered in the specialty of Clinical Neurophysiology. The valuable

experiences derived from learning and working together cannot be matched in any

other way.

YL Lo

222

INTRODUCTION

Cervical spondylotic myelopathy (CSM) is a progressive, degenerative mechanical

compression of the cervical cord, with impingement by osteo-cartilaginous elements

within the spinal canal1,2. It is mostly a slow and gradual process3 in which patients

present at various clinical stages of severity4. Most studies, largely using plain radiography

and myelography, have correlated clinical signs with electrophysiological findings5–7.

Conflicting results have been reported in studies relating electrophysiological changes

and levels of cord compression8,9. Conversely, it has been reported that corticospinal

abnormalities can exist in asymptomatic patients with radiological cord compression on

myelography, CT myelography and MRI10,11.

Transcranial magnetic stimulation (TMS) is a quick, safe, and painless technique to study

conduction in the descending corticospinal pathways12–15. It involves motor cortex

stimulation by means of magnetic flux. The conduction time from the motor cortex

to the anterior horn cell (central motor conduction time (CMCT)) is a measure of the

integrity of corticospinal pathways. TMS has been effectively used to assess corticospinal

abnormalities in multiple sclerosis16,17, motor neuron disease18,19 and degenerative

ataxias20. It has also contributed to the evaluation of dynamic subclinical corticospinal

abnormalities in the Miller Fisher syndrome21.

Cervical Disorders1616.1 CERVICAL MYELOPATHY AND MRI

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IV

CERVICAL MYELOPATHY AND MRI

There are no large studies addressing systematic correlation between TMS findings and

MRI abnormalities in patients with various degrees of CSM. This study aims to critically

analyse the actual correlation of TMS findings with the degree of cord compression on

MRI scans in patients presenting with symptoms and signs suggestive of CSM.

Secondarily, this study aims to determine if TMS can be potentially used to screen

warranted cases for early MRI, with view to surgery, hence saving health costs by

reducing or delaying the need for an expensive imaging technique.

METHODS

Participants One hundred and forty-one patients (46 females) with a mean age of 51 years (range: 36

to 78) were prospectively entered into the study over a 3.5-year period. They were referred

with a clinical diagnosis of CSM after consultation with an experienced orthopaedic

surgeon. Presenting symptoms included bilateral hand or feet numbness, difficulty

walking, clumsiness or weakness of limbs, neck pain, radicular symptoms and cramps. A

detailed history, physical examination by a neurologist and relevant investigation were

included to rule out other conditions which may confound the study. Patients who were

not fit for TMS study or did not undergo MRI within the allocated time frame of eight

weeks were excluded.

Twenty-five healthy volunteers (nine females) with an age range of 20 to 75 years were

also entered into the study with informed consent. Controls were screened strictly to

exclude cervical disease and other neurological problems by the authors.

During the period of study, two patients with motor neuron disease, two with

demyelinating disease, three with stroke and one with syringomyelia were incidentally

encountered. TMS, MRI and electrophysiological studies were performed on them

as well.

Materials and Procedure MRI

All patients had MRI of the cervical spine on either a 1.0 T or 1.5 T superconducting unit,

using the tailored cervical spine phased-array coil. The following pulse sequences were

used with a 3 mm section thickness and a 0.3 mm gap: (a) sagittal turbo spin-echo T1-

weighted (600 –660 ms/12 ms/2 [TR/TE/excitations]), (b) sagittal turbo spin-echo T2-

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CERVICAL DISORDERS

weighted (4500 ms/112 ms/3, echo train length 15) and (c) axial gradient-echo (500–660

ms/22 ms/2, flip angle 30 degrees) sequences. The sagittal sequences were obtained

using a 188 x 250 mm field of view (FOV) and a 180–240 x 256 matrix; and the axial

sequences, a 175 x 200 mm FOV and 192–256 x 256 matrix.

The patients were separated into four groups according to the degree of cord

compression by degenerative osteo-cartilaginous elements at the most significant level

on MRI:

Group 1: Cervical spondylosis with or without contact with the cord, but cord deformity

is absent

Group 2: Mild indentation or flattening of the cord with resultant anterior-posterior (AP)

cord diameters not less than two-thirds of the original (mild cord compression)

Group 3: Significant cord indentation by osteo-cartilaginous elements with resultant

AP cord diameters less than two-thirds of its original, but not associated with

hyperintense T2 signal within the cord (moderate cord compression)

Group 4: Significant cord indentation by osteo-cartilaginous elements with resultant AP

cord diameters less than two-thirds of its original, and associated with hyperintense

T2 signal within the cord (severe cord compression)

The original AP cord diameter was the average of the AP diameter of the spinal cord at

the mid-vertebral body levels directly above and below the disc level assessed, based on

actual measurements on MRI images.

All MRI studies were reviewed by two experienced radiologists. In the event of

discordance, findings were based on a consensus opinion. For further standardisation,

all patients included in the study had MRI performed within eight weeks of the

TMS study.

TMS

All patients had informed consent before TMS was performed. Patients with a

past history of seizures, heart disease and intracranial operations were excluded.

Magnetic stimulation was performed with a Dantec Mag 2 Stimulator (Dantec, Skovlunde,

Denmark) by means of a Dantec S100 circular 10 cm diameter coil generating up to

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IV


1.9 T in output. Motor evoked potential (MEP) recordings were made with adhesive

surface electrodes on the FDI for upper limb (UL) and AH for lower limb (LL) muscles.

The coil was positioned over the scalp vertex to obtain consistent MEPs of maximum

amplitude with the relevant muscle in slight contraction. For AH recordings, the site

of stimulation was 2 cm anterior from the vertex22. Patients received multiple cortical

stimulations, up to 10 for each muscle, to obtain distinctly recordable MEPs of consistent

morphology. The average latency of the shortest of three most consistent responses

was analysed. The minimum latency of 20 F responses was obtained.

CMCT was calculated with the formula: MEP latency − (F latency + M latency − 1)/2 in

ms23. MEP responses were considered absent if 10 consecutive TMSs up to 100%

stimulator output consistently failed to elicit a reproducible MEP. For most patients,

stimulator output of 80% was adequate to elicit consistent MEPs of similar morphology.

CMCT measurements were also performed on the controls for comparison.

Electrophysiological Studies

NCSs of the median, ulnar, sural, tibial and peroneal nerves with relevant late responses

were performed according to previously described methodology (see Section 1 "Nerve

Conduction Study"). Needle EMG of UL muscles comprising C5 to T1 root levels were

performed as part of the neurodiagnostic workup. Additional tests, including evoked

response studies, were performed if clinically indicated.

Statistical Analysis

In this study, we focused on actual clinical scenarios in which patients were referred

for neurophysiological assessments, followed by MRI. All patients who did not have

contraindications had TMS regardless of clinical features or the presence of root

abnormalities. TMS data were finally collated and only excluded after MRI studies,

according to the exclusion criteria set above.

The CMCT data were analysed with SPSS for Windows software.

Mann-Whitney test for non-parametric statistical data was employed, with a p-value

of significance set at 0.05. For sensitivity and specificity calculations, absent MEPs,

abnormal CMCT in any limb or abnormal side-to-side CMCT comparisons were regarded

as pathological for each patient.

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CERVICAL DISORDERS

RESULTS

Clinical71% of the patients presented with sensory symptoms. 75% had hyperreflexia and upper

or lower limb weakness. 25% had gait abnormalities of which 5% needed walking aids.

None complained of bowel or bladder disturbance.

NCS and EMG showed changes supportive of radiculopathy in 72% of patients.

MRITwenty-eight, 49, 28 and 36 patients were classified into Groups 1 to 4 respectively. The

concordance rate of the two radiologists reviewing MRI films was 97%. The most

significant level of cord impingement or compression in all 141 patients were localised to

C3/4 in 23% of patients, C4/5 in 26%, C5/6 in 43% of patients and C6/7 in 8% of patients.

Amongst the patients in Group 4, 34%, 29%, 29% and 8% of patients had increased T2

signal changes at C3/4, C4/5, C5/6 and C6/7 levels respectively. Therefore, the level of

hyperintense T2 signals did not always correlate with the most significant levels of cord

indentation or compression on MRI.

Figure 16.1 shows examples of MRI and TMS tracings of patients in Groups 1 to 4.

TMS (Controls)Mean (SD) for UL and LL CMCTs in normal controls were 5.5 (1.11) ms and

12.26 (1.88) ms respectively. The upper limit of normality at 2 SDs were 7.72 and

16.02 ms. For all control subjects, upper and lower limb MEPs were easily obtainable and

reproducible with stimulator outputs of between 70% to 80%.

Mean right and left CMCT differences (RLD) were 0.84 (0.88) ms and 1.27 (1.12) ms for

UL and LL respectively. The upper limits of normality at 2 SDs were thus 2.57 ms

and 3.51 ms.

TMS (Patients)CMCT

The mean (SD) UL CMCTs for Groups 1 to 4 were 5.14 (1.07) ms, 6.82 (1.88) ms, 12.09

(3.69) ms and 12.91 (3.14) ms respectively. For the LL, they were 12.51 (1.54) ms, 15.32

(2.46) ms, 21.29 (4.63) ms and 21.48 (4.59) ms respectively.

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Mean UL and LL CMCTs were seen to increase with severity of MRI cord compression.

UL and LL CMCTs both correlated significantly with MRI groups (Spearman's correlation

coefficient: 0.75 and 0.73 respectively; p<0.01).

There was no significant difference in mean CMCTs between Group 1 and the

control group. Comparison between groups revealed significant differences (p<0.0005)

in mean UL and LL CMCTs for all pairs of groups, with the exception of Groups 3 and 4 for

both UL (p=0.38) and LL (p=0.99).

In Group 1, there were no patients with absent MEPs or abnormal CMCTs in the ULs

and LLs.

In Group 2, one patient (2%) had absent MEP in the right LL and 39 patients (79%) had at

least one limb with abnormal CMCT. This includes nine with UL, 24 with LL and six with

both UL and LL abnormalities.

In Group 3, nine patients (32%) had absent MEPs, including three in the ULs and six in

the LLs. 28 patients (100%) had at least one limb with abnormal CMCT. This includes two

with UL, two with LL and 24 with both UL and LL abnormalities.

In Group 4, 24 patients (67%) had absent MEPs, including two in the ULs, 17 in the

LLs and five in both ULs and LLs. 36 patients (100%) had at least one limb with

abnormal CMCT. This included none with UL, one with LL and 35 with both UL and

LL abnormalities.

Side-to-side CMCT Comparison

Mean UL RLDs were 0.8 (0.65) ms, 1.53 (1.59) ms, 2.72 (3.51) ms, and 2.03 (2.19) ms for

Groups 1 to 4 respectively.

Mean LL RLDs were 1.01 (0.8) ms, 2.26 (1.91) ms, 2.45 (3.35) ms and 2.69 (2.51) ms for

Groups 1 to 4 respectively.

RLDs for UL and LL between Groups 1 to 4 were not significantly different except for LLs

between Groups 1 and 2 (p<0.001) and Groups 1 and 4 (p<0.03). In addition, there was

no significant difference in RLD between Group 1 and the control group.

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CERVICAL DISORDERS

Group 1 Group 2

1A 1B 2A 2B

1C 2C

1D 2D

Fig. 16.1. MRI and TMS tracings of patients in Groups 1 to 4. A and B: MEPs of UL and LL respectively. Latency, vertical gain and sweep speeds are as shown on the recordings.

2 mV/D 5 ms/D50.0 ms

500 µV/D 8 ms/D80.0 ms

Lat: 21.09 ms Lat: 40.63 ms


500 µV/D 8 ms/D80.0 ms

Lat: 20.70 ms Lat: 46.25 ms

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IV


Group 3 Group 4

3A 3B 4A 4B

3C

3D 4D

C and D: Sagittal turbo-spin echo T2-weighted (C) and axial gradient echo images of the cervical spine (D), demonstrating osteo-cartilaginous bars causing increasing degrees of cord impingement/compression as defined in text. The Group 4 patient did not have a recordable MEP in the LL recording.


200 µV/D 8 ms/D80.0 ms


500 µV/D 8 ms/D80.0 ms

Lat: 25.00 ms Lat: 51.88 ms Lat: 28.91 ms Lat: 0.00 ms

4C

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CERVICAL DISORDERS

In Group 1, there were no patients with RLD exceeding normal control values in both UL

and LL.

In Group 2, there were nine patients in UL, 10 in LL and one patient in both UL and LL

with RLD exceeding normal control values.

In Group 3, there were 10 patients in UL and five in LL with RLD exceeding normal

control values.

In Group 4, there were seven patients in UL, three patients in LL and two patients in both

UL and LL with RLD exceeding normal control values.

Although RLD for LL between Groups 1 and 4 reached statistical significance, a large

proportion of these patients had absent MEPs, in keeping with the severity of cord

compromise. Hence, TMS findings were analysed in greater detail in terms of RLDs

compared with MRI findings only in Group 2. For UL, only 29% with significant RLD had

lateralised disc herniation corresponding to the affected side from CMCT calculations.

The other patients had central disc herniations and/or osteophytes on MRI. For LL, only

22% of patients with significant RLD had lateralised disc herniation corresponding to

the affected side from CMCT calculations. The other patients again had central disc

herniations on MRI.

All patients and controls tolerated the TMS procedure well with no reported

complications. Each TMS study, including preparation and explanation, took an

average of 12 minutes to perform.

TMS and MRI Combined Findings

Based on TMS findings in relation to MRI, all 28 subjects in Group 1 (no MR cord

compression) had normal TMS findings. Forty of 49 patients in Group 2 had at least

one limb with abnormal CMCT while the other nine had right-left CMCT differences

exceeding control values. All 28 and 36 patients in Groups 3 and 4 had at least one limb

with abnormal CMCT.

Additionally, of the eight patients incidentally encountered during the study who had

other conditions, three patients (two with demyelination, one with syringomyelia) also

had abnormal MRI and TMS. The other five patients (two with motor neuron disease,

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three with stroke) had normal MRI but abnormal TMS. No patient with normal MRI had

abnormal TMS studies. In sum, all eight patients had abnormal CMCTs for ULs, LLs,

or both.

Thus, with MRI as the reference standard, the sensitivity and specificity of TMS for cord

abnormality was 100% and 84.8% respectively. The findings also corresponded to a

positive predictive value of 95.9% and a negative predictive value of 100%.

DISCUSSION

Clinical AspectsThe clinical presentations and levels of MRI abnormalities in this study appeared

comparable with smaller series published previously5,10. Hence, this larger series

can be considered representative of a typical group of patients presenting to the

neurophysiologist for functional evaluation.

While asymptomatic cord compression may be encountered in individuals, especially

in advanced age24,25, it can be clinically difficult to distinguish symptoms and signs

of radiculopathy from myelopathy, particularly if pyramidal signs of spasticity, gait

changes and hyperreflexia are equivocal. A previous study6 comprising 25 patients

showed that MEPs and SSEPs were normal in asymptomatic individuals but the

correlation of TMS findings with the degree of cord compression on MRI has not

been systematically evaluated.

PathophysiologyThe pathogenetic factors of CSM are often multiple and interactive. These include

congenital spinal narrowing26, spondylotic bars, discs, hypertrophic facets, disturbed

blood flow and demyelination27. Pathological studies suggest that the corticospinal

tracts are affected early28. Mouse models of spinal cord compromise have been used

to achieve reproducible degrees of spinal compression29. A separate mouse study

showed that 20% occupation rate, a measure of the severity of spinal canal stenosis

by ossified lesions, may be the critical level for functional changes in the spinal

motor neurons30. Hence, our MRI grouping criteria (in Groups 1 and 2) of preservation

of two-third cord diameter is a reasonable close approximation of this parameter.

Posterolateral compression in another mouse model resulted in linear correlation of

the reduction in number of motor neurons with the extent of ipsilateral compression31.

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CERVICAL DISORDERS

Moreover, spinal motor neurons were shown to translocate immediately rostral to the

area of external compression32. A canine model of progressive myelopathy separately

revealed grey matter vascular morphology changes in addition to spinal motor neuron

loss using histological techniques33.

It is well known in human CSM that the lateral corticospinal tracts are first to be

affected in minor compression10,34. Moreover, it is known from the somatotopic

arrangement of the spinal cord that fibres to the LLs are located more laterally than those

to the ULs35. These facts are most relevant in the explanation of TMS and MRI findings of

this study as described below.

MRI Most patients in the study were eventually classified as Group 2 after MRI, suggesting

that in the actual clinical setting, mild CSM is most commonly encountered.

Simultaneous use of both T1 and T2-weighted MR sequences are well shown to be of

value in evaluating CSM36,37.

The levels of high T2 signals in the spinal cord did not correlate directly with the most

significant levels of cord compromise in many patients, suggesting that other factors,

including oedema, gliosis, ischaemia or disturbed blood flow may play a role in addition

to mechanical factors38–42. In addition, the presence of T2 signal change in the cord may

not always be directly related to the degree of cord compression. A mild disc herniation

may occasionally cause intramedullary cord T2 signal change if this was complicated

by direct trauma or cord contusion against the disc43. As the cervical spine is a dynamic

structure, significant mechanical tension has also been shown to occur within the cervical

cord during neck flexion, which may be clinically relevant for patients with CSM44.

It is, however, evident that patients in Group 4 with T2 signal changes had the most

severe TMS abnormalities, including 67% with absent MEPs and 100% with at least one

limb showing abnormal CMCT.

TMSThe use of TMS in the evaluation of CSM is well-described7,45. MEP amplitudes have

not been shown to be of value for CSM10, although one small study46 found lower MEP

amplitudes in patients with multilevel lesions compared with those with single level

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lesions. Hence, central motor conduction latencies were employed as a measurement,

as in previous studies. CMCT reflects function in the fast conducting pyramidal

fibres15,47,48 and prolonged CMCT reflects desynchronisation, temporal dispersion,

conduction block or even axonal degeneration in the fastest conducting fibres16.

Intraoperative electrophysiological studies have documented prolonged CMCT with

only a minor degree of conduction slowing in the corticospinal tract in compressive

CSM, likely contributed by impaired summation of multiple descending potentials after

TMS49. CSM is also more likely to produce corticospinal tract rather than dorsal column

compression. Hence, SSEPs, which are known to be less sensitive than MEPs in CSM50,51,

were not included as a study parameter. The FDI was suitable as a recording site as

CMCT abnormalities are more likely to be found in muscles below the site of the spinal

lesion5. Additionally, LL recording made from the AH muscle was utilised as the lateral

corticospinal tract is known to be involved early in extramedullary compression10,34. LL

MEPs are more sensitive to cervical cord compression as descending volleys in the motor

tracts traverse the entire cervical cord before reaching the lumbar segments6. The F wave

method has been shown to be ideal for measurement of CMCT in the presence of a

peripheral nerve lesion52.

In this study, the mean CMCTs were positively correlated with the severity of cord

compression from Groups 1 to 4. Inter-group testing also revealed statistical significance

with the exception of Groups 3 and 4. This finding supports the reliability of CMCT as a

tool for functional evaluation of the different degrees of corticospinal tract dysfunction.

Of the 141 patients enrolled in this study, TMS reliably selected 28 (20%) of patients into

Group 1, all with normal CMCTs to ULs and LLs and no RLDs exceeding controls. These

patients could have had an expensive MRI of the cervical spine deferred or be managed

medically. On the other hand, absent MEPs in one or more limbs suggest significant cord

compression (Groups 3 and 4) and further MR imaging was then warranted with a view

to surgical intervention.

The findings of significant RLD between Groups 1 and 2 in the LLs corroborates mild

early cervical cord indentation in Group 2. This can be useful in the clinical setting to

screen patients with mild CSM for more vigilant follow-up and eventual imaging. The

high proportion of LL RLD in Group 2 as compared with Groups 3 and 4 can be explained

by early involvement of lateral corticospinal tracts and length traversed by motor tracts

before reaching the AH (as discussed above). In addition, there is also the possibility

of asymmetric disc herniation in early CSM, progressing to centralisation as the disc

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CERVICAL DISORDERS

herniation enlarges. Thus, the collective TMS findings pointing to Group 2 from this

study were universal presence of MEPs, abnormal CMCT to one limb, particularly the LL,

and significant RLDs.

The side correlation of TMS and MRI findings were low for patients with significant UL

and LL RLD in Group 2. This can be partly explained in relation to the dynamic state of

herniated discs in CSM53 and lumbar disc herniation54,55. A previous study of 38 patients

with serial MRI over several months demonstrated reduction in cervical disc herniation

in 40% of patients, especially in the early stages of disease56. It was also shown that

the lateral type of herniation regresses more frequently. Vascular factors, resorption

of hematoma by macrophages and dehydration of nucleus pulposus have been cited

as possible mechanisms. This is in contrast to large central disc herniations causing

significant myelopathy which are not resorbable. It is also well known that the cervical

cord is a dynamic structure during neck flexion and extension44. A small central disc seen

on MRI in many cases in Group 2 may impinge on the left or right side of the cord in

relation to dynamic neck movements. The presence of these factors may account for the

lack of side correlation between TMS and MRI features in Group 2.

The lack of differences in mean CMCTs between Groups 3 and 4 suggest that the

disease has reached a severe plateau stage of corticospinal tract dysfunction. However,

Group 4 has a distinctly larger proportion of patients (67% vs. 32%) with absent MEPs,

which may reflect the underlying mechanisms leading to increased T2 MRI changes

mentioned above.

Finally, during the course of study, eight patients with incidental diagnoses other than

CSM were screened out successfully for further management, suggesting further utility

of TMS as a clinical adjunct.

Practical ImplicationsThere are implications of the findings in this study with respect to the pathogenesis,

clinical management and health costs of CSM.

CSM is an almost universal consequence of human aging57, and prevalence is increased

concomitant with age24,58,59. This study has examined a cross-section of patients

presenting at various stages of severity. From MRI classification, Groups 1 to 4 can be

regarded as Stages 1 to 4 of the disease. The findings of significant LL RLD in Group 2

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IV


suggests that the condition progresses from minimal spondylosis and root changes, to

small potentially resorbable disc herniation with lateral cord impingement, to overt cord

compression and eventual intramedullary changes detected with MRI.

The evidence for surgical management of CSM is not plentiful60. In the Cochrane Review61,

only two randomised trials comprising 130 patients were noted, both of which did not

show any significant difference between conservative and surgical treatment62,63.

Our results point to the high sensitivity and specificity of TMS in differentiating patients

with and without cervical cord abnormalities. Furthermore, with the high cost of MRI

compared to TMS, and the evidence of excellent correlation between TMS findings and

MRI outcomes from this large study, TMS can be recommended as a non-invasive, less

costly and less time-consuming technique for screening and serial evaluation of CSM.

Only patients with TMS evidence pointing to more severe disease can then be imaged,

with a view to possible surgical intervention.

Finally, all patients had initial clinical diagnoses of significant CSM despite careful

examination by an experienced doctor. Much of the difficulty arises in view of the

large number of mild cases (Group 2), as well as the coexistence of myelopathy with

root pathology, which form a large group highlighted in our series. This renders clinical

examination difficult and signs equivocal due to the combination of upper and lower

motor neuron features. Here, TMS adds considerable information to the functional

evaluation of upper motor neuron corticospinal pathways in CSM.

CLINICAL NOTES

This chapter outlines our standard technique to determine CMCT for cervical

spine disorders. It should be cautioned, however, that while the role of TMS as

a screening tool to MRI in CSM is highly promising, an MRI should not be deferred in

clinically doubtful cases of CSM, since it can demonstrate other non-spondylotic causes

of myelopathy.

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