Massimo surgery for_low_back_pain

massimo.balsano@gmail.com
123
Surgery for
Low Back Pain
Marek Szpalski
Robert Gunzburg
Björn L. Rydevik
Jean-Charles Le Huec
H. Michael Mayer
Editors

Surgery for Low Back Pain

Marek Szpalski
Robert Gunzburg
Björn L.Rydevik
Jean-Charles Le Huec
H.Michael Mayer (Eds.)
Surgery for
Low Back Pain

ISBN: 978-3-642-04546-2 e-ISBN: 978-3-642-04547-9
DOI: 10.1007/978-3-642-04547-9
Springer Heidelberg Dordrecht London New York
Library of Congress Control Number: 2009938032
© Springer-Verlag Berlin Heidelberg 2010
This work is subject to copyright. All rights are reserved, whether the whole or part of the material is
concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting,
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to prosecution under the German Copyright Law.
The use of general descriptive names, registered names, trademarks, etc. in this publication does not imply,
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Printed on acid-free paper
Springer is part of Springer Science+Business Media (www.springer.com)
Marek Szpalski, MD
Department of Orthopedic Surgery
Hôpitaux Iris Sud
Université Libre de Bruxelles
142 rue Marconi
1190 Brussels, Belgium
Department of Orthopedics
New York University
New York, USA
mszp@skynet.be
Robert Gunzburg, MD
Eeuwfeestkliniek
Algemeen Ziekenhuis Monica
Harmoniestraat 68
2018 Antwerpen
Belgium
robert@gunzburg.be
Björn L. Rydevik, MD, PhD
Sahlgrenska University Hospital/Sahlgrenska
Department Orthopaedic Surgery
413 45 Göteborg
Sweden
bjorn.rydevik@orthop.gu.se
Jean-Charles Le Huec, MD
CHU Bordeaux Hôpital Pellegrin
Service d’Orthopédie Traumatologie
Place Amalie Raba Leon
33076 Bordeaux CX
France
j-c.lehuec@chu-bordeaux.fr
H. Michael Mayer, MD, PhD
Orthopädische Klinik
München-Harlaching
Wirbelsäulenzentrum
Harlachinger Str. 51
81243 München
Germany
mmayer@schoen-kliniken.de

v
Low back pain is one of the most common conditions encountered in clinical prac-
tice; however, its definition itself is subject to debate and precise knowledge about it
is conflicting. It can be attributed to a great number of different origins although,
often, the true cause of nociception cannot be precisely defined. Furthermore, psy-
chosocial variables have an important influence on the reporting back pain symp-
toms. Nevertheless, low back pain and the pathologies believed to be its cause are the
main indication for spine surgery in most area of the world while true evidence about
indications remains elusive and there is much discussion about the very different
techniques used.
The goal of this book is to shed some light on this complex subject. The indispens-
able bases of biology and biomechanics of spinal structures are covered as well as the
important psychosocial determinants associated with back complaints. Diagnosis is
now enhanced by new magnetic resonance techniques described thoroughly.
Conservative treatment is still the base of low back pain handling, and natural his-
tory of the condition as well as the main conservative therapeutic options are described
in detail. Medications, rehabilitation, back schools, manipulative therapies, and
orthoses are the subject of fully documented chapters.
Surgical techniques abound for the treatment of lumbar spine disorders and this
book tries to clarify their indications and results. For many years fusion was the most
used technique and became the “de facto” gold standard. The role of pelvic girdle
pain and facet syndrome is subject to debate and the possible surgical treatment is
discussed in those conditions. Chapters will cover different technique as well as the
possible drawbacks like blood loss and adjacent level degeneration. The latter has led
to the development of “nonfusion” technologies like artificial disks, semirigid fixa-
tion techniques, or interspinous implants. Indications, counter indications, techniques,
and complications of those different techniques are presented and lead to discussion
about what evidence we have for their effectiveness.
Outcome assessment is paramount to finding evidence for treatments of low back
pain. The principles of outcome assessment in back pain as well as the review of
actual available evidence ends the book.
This book is intended for clinicians as well as researchers in many fields of spinal
disorders. It is of use to orthopedic and neurosurgeons, rheumatologists, neurologists,
physiatrists, physical therapists, as well as psychologists and social security and
insurance specialists.
Brussels, Belgium Marek Szpalski
Antwerp, Belgium Robert Gunzburg
Preface

vii
Contents
Part I Basics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
1.1 The Biology of Intervertebral Disc Degeneration . . . . . . . . . . . . . . . . 3
Cornelia Neidlinger-Wilke and Hans-Joachim Wilke
1.2 Low Back Pain: Where Does the Pain Come From? . . . . . . . . . . . . . . 11
Helena Brisby
1.3 The Role of Cytokines in the Degenerative Spine . . . . . . . . . . . . . . . . 17
Björn Rydevik and Helena Brisby
1.4 Psychosocial Aspects of Low Back Pain . . . . . . . . . . . . . . . . . . . . . . . . 23
Christine Cedraschi and Valérie Piguet
1.5 Instability and Low Back Pain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29
Tommy Hansson
Part II Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37
2.1 Dynamic MRI of the Spine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39
J. J. Abitbol, Soon-Woo Hong, Sana Khan, and Jeffrey C. Wang
2.2 Assessment of Status of End Plate and Diffusion
in Degenerative Disc Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47
S. Rajasekaran
2.3 The Role of Physician Extenders in a Low Back Pain Practice . . . . . 57
Michael R. Zindrick, Michael N. Tzermiadianos, Cary R. Templin,
and Raymond E. Hines III
Part III Conservative Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63
3.1 Natural Evolution of Nonspecific Low-Back Pain . . . . . . . . . . . . . . . . 65
Michel Benoist and Thibaut Lenoir
3.2 Prescribing Conservative Treatment for Low Back Pain . . . . . . . . . . 73
F. Balagué and J. Dudler

viii Contents
3.3 Comprehensive Rehabilitation for Low back Pain
and Back Schools . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79
Margareta Nordin
3.4 The Place of Chiropractic Care in the Treatment
of Low Back Pain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85
Christopher J. Colloca
3.5 Efficacy of IDET and PIRFT for the Treatment
of Discogenic Low Back Pain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 95
Brian J. C. Freeman
3.6 Lumbar Orthoses to Prevent and Treat Low-Back Pain . . . . . . . . . . . 101
Michel Benoist and Thibaut Lenoir
Part IV Surgical Treatment: Fusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 107
4.1 Indication for Lumbar Spinal Fusion . . . . . . . . . . . . . . . . . . . . . . . . . . 109
Max Aebi
4.2 Evidence for Efficacy of Pedicle-Based Systems . . . . . . . . . . . . . . . . . 123
Jeremy Fairbank
4.3 Low Back Pain Is Not an Indication for Stabilisation
in Patients Operated for Lumbar Spinal Stenosis . . . . . . . . . . . . . . . . 127
E. Munting
4.4 Hybrid Construct for DDD in the Lumbar Spine:
The Compromise Between Fusion and Nonfusion . . . . . . . . . . . . . . . . 131
J. C. Le. Huec, R. Meyrat, F. Debusscher and S. Aunoble
4.5 The Management of Spondylolysis and Spondylolisthesis . . . . . . . . . 137
Brian J. C. Freeman and Ujjwal K. Debnath
4.6 Transpedicular-Transdiscal-Transcorporal (TPDC)-Fixation . . . . . . 147
Max Aebi
4.7 Facet Problems: A Surgical Indication? . . . . . . . . . . . . . . . . . . . . . . . . 155
F. Pellisé
4.8 Adjacent Level Disease: “Myth” or “Fact” . . . . . . . . . . . . . . . . . . . . . 159
David A. Wong and Katherine E. Wong
4.9 Pelvic Girdle Pain: Indication for Surgery? . . . . . . . . . . . . . . . . . . . . . 165
Bengt Sturesson
4.10 Blood Loss Management in Major Spine Surgery . . . . . . . . . . . . . . . . 169
Serena S. Hu and Jeremy A. Lieberman

Contents ix
Part V Surgical Treatment: Other Technologies . . . . . . . . . . . . . . . . . . . . . 175
5.1 How Disc Replacement Fits in the Treatment
Algorithm for Degenerative Disc Disease:
Refining Indications for Disc Replacement . . . . . . . . . . . . . . . . . . . . . 177
Richard D. Guyer and Donna D. Ohnmeiss
5.2 Clinical Factors that May Affect Outcome
in Lumbar Total Disc Replacement. What Is the Evidence? . . . . . . . 183
Michael R. Zindrick, Mark Lorenz, Leonard I. Voronov,
Michael N. Tzermiadianos, and Alexander Hadjipavlou
5.3 A Prospective Randomized Comparison
of Two Lumbar Total Disk Replacements . . . . . . . . . . . . . . . . . . . . . . 193
Richard D. Guyer and Donna D. Ohnmeiss
5.4 Limitations of Lumbar Disk Arthroplasty . . . . . . . . . . . . . . . . . . . . . . 199
Serena S. Hu
5.5 Is Posterior Dynamic Stabilization an Option
to Avoid Adjacent Segment Decompensation? . . . . . . . . . . . . . . . . . . . 207
Missoum Moumene and Jürgen Harms
5.6 Immediate Biomechanical Effects
of Lumbar Posterior Dynamic Stabilisation . . . . . . . . . . . . . . . . . . . . . 213
Brian J. C. Freeman and Caspar E. W. Aylott
5.7 Overview of Pedicle Screw-Based Posterior
Dynamic Stabilization Systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 221
Richard D. Guyer, Donna D. Ohnmeiss, and Kevin R. Strauss
5.8 Semirigid Fixation System for the Lumbar Spine . . . . . . . . . . . . . . . . 227
Dieter Grob, Andrea Luca, and Anne F. Mannion
5.9 Nonrigid Stabilization of the Spine – Problems Observed:
Screw Loosening/Breakage/Implant Failure/Adjacent
Segment Degeneration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 233
Paul F. Heini
5.10 Interspinous Implants: State of the Art
and Research of Evidence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 241
Marek Szpalski, Robert Gunzburg, Christopher J. Colloca,
and Robert J. Moore
5.11 NuBac Disc Arthroplasty System:
Rationale and Clinical Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 249
Massimo Balsano, Domagoj Coric, and Margreet Derks

x Contents
Part VI Outcomes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 257
6.1 Outcome Assessment for Cost-Utility Evaluations:
SF-6D vs. EQ-5D . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 259
Rikke Søgaard, Terkel Christiansen, and Finn Bjarke Christensen
6.2 Review of the Medical Evidence Regarding
the Surgical Treatment of Low Back Pain . . . . . . . . . . . . . . . . . . . . . . 267
Andrew P. White, Justin G. Brothers, and Alexander R. Vaccaro
Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 279

xi
J.J. Abitbol California Spine Group, 5395 Ruffin Road Suite 103, San Diego,
CA 92123, USA
jjspine@aol.com
Max Aebi Center for Orthopaedic Research, University of Bern,
Stauffenbachstrasse 78, 3014, Bern, Switzerland
max.aebi@memcenter.unibe.ch
S. Aunoble Spine Unit, Bordeaux University Hôpital, CHU Bordeaux,
33076 Bordeaux, France
Caspar E. W. Aylott Department of Spinal Surgery, Level 3, Theatre Block,
Royal Adelaide Hospital, North Terrace, Adelaide, SA 5000, Australia
Federico Balagué Service de Rhumatologie, Médicine Physique et Réhabilitation,
HFR- Hospital Cantonal, Case postale, 1708 Fribourg, Switzerland
balaguef@h-fr.ch
Massimo Balsano Spinal Regional Department, ULSS 4, Schio, Vicenza, Italy
Michel Benoist University of Paris VII, Hôpital Beaujon, 100 Bd. du Gl. Leclerc
92110 Clichy, France
deuxmice@aol.com
Helena Brisby Department of Orthopaedics, Sahlgrenska University Hospital,
413 45, Gothenburg, Sweden
helena.brisby@vgregion.se
Justin G. Brothers Thomas Jefferson University, Philadelphia, PA, USA
justin.brothers@jefferson.edu
Christine Cedraschi Division of Internal Medicine for Rehabilitation, Geneva
University Hospitals, Rue Gabrielle Perret-Gentil 4, 1211 Geneva 14, Switzerland
Christine.Cedraschi@hcuge.ch
Finn Bjarke Christensen Health Economics Unit, Institute of Public Health,
University of Southern Denmark, J.B. Winsløws Vej 9, 5000 Odense C, Denmark
Terkel Christiansen Health Economics Unit, Institute of Public Health,
University of Southern Denmark, J.B. Winsløws Vej 9, 5000 Odense C, Denmark
tch@sam.sdu.dk
Contributors

xii Contributors
Christopher J. Colloca Department of Kinesiology, Arizona State University,
101 South Roosevelt Avenue, Chandler, AZ 85226, USA
drc100@aol.com
Domagoj Coric Carolina Neurosurgery and Spine Associates, 225 Baldwin
Avenue, Charlotte, NC 28207, USA, dom@cnsa.com
Ujjwal K. Debnath Department of Orthopaedic Surgery, Letterkenny General
Hospital, Donegal, Ireland
F. Debusscher Spine Unit, Bordeaux University Hospital, CHU Bordeaux,
Margreet Derks Pioneer Surgical Technology BV, Princenhof Park 10,
3972 NG Driebergen, The Netherlands, margreetderks@pioneersurgical.eu
Jean Dudler Service de Rhumatologie, Médecine Physique
et Réhabilitation, CHUV Hôpital Orthopédique, Avenue Pierre-Decker 4,
1011 Lausanne, Switzerland, jean.dudler@chuv.ch
Jeremy Fairbank Nuffield Orthopaedic Centre, Oxford OX3 7LD, UK
Jeremy.fairbank@ndorms.ox.ac.uk
Brian J.C. Freeman Department of Spinal Surgery, Level 3, Theatre Block,
Royal Adelaide Hospital, North Terrace, Adelaide, SA 5000, Australia
brian.freeman@health.sa.gov.au
Dieter Grob Spine Center, Schulthess Klinik, Lengghalde 2,
8008 Zürich, Switzerland
dieter.grob@kws.ch
Robert Gunzburg Eeuwfeestkliniek, Algemeen Ziekenhuis Monica,
Harmoniestraat 68, 2018 Antwerpen, Belgium
robert@gunzburg.be
Richard D. Guyer Texas Back Institute, 6020 West Parker Rd. 200, Plano,
TX 75093, USA, rguyer@texasback.com
Alexander Hadjipavlou University of Crete, Heraklion, 71110 Crete, Greece
ahadjpa@med.uoc.gr
Tommy Hansson Department of Orthopaedics, Sahlgrenska Academy,
413 45 Göteborg, Sweden, tommy.hansson@orthop.gu.se
Jürgen Harms Department of Orthopaedic Traumatology I, Spine Surgery,
Klinikum Karlsbad-Langensteinbach, 76307 Karlsbad, Germany
Juergen.harms@kkl.srh.de
Paul F. Heini Spine Ortho center, Klinik Sonnenhof 3006 Bern, Switzerland,
paulheini@sonnenhof.ch
Raymond E. Hines III Hinsdale Orthopedic Associates, Hinsdale,
IL 60521, USA
Soon-Woo Hong California Spine Group, 5395 Ruffin Road, Suite 103, San Diego,
CA 92123, USA

Contributors xiii
Serena S. Hu Department of Orthopedic Surgery, 500 Parnassus Avenue, Room
MU320 West, San Francisco, CA 94143, USA, hus@orthosurg.ucsf.edu
J.C. Le Huec Spine Unit, Bordeaux University Hospital, CHU Bordeaux,
33076 Bordeaux, France, j-c.lehuec@u-bordeaux2.fr
Sana Khan California Spine Group, 5395 Ruffin Road, Suite 103, San Diego,
CA 92123, USA
Thibaut Lenoir Department of Orthopaedic Surgery, Hôpital Beaujon,
100 Bd. du Gl. Leclerc, 92110 Clichy, France, lenoirthibaut@yahoo.fr
Mark Lorenz Hinsdale Orthopaedic Associates, SC, Hinsdale, IL 60521, USA
orthospine@aol.com
Andrea Luca Spine Center, Schulthess Klinik, Lengghalde 2, 8008 Zürich,
Switzerland
Anne F. Mannion Spine Center, Schulthess Klinik, Lengghalde 2, 8008 Zürich,
Switzerland, anne.mannion@yahoo.com
R. Meyrat Spine Unit, Bordeaux University Hospital, CHU Bordeaux,
Robert J. Moore The Adelaide Centre for Spinal Research, Institute of Medical
and Veterinary Science, Adelaide, SA, Australia, rob.moore@imvs.sa.gov.au
Missoum Moumene Department of Research and Development, DePuy Spine
Inc., Raynham, MA, USA, mmoumene@its.jnj.com
E. Munting Clinique Saint Pierre, 1340 Ottignies Louvain-la-Neuve, Belgium,
ev.munting@clinique-saint.pierre.be
Cornelia Neidlinger-Wilke Institute of Orthopaedic Research and Biomechanics,
Centre of Musculoskeletal Research, University of Ulm, Helmholtzstraße 14,
89081 Ulm, Germany, cornelia.neidlinger-wilke@uni-ulm.de
Margareta Nordin Occupational and Industrial Orthopaedic Center (OIOC),
Graduate Program of Ergonomics and Biomechanics, New York University (NYU)
Hospital for Joint Diseases, NYU Langone Medical Center, CDC/NIOSH Education
and Research Center (ERC), New York University, New York, NY, USA
margareta.nordin@nyu.edu
Donna D. Ohnmeiss Texas Back Institute Research Foundation, 6020 West Parker Rd.
200, Plano, TX 75093, USA, dohnmeiss@texasback.com
F. Pellisé Unitat de Cirugia del Raquis Vall d’Hebron, Hospital Vall d’Hebron,
Barcelona, Vall d’Hebron 119-129, 08035 Barcelona, Spain
24361fpu@comb.es
Valérie Piguet Multidisciplinary Pain Centre, Division of Clinical Pharmacology
and Toxicology, Geneva University Hospitals, Rue Gabrielle Perret-Gentil 4,
1211 Geneva 14, Switzerland, valerie.piguet@hcuge.ch

xiv Contributors
S. Rajasekaran Department of Orthopaedic and Spine Surgery, Ganga Hospital,
313 Mettupalayam Road, Coimbatore, 641043 Tamil Nadu, India
sr@gangahospital.com
Björn Rydevik Department of Orthopaedics, Sahlgrenska University Hospital,
413 45, Gothenburg, Sweden, bjorn.rydevik@gu.se
Rikke Søgaard CAST–Centre for Applied Health Services Research and
Technology Assesment, University of Southern Denmark, J.B. Winsløws Vej 9,
5000 Odense C, Denmark, ris@cast.sdu.dk
Kevin R. Strauss K2M, Inc., Leesburg, VA, USA
Bengt Sturesson Department of Orthopaedics, Ängelholm Hospital,
262 81 Ängelholm, Sweden, bengt.sturesson@ektv.nu
Marek Szpalski Department of Orthopedic Surgery, Hôpitaux Iris Sud, Université
Libre de Bruxelles, 142 rue Marconi, 1190 Brussels, Belgium
Department of Orthopedics, New York University New York, USA
mszp@skynet.be
Cary R. Templin Hinsdale Orthopedic Associates, Hinsdale, IL 60521, USA
Michael N. Tzermiadianos Hinsdale Orthopedic Associates, Hinsdale,
IL 60521, USA
45, Eleftheria Square (Electra BLD, 1st floor) 71201 Heraklion, Crete, Greece
mikethernci@yahoo.gr
Alexander R. Vaccaro Department of Orthopaedic Surgery and Neurosurgery,
Rothman Institute at Jefferson University Hospital, Thomas Jefferson University,
Philadelphia, PA, USA, alexvaccaro3@aol.com
Leonard I. Voronov Loyola University Medical Center, Maywood, IL, USA
Jeffrey C. Wang Department of Orthopaedic Surgery, Santa Monica – UCLA
Medical Center and Orthopaedic Hospital, 1250 16th Street, 7th Tower, No. 745,
Santa Monica, CA 90404, USA
Jeremy A. Lieberman Spine Anesthesia Service Department of Anesthesia and
Perioperative Care, University of California, San Francisco, 521 Parnassus Ave.,
Box 0648, Room L-008, San Francisco, CA, lieberman@anesthesia.ucsf.edu
Andrew P. White Carl J. Shapiro Department of Orthopaedics - Stoneman 10,
Harvard Medical School, Beth Israel Deaconess Medical Center, 330 Brookline
Ave, Boston, MA 02215, USA, apw.spine@gmail.com
Hans-Joachim Wilke Institute of Orthopaedic Research and Biomechanics,
Centre of Musculoskeletal Research, University of Ulm, Helmholtzstraße 14,
89081 Ulm, Germany, hans-joachim.wilke@uni-ulm.de
David A. Wong Advanced Center for Spinal Microsurgery, Presbyterian St. Luke’s
Medical Center, Denver, CO 80218, USA, ddaw@denverspine.com
Katherine E. Wong Denver Spine, Advanced Center for Spinal Microsurgery,
Presbyterian St. Luke’s Medical Center, Denver, CO 80111, USA
Michael R. Zindrick Hinsdale Orthopedic Associates, Hinsdale, IL 60521, USA
zindrickmike@cs.com

Part
Basics
I

3M. Szpalski et al. (eds.), Surgery for Low Back Pain,
DOI: 10.1007/978-3-642-04547-9_1.1, © Springer-Verlag Berlin Heidelberg 2010
Introduction: The Normal
Intervertebral Disc
Intervertebral discs act as the joints of the spinal col-
umn and provide it with mobility and flexibility. The
predominant mechanical functions of intervertebral
discs are to transmit the compressive loads through the
spine and to allow it to bend and twist. These complex
mechanical functions depend on the structural and bio-
chemical composition of the disc matrix: the disc cells
that are responsible for the synthesis and maintenance
of these matrix molecules.
Morphologically, intervertebral discs consist of a cen-
tral nucleus pulposus surrounded by the fibrous annulus
lamellae. The discs are enclosed axially by the cartilagi-
nous endplates, which form the interface between the
disc and the adjacent vertebrae. The major components
of the disc matrix are water, collagen and proteoglycans,
mainly aggrecan. There is a gradient in the proportion of
these three matrix constituents throughout the disc; the
outer annulus has the highest collagen concentration and
the lowest aggrecan and water content, while aggrecan
and water concentration increase towards the central
nucleus, with a decrease in collagen content.
Although disc cells occupy only one percent of the
whole tissue, the annulus and nucleus cells produce
and maintain all of the matrix molecules so that each
disc cell is responsible for a large volume of matrix. As
discs are avascular, oxygen and other nutrients must
diffuse from these blood vessels across the endplate
and through the matrix to reach the cells of the disc,
and products of metabolism must be removed by the
reverse route. In addition, since the discs are subjected
to mechanical loading at all times, disc cells are also
exposed to multiple physical stimuli including tension,
compression and also fluid flow (because discs lose
and regain about 25% of their fluid during a diurnal
cycle). The consequence of hydration and dehydration
of the disc is a change in the physicochemical environ-
ment of the disc cells since concentrations of matrix
molecules, ions and hence, osmolarity are influenced
by fluid loss and regain. All these factors are thought to
affect the activity of disc cells and play an important
role in the maintenance of a balance between the
matrix forming and degrading processes.
Recent studies suggest that all these environmental
factors and their complex interactions influence disc
physiology. Changes in these factors, either as a cause
or a consequence of degenerative changes in the disc
tissue, are thought to influence disc matrix turnover.
Besides these external factors, a strong familial predis-
position for disc degeneration has been noted, suggest-
ing that genetic effects are the highest risk factor for
disc degeneration. The present review summarizes
recent knowledge on the biology of disc degeneration
and the open questions that remain to be investigated.
Biology of Disc Degeneration
Intervertebral disc degeneration is one of the main rea-
sons for back pain and a very common burden for the
affected patient as well as the society because of the
high costs for the health system [28]. Though it is not
known how much the degenerated disc itself contrib-
utes to chronic back pain, it can be estimated that more
The Biology of Intervertebral
Disc Degeneration
Cornelia Neidlinger-Wilke and Hans-Joachim Wilke
C. Neidlinger-Wilke (*)
Institute of Orthopaedic Research and Biomechanics,
Centre of Musculoskeletal Research, University of Ulm,
Helmholtzstraße 14, 89081 Ulm, Germany
e-mail: cornelia.neidlinger-wilke@uni-ulm.de
1.1

4 C. Neidlinger-Wilke and H.-J. Wilke
than 90% of all surgical spine treatments are performed
as a consequence of disc degeneration.
There was very little research activity in the disc
field for a long time, but during the last few years a
number of studies investigating epidemiological [6, 7],
biological [49, 50] and biomechanical aspects [1, 47]
of disc degeneration have been published.
Histological Findings and Biomechanical
Effects of Disc Degeneration
From a biomechanical point of view, the disc is a fas-
cinating structure. The nucleus of the disc in the early
life or in only slightly degenerated discs acts like a
gelatinous mass. A compressive load decreases disc
height and can increase the hydrostatic pressure up to
a considerable magnitude [52], which pushes the sur-
rounding structures in all directions away from the
centre of the nucleus. This leads to a bulging of the
endplates of the vertebrae and of the outer annulus,
which leads to an almost equal stress distribution
throughout the disc [13]. In flexion, extension or lat-
eral bending, the inner and middle annulus is also
compressed but the outer annulus has to resist more
strain. During the day, load reduces the disc height
mainly because of water being squeezed out, and also
due to creep of the viscoelastic collagen fibres of the
annulus. Both effects are reversible in healthy discs
when unloading the spine, e.g. during a night’s bed rest
[52]. The longer the load acts on the spine, the more
the annulus bulges and the more the facet joints are
loaded. Degenerated discs alter their structure and
function [2, 53]. Finite element studies showed that the
risk of prolapses is highest in the posterior and poste-
rolateral annulus under load combinations, especially
in a non- and mildly degenerated disc [42, 43].
Moderate or strongly degenerated discs have a lower
risk for a prolapse.
The histomorphological alterations of the disc tis-
sue are complex as recently reviewed [38]. The central
nucleus, which has a very high water-binding capacity
in young age, gets more and more dry and the gelati-
nous structure changes into a more fibro-cartilaginous
tissue. Cleft formation with fissures is often observed.
In the nucleus of degenerated discs, the formation of
cell clusters and an increased level of cell senescence
has been reported [39]. The finding of an increased
number of senescent cells predominantly in the nucleus
of herniated discs suggests that cell senescence plays
an important role in disc degeneration. Also the annu-
lus structure changes during degeneration. The annu-
lus lamellae become more irregular with a more
disorganized collagen and elastin network. Annular
tear formation is considered as a morphological sign of
degeneration in many discs [32]. These enormous
structural changes result in a decreased flexibility and
a reduced water-binding capacity of degenerated disc
with the consequence that the discs have impaired
load-bearing properties.
Epidemiology and Diagnosis
of Disc Degeneration
For an epidemiological investigation of disc degenera-
tion, these structural changes can be diagnosed by
magnetic resonance imaging (MRI). Low disc signal
intensity is considered as a sensitive sign of disc degen-
eration. It, together with the determination of other
important disc features (such as disc height, annulus
fibrosus contours, tears in the annulus, fissures in the
nucleus, end-plate morphology), is the basis of scoring
the degree of disc degeneration [37, 50]. Twin studies
using this technique have shown the high influence of
genetic factors. However, recent MRI techniques also
have limitations because of their poor specificity in the
evaluation of significant disc degenerative changes.
Measurements of intervertebral disc water (through
determination of diffusion coefficients) might provide
better means of determining impaired disc integrity
and degrees of degeneration. In the future, quantitative
dynamic MR imaging of patients during exposure to
physiological loads could be a promising tool for a bet-
ter diagnosis of disc degeneration.
Aetiology of Disc Degeneration
Disc degeneration is a complex problem with multiple
factors contributing to this phenomenon. Mechanical
loads, genetic predisposition, and alterations of the phys-
icochemical environment of the disc are all discussed

51.1 The Biology of Intervertebral Disc Degeneration
to be contributors to degenerative pathways; it is not
known, however, exactly how these different aspects
interact and influence each other.
Influence of Mechanical Loading
Though it was thought for a long time that disc degen-
eration is mainly caused by abnormal loading, no
direct evidence for mechanical load-induced disc
degeneration has yet been found possibly because its
interactions with occupational and psychosocial fac-
tors make a clear separation of mechanical from other
factors difficult.
In animal experiments the direct influence of
mechanical loading has found that discs exposed to
abnormal compressive or vibration forces showed signs
of degenerative changes [16, 23, 25, 26]. On the other
hand, other well-controlled studies found no adverse
effects on the disc after long-term compression or
intense exercise [15, 36]. In a treadmill training study
with young beagle dogs, measurements of disc collagen
and proteoglycans supported the hypothesis that an
adaptation of the tissue to enhanced motion and stress is
possible. In vitro studies using human-disc cells taken
from discs removed at surgery suggest that mechanical
loads could influence gene expression of matrix-form-
ing proteins or matrix-degrading enzymes [29, 30].
However, the effects of load were quite low and showed
high variability between different patients. Effects on
animal cells differ between studies. Physiological ranges
of intermittent hydrostatic pressure applied to canine
disc cells in alginate beads increased proteoglycan bio-
synthesis [14]. On the other hand, high frequencies
(around 5 Hz) of dynamic hydrostatic loading disrupted
protein metabolism of pig intervertebral disc cells [20].
Thus, in vitro studies using disc cells suggest that
mechanical loads can influence disc matrix turnover via
alteration of gene expression or biosynthesis of disc
matrix proteins or matrix degrading enzymes. In sum-
mary, the results of most animal studies suggest that at
least certain forms of mechanical loads can contribute to
the induction of disc degeneration, while clinical studies
failed to prove a strong causal link between occupa-
tional exposures and disc degeneration. These results
suggest that while mechanical factors have some influ-
ence, other factors also contribute to the complex aetiol-
ogy of disc degeneration.
Genetic Predisposition
Evaluations of questionnaires helped to identify envi-
ronmental risk factors for disc degeneration like ciga-
rette smoking, repetitive mechanical loading and lifting
of heavy loads; relatively recent studies suggest, how-
ever, that genetic influences might be the highest risk
factor, and that environmental factors have only modest
effects. Based on the results of many studies, genetic
inheritance is now considered to be the highest risk fac-
tor for disc degeneration [6].
From the findings of twin studies, genetic factors
are estimated to contribute 60–70% to disc degenera-
tion [7, 27, 41]. DNA-genotyping of blood samples of
patients with disc degeneration and age-matched con-
trols have led to the identification of a number of varia-
tions (single nucleotide polymorphism) in individual
genesassociatedwithdiscdegeneration.Polymorphisms
in genes encoding for aggrecan, collagen I, II, and IX
have been correlated with degeneration-associated
alterations of the disc matrix. Also variations in non-
collagenous matrix proteins like CILP (cartilage inter-
mediate layer protein) or in genes encoding for
inflammation factors (interleukins (IL1, IL6) have
been reported. Polymorphisms in genes encoding for
matrix degrading enzymes like MMPs and in the vita-
min D receptor genes have been found to accelerate
degenerative changes though the exact mechanism is
often unknown.
Initiation of Disc Degeneration:
Alterations of the Physicochemical
Environment
In normal intervertebral discs, the maintenance and
turnover of the disc matrix are in a balanced state,
which means that matrix formation and matrix degra-
dation compensate each other (Fig. 1.1.1). Disc degen-
eration starts when the catabolic processes prevail and
exceed the synthesis of matrix-forming proteins. The
changes of the disc tissue during degeneration have
been recently reviewed [50].
The most striking biochemical alteration of disc
matrix during degeneration is a degradation of aggre-
can, the predominant disc matrix proteoglycan. These
huge macromolecule aggregates with their high density

of fixed negative charges are responsible for the unusual
high osmotic pressure, and thus, the high water-binding
capacity of the disc tissue. Shorter molecules of aggre-
can and a lower concentration explain the decreased
hydration capacity of degenerated discs.
Impaired Nutrient Supply
Many environmental factors that are believed to contrib-
ute to the initiation of these degenerative changes are
discussed whereas decreased nutrition is assumed to be a
key contributor [51]. Normal discs are avascular, and
nutrient supply and removal of metabolic degradation
products occur predominantly via diffusion from the
blood vessels at the cartilaginous endplate. A reduction
of this nutrient supply is assumed to be one – if not the
major – reason for disc degeneration. Calcification of the
cartilaginous endplates leads to a decreased permeability
for nutrients and metabolites. In vivo measurements with
microelectrodes have shown that the nutrient supply in
the centre of many degenerated discs is low [5].
Disc cells are very sensitive to alterations of these
environmental conditions. In vitro experiments have
shown that the disc cells need critical concentrations of
glucose, a suitable pH and oxygen supply to stay viable
and metabolic active [8, 9]. The cells are particularly
sensitive to the accumulation of lactic acid, which
decreases the pH [5]. In vitro studies have shown that
an acidic pH decreases proteoglycan biosynthesis of
disc cells, but does not decrease the activity of matrix-
degrading enzymes. All of these alterations in the
nutritional environment may result in adverse effects
on disc cell function, and thus, contribute to degenera-
tive changes of intervertebral discs [31].
Intervertebral disc cells exist in an unusual high
osmotic environment compared to cells in other connec-
tive tissues [48]. Due to reversible hydration and dehydra-
tion of the disc, the osmotic environment is not constant,
but underlies diurnal variation, with the highest value at
the end of a working day when almost 25% of the disc
fluid is extruded from the disc tissue, and the lowest val-
ues in the morning after water imbibition, which occurs
during the night when the axial load is very low [46].
Degeneration results in alterations to the osmotic
environment: degradation of disc proteoglycans leads to
a fall in osmolarity in the disc tissue. In vitro experi-
ments with disc cells [54] and full-organ cultures of
intervertebral discs [12] have shown that osmolarity can
directly influence matrix formation and degradation as
the expression of genes that are responsible for these
anabolic or catabolic processes can be up- or down-reg-
ulated by osmotic conditions [54]. Both diurnal changes
Fig. 1.1.1 Scheme of a normal disc. Annulus and nucleus cells
produce matrix proteins (collagens and proteoglycans) and matrix
degrading enzymes. Both processes are in balance. There is no
vascularization and innervation of the disc. It is suggested that
intact aggrecan macromolecules have an inhibitory influence (…)
on disc vascularization and innervation
disc cells produce
- matrix proteins:
collagens
balance
- matrix degrading
enzymes:
MMPs, TIMPs
normal disc
nerves
blood vessels
anulus cells
nucleus cells
proteoglycans
(aggrecan)

and long-term alterations of the disc osmolarity as
caused by degeneration may alter disc cell responses to
mechanical loading.
Innervation and Vascularization
In degenerated discs, ingrowth of blood vessels and
pain fibres is observed [11, 18]. Both processes are
associated, and therefore may play a direct role in the
development of discogenic back pain. It has been sug-
gested that there is a causal relationship between the
decreased proteoglycan and pressure and an increased
vascularization and innervation of degenerated discs
(Fig. 1.1.2). A possible role of angiogenic and neu-
rotrophic growth factors in the regulation of disc neo-
vascularization and innervation is supported by a
recent immunohistological study [17]. An increased
level of inflammatory mediators and matrix fragments
in degenerated disc tissue is discussed to be responsi-
ble for a progression of the degeneration process
[3, 39]. As an association of degeneration with poly-
morphisms of pro-inflammatory genes (IL-1, IL-6,
COX-2) has been demonstrated, these inflammation
factors might play a role in the disc degradation path-
way. There are an increasing number of studies inves-
tigating the role of mediators, growth factors and
inflammation molecules in disc pathogenesis.
Molecular Aspects of Disc Degeneration
For an explanation of the mechanism of disc degenera-
tion, it is important to know how all the above mentioned
factors, which may contribute to degenerative processes,
directly influence disc cell function as the disc cells,
though they occupy less than 1% of the disc tissue, are
responsible for disc matrix turnover and maintenance.
Alterations of the discs’ physical and biochemical
environment could be transduced into cellular res
ponses via proteins and receptors in the cell membrane,
ion channels and receptors. A high number of signal-
ling transduction pathways is reported and both
mechanical loads and alterations of the metabolic envi-
ronment can initiate via specific pathways intracellular
mechanisms that finally lead to an up- or down-regula-
tion of genes for matrix forming proteins or matrix
degrading enzymes.
Fig. 1.1.2 Scheme of tissue alterations that are discussed to con-
tribute to disc degeneration. There is an imbalance between
matrix formation and degradation, whereas degradation exceeds
biosynthesis. Impaired disc nutrition leads to cell senescence and
apoptosis. Cell death is observed in degenerated discs. The pre-
dominant disc proteoglycan aggrecan is degraded. Therefore,
degenerated discs have a reduced water binding capacity.
Moreover, it is suggested that degraded aggrecan macromolecules
reduce their inhibitory influence on disc vascularization and
innervation, and nerves and blood vessels can invade into the disc
tissue. Recent studies suggest that these disc matrix alterations
are regulated by angiogenic and neurotrophic factors, inflamma-
tion factors and mechanical influences. Their exact role in the
pathogenesis of disc degeneration remains to be investigated
less biosythesis,
more degradation:
MMPs, TIMPs,
Cathepsins
degenerated disc
Pleiotrophin
VEGF
nerves
aggrecan degradationcell death
impaired
nutrition
blood vessels

Degradation and disorganization of the disc matrix
is a visible sign of the degeneration process.
Matrixmetalloproteinases (MMPs) are a well-char-
acterized group of enzymes which are known to play a
crucial role in the degenerative pathways, though the
mechanisms are still unknown. Their activity is modu-
lated by the tissue inhibitors of metalloproteinases
(TIMPs) [22, 44]. Under normal conditions, MMPs and
TIMPs are in balance, but an imbalance between MMPs
and TIMPs can increase MMP activity and degradation.
In the literature, there are reports that several MMPs
(MMP-1, -2, -3, -7, -9, and -13) are increased during
disc degeneration [24, 40]. Many disc matrix collagens
and other macromolecules are possible substrates for
these enzymes. The fact that degradation products that
result from MMP-activity might also have regulatory
functions indicates the high complexity of this aspect of
matrix breakdown. Moreover, the possible role of aggre-
can degrading enzymes (ADAMTs) in disc breakdown
is also discussed in the literature [45].
Another group of matrix-degrading enzymes, the
cathepsins, might also play a role in disc matrix degra-
dation. As these enzymes show their optimum activity
in a more acidic environment, these enzymes could
play a role in later steps of matrix degradation when an
accumulation of lactic acid has already decreased the
pH of the disc matrix [33].
The role of inflammatory mediators in interverte-
bral disc degeneration has been recently reviewed [35].
A number of mediators including nitric oxide, inter-
leukins, PGE2, TNF-alpha and other cytokines have
been implicated in the degeneration of intervertebral
discs (reviewed by Paesold et al. [33]). However,
though these studies show that disc cells have the
potential to produce inflammatory mediators and
cytokines, the exact mechanisms of their role in the
degenerative pathway and their possible contribution
to discogenic back pain remain to be investigated.
In degeneration matrix, breakdown predominates over
synthesis. Upregulation of the responsible proteases such
as MMPs and ADAMTs (a disintegrin and metalloprotei-
nase-1 with thrombospondin motifs) by cytokines includ-
ing IL-1, IL-6 and TNF-alpha, which were all found in
degenerated [34] and herniated discs [4], could play an
important role in the progression of disc degeneration. As
thesecytokinesareallproducedbybothdisccells[19]and
by inflammatory cells like mast cells and macrophages
[21], the source of these cytokines (disc cells or blood
cells) is still unclear. Thus, disc vascularization might
play an important role in the initiation of degradative
pathways regulated by inflammation factors. However, as
disc cells have the potential to produce the inflammatory
cytokines that are necessary to mediate an inflammation
reaction [33], the role of the disc itself in the initiation of
these processes remains to be investigated.
Summary
In summary, though the present results suggest that
disc degeneration might be genetic in origin, the identi-
fication of these genes alone will not provide clinical
solutions for an understanding of pathogenesis path-
ways of disc degeneration. Our knowledge of the biol-
ogy of disc degeneration has increased during the past
years, but there are many unanswered questions that
remain to be investigated: There is still no clear diagno-
sis in approximately 85% of disc degeneration related
disorders and no clinical consensus on indications of
methods and treatment. Functional genetic strategies
will be necessary to identify those genes involved in
disc-degeneration linked pathologies, which can act as
targets for the development of diagnostic and repair
strategies. These techniques have to be based on the
knowledge of disc physiology, cell biology and biome-
chanics to prevent inappropriate or very expensive
treatments of disc degeneration-related disorders.
Acknowledgement TheauthorsthankDr.JillUrban,Department
of Physiology, Anatomy and Geneticsy, Oxford University, UK,
for reviewing this manuscript.
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Introduction
Patients with low back pain constitute a common
patient group and can be divided into the acute group
where the pain may be severe but short standing, and
the group where the pain continues for a longer time
and often influences many aspects of life. Patients with
persisting low back pain, lasting longer than 3 months,
are usually referred to as chronic [4], but perhaps a bet-
ter expression for the condition is long-lasting low back
pain (LLBP). One reason for using long-lasting instead
of chronic is that in low back pain, as in conditions
known to follow the patient for the rest of his/her life, a
well-defined test does not set a precise diagnosis (com-
pare with classic chronic diseases such as diabetes,
heart failure and rheumatoid arthritis). Patients with
LLBP suffer from more or less well-defined conditions
that involve different anatomical structures and path-
ways in the pain system, and only 10–15% of patients
with low back pain get a specific diagnosis [17].
There is a rapid ongoing development in surgical
implants and surgical techniques, as well as suggested
non-surgical treatment methods, for patients with low
back pain. However, the lack of instruments to set a
precise diagnose and/or identify the pain foci in many
of these patients still remains. There are probably mul-
tiple reasons for the somewhat slow development of
diagnostics compared to the rapid development in the
treatment area. One reason for this might be the anat-
omy of the spinal structures with multiple flexible
parts; another, the complexity of the nervous system
where pain may arise from a direct influence of the
peripheral and/or central nervous system as well as the
stimulation of nociceptors located in different spinal
structures. Hence, the slow development of diagnostic
tools may also be caused by the fact that research in the
area of diagnostics for lumbar pain is not only difficult
and time consuming, but also not economically sup-
ported to the same extent as new treatment methods,
where the economical potential can be defined more
easily in a business perspective.
In this article possible pain sources for acute and
chronic low back pain, as well as existing diagnostic
tools to support or reject possible pain foci, are
described. Further, the nervous system response and
modulation mechanisms in response to long-standing
pain, as well as psychological/personality factors influ-
encing pain experiences, are discussed.
Intervertebral Discs
Intervertebral discs are today considered as the main
pain foci in patients with long-standing or chronic low
back pain. The disc is the largest mobile part of the
three-joint system building a motion segment in the
spine (one motion segment defined as two vertebrates
with connecting disc and bilateral facet joints). The
highest shear and fibre strains of the disc have been
demonstrated to occur posterolaterally in response to
combined movements [37]. It is, therefore, not surpris-
ing that disc deterioration often is seen at the posterior
part of the disc as a posterolateral or central disc her-
niation, a disc bulging, or by an increased fluid content
at the posterior border of the disc in MRI (high inten-
sity zone, HIZ).
Low Back Pain: Where Does
the Pain Come From?
Helena Brisby
H. Brisby
Department of Orthopaedics, Sahlgrenska University Hospital,
e-mail: helena.brisby@vgregion.se
1.2

12 H. Brisby
Patients with disc herniations often report preced-
ing low back pain before the onset of sciatic pain. This
pain experience is suggested to be caused by stimula-
tion of nerve endings in the annulus fibrosus due to the
annular tear.
In parallel with investigations on mechanical prob-
lems in the spine, different inflammatory and sig
nalling substances have been suggested to be of
importance in the development and persistence of
back pain. A number of experimental studies have
demonstrated negative effects of disc tissue, and in
particular, nucleus pulposus (NP) on nerve roots. NP
can reduce spinal nerve root conduction velocity [32],
induce nerve fibre degeneration, increase nerve fibre
discharges [40], attract inflammatory cells [31] and
induce increased intraneural capillary permeability
[12]. Pro-inflammatory factors, which include cytok-
ines (e.g. TNF and various interleukins), have been
demonstrated to be present in disc herniation tissue
[2]. High levels of pro-inflammatory mediators (IL-6
and IL-8) have also been found in disc tissue from
patients considered to have discogenic low back pain
undergoing fusion surgery [11].
In non-degenerated discs the presence of nerve fibres
are detected in the absolute outer layers of the annulus
fibrosus [33, 36]. These nerve fibres have been demon-
strated to be both substance P-, calcitonin-gene-related
peptide- (CGRP-) and vasoactive intestinal polypep-
tide- (VIP)- immunoreactive [25]. Nerve impulses sig-
nalling sensory information from the intervertebral disc
have in animal studies been demonstrated to be con-
ducted through the sinuvertebral nerve into rami com-
municantes to sensory neurons in more cranially located
dorsal root ganglia.
In degenerated discs nerve endings have been found
to extend into deeper layers of the annulus fibrosus
[15, 27] and even into the NP [34]. The nerve fibres
have been detected both in the anterior and the poste-
rior parts of disc specimens following vascularized
granulation tissue [25, 34]. The stimulation of these
nerve endings may correlate with the dull chronic ache,
exacerbated by the mechanical load of the spine, that is
experienced by chronic low back pain patients and is
often referred to as discogenic pain.
The main diagnostic tool today to detect disc degen-
eration is magnetic resonance imaging (MRI) where
a number of signs as a decrease in water content,
decreased disc height, disc bulging and/or indirect
signs as vertebrae oedema can be detected. However,
disc degeneration changes seen by MRI investigations
can also be seen at high frequency in asymptomatic
individuals [6, 7, 21].
Another tool that is widely used and debated is dis-
cography. The mechanism of discography involves the
theory of increasing the intradiscal pressure for stimu-
lation of mechanical nociceptors in the annulus fibro-
sus. Based on this assumption, discography has been
suggested to be a tool for evaluating pain characteris-
tics and the precise level of pain generation. However,
concordant pain during a discography is not always
combined with a fissured and ruptured disc on discog-
raphy/CT discography [28] and discography has not
conclusively been demonstrated to be helpful to
increase the result of spinal fusions in chronic low
back patients [13, 14].
Another way to use discography is to look at the
decrease in pain after local anaesthetics are injected;
however, studies in this field are not conclusive.
Facet Joints
In the normal capsule of the facet joint both sensory
and autonomic nerve fibres have been detected, and
thus, the facet joint capsule has a structural basis for
pain perception [38]. As in all joints, osteoarthrosis of
the facet joint may occur and is more common in
patients with disc degeneration. An inflammatory reac-
tion is common in joints with osteoarthrosis and may
stimulate nociceptors. Also mechanosensors may be
influenced if the joint destruction leads to changes in
the mobility of the joint such as in degenerative spon-
dylolisthesis. Facet joint injections are sometimes used
in elderly patients with facet joint osteoarthrosis to
decrease low back pain with a minimal procedure.
Measurement of nitric oxide has been performed in
other osteoarthritic joints such as the knee joint and
temporomandibular joint, and a relationship between
NO and osteoarthrosis, as well as pain, has been
observed [23, 39]. Recently, increased concentration
of NO in, or in close relation to, the facet joints was
also demonstrated in patients with facet joint osteoar-
thritis and low back pain [8].
If measurement of inflammatory markers or pain
markers can be used as diagnostic tools to diagnose
pain originating from the facet joints or some other
part of a painful spinal segment is not yet clear.

131.2 Low Back Pain: Where Does the Pain Come From?
Muscles
Most muscles are well innervated and changes in their
normal function may contribute to the pain experience
both in acute and long-standing low back pain.
In acute low back pain the muscle spasm is often
extensive and has been suggested to be the main reason
for the, often quite severe, pain that may hold back these
patients from almost all movements the first day(s).
However, if the muscle response in acute low back pain
is a primary or a secondary event remains unclear.
The activation patterns for the trunk muscles (both
abdominal and lumbar) have been demonstrated to be
changed in patients with chronic low back pain in
both experimental and clinical studies [16, 22]. If
this, in concordance with the spasm in acute pain, is
a response aiming to stabilize a degenerated spinal
segment by decreasing movement and pain (pain-
adaptation model) or if the changed muscle function
contributes to the pain (pain-spasm-pain model) is,
however, unclear [41].
Ligaments
Nerve fibres have been detected in the posterior-
longitudinal ligament (PLL) [25], but not in some of
the other ligaments such as the ligamentum flavum.
The disc and the PLL have a close anatomical relation-
ship, and it is reasonable to believe that a gradual loss
of disc height causing bulging of the posterior part of
the disc will influence the PLL and thus initiate stimu-
lation of nociceptors in the PLL. This may be caused
by stretching or by chemical factors released from the
disc. However, little is known of the role of PLL and
other ligaments in pain signalling and no diagnostic
tools to look at these structures in vivo in regard to
pain signalling exist.
Vertebraes
Nociceptors have been demonstrated to be present in
bone structures also. Compression fractures in the
spine are a common cause of pain in the spine in older
and/or osteoporotic patients. These can occur without
trauma and can be visualized with x-ray, CT or MR
scans.
In patients with low back pain and disc degeneration,
changes in the vertebrae are also often noticed in MRI.
Signal changes in the bone marrow of the vertebral
body adjacent to a degenerated disc are called Modic
changes and are suggested to be oedema caused by
micro fractures or inflammatory changes [3]. Exactly
how this influence nociceptors is unclear; however,
some correlations between Modic changes and pain
symptoms have been described [24, 26].
Nervous System Involvement
and Adaptation
Free nerve endings present in various spine struc-
tures respond to mechanical pressure/deformation
and chemical stimuli just as in other organs. The pain
impulses are conducted through myelinated A delta
and unmyelinated C fibres to the dorsal root ganglion
and continues via the spinothalamic tract to the thal-
amus and gives rise to the pain experience when
reaching the somatosensory cortex.
Inflammatory substances from a deteriorated disc
or from facet joint arthrosis may influence nerve roots
and DRG, as well as nociceptors in different surround-
ing structures. Biochemical and mechanical factors
may also act together to increase direct negative effects
on nerve roots. Nerve tissue damage may also by itself
increase inflammation by stimulation of macrophage
infiltration and increasing the number of activated
T cells, which may add to the pain [1, 29]. Several bio-
markers associated to pain and/or neurotransmission
have been studied in CSF and serum in patients with
chronic low back pain and also in patients with sciatica
[5, 9, 10, 18]. However, no clear diagnostic help has
been demonstrated by the use of biomarkers in patients
with low back pain.
When handling pain patients, one always has to
bear in mind that pain perception is a subjective expe-
rience. The function of pain perception is primarily the
detection of tissue damage, a mechanism extremely
important for the survival of the individual, but may
also cause major clinical problems. In response to
stimulation of free nerve endings, the somatosen-
sory system may increase its sensitivity resulting in a

14 H. Brisby
non-functional way to respond – normally innocuous
stimuli result in an amplified response (peripheral
sensitization).
Pain impulses may also be modulated at higher cen-
tres, both at the spinal and the supraspinal level (cen-
tral hyperexcitibiability). The first possible level for
impulse modulation is the DRG. The changed magni-
tude of perceived pain is often referred to as neural
plasticity and is considered to play a critical role in the
evolution of chronic pain.
Upregulation of chemokines within the nervous
system, which can be released by astrocytes or micro-
glia, may also contribute to pain modulation and the
development of chronic pain [1]. Augmented central
pain processing has been demonstrated in chronic low
back pain patients with fMRI [19]. Hyperalgesia and
increased neural activity measured by fMRI after
thumbnail pressure were seen in this patient group
when compared to controls. Chronic low back pain
patients have also been demonstrated to have brain
chemistry alterations demonstrated by proton mag-
netic resonance spectroscopy. A reduction of N-acetyl
aspartate and glucose has been found in dorsolateral
prefrontal cortex in these patients [20].
The way people “think” about chronic low back
pain has also been suggested to influence move-
ments, and it has been demonstrated that pain physi-
ology education can markedly alter brain activity,
registered by fMRI, during performance of a specific
task [30].
The Psychosocial Aspects
of Chronic Pain
Since pain is a subjective experience, it can, as with
most experiences, be affected by psychosocial fac-
tors. Low back pain patients with certain psycholog-
ical characteristics such as pain-related anxiety and
low acceptance of pain have been demonstrated to be
less sensitive to treatment [35]. On the other hand,
long-standing severe pain may also affect a person
psychologically and it is, therefore, difficult to ascer-
tain the role psychological factors play in the devel-
opment of chronic pain. However, most authors
agree that psychosocial factors contribute to the indi-
vidual perception of long-standing pain and coping
with it.
Summary
In summary, many structures in the spine can theoreti-
cally contribute to acute low back pain as well as long-
standing low back pain. The intervertebral disc, the
facet joints and the muscle are the most likely local
actors for initiation and maintenance of low back pain
(both acute and long-standing).
There are mechanical as well as biological ratio-
nales behind the theory that the disc is a tissue of major
interest in low back pain. However, when it comes to
diagnostics, investigations/test(s) to detect disc degen-
eration do exist, but are still inconclusive in pointing
out a certain disc as the pain foci. As for the facet
joints, ligaments and the vertebras, still less is known
regarding their role in low back pain patients. In
patients with low back pain, changed activity of the
muscles localized around the spine is common; how-
ever, whether this is a secondary response or not is less
clear. When the complexity of the nervous system and
psychological factors is added, the need for more
research and better diagnostic tools in this patient
group becomes obvious.
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Introduction
The intervertebral disc has traditionally been regarded
as a biomechanically important structure in the spine,
with characteristic biomechanical properties related to
both the annulus fibrosus and the nucleus pulposus.
However, research performed during the last 15 years
has revealed that the intervertebral disc is also biologi-
cally active, and the disc cells have been demonstrated
to produce different pro-inflammatory cytokines, for
example, TNF and various interleukins [7, 18, 22, 24].
These different factors have been shown, in a number
of studies, to play important roles in the pathophysiol-
ogy of disc degeneration and disc herniation. This
chapter provides an overview of the role of cytokines
in degenerative disorders of the spine.
Cytokines
Cytokines constitute a group of small trophic regulatory
proteins and can be divided into, for example, growth
factors, interleukins and interferones. Cytokines are
produced by a large number of different cells through-
out the body and participate in inflammatory responses,
but also take part in other processes such as immuno-
reactions, pain regulation and hematopoesis [37].
Cytokines act by binding to specific membrane
receptors and influence cells in their close surrounding
also at low concentrations. The increased expression
of one cytokine often initiates a cascade of other cytok-
ines, which may lead to synergistic effects, for exam-
ple, an active inflammatory reaction. Some cytokines,
however, may also act as antagonists and have, e.g.
anti-inflammatory effects. The actions of cytokines are
also often closely related to other inflammatory sub-
stances, for example, nitric oxide (NO).
One of the most well-known pro-inflammatory
cytokines is tumour necrosis factor alpha (TNF-alpha),
often referred to nowadays as just Tumour Necrosis
Factor, TNF. TNF has been demonstrated to play a
major role in severe inflammatory events such as sep-
sis and joint destruction in rheumatoid arthritis patients
[12–14, 25, 37].
TNF and Disc Herniation
The observations by Mixter and Barr in 1934 indicated
that sciatica due to lumbar disc herniation was mainly a
mechanical problem related to compression of the nerve
root by the herniated part of the disc [23]. However,
during the last 15 years an alternative concept has grad-
ually evolved pointing out that biological factors related
to various components of the intervertebral disc also
are of major importance in the pathophysiology of sci-
atic pain [27]. Olmarker and co-workers demonstrated
for the first time that autologous nucleus pulposus in a
pig model can induce structural nerve fibre damage as
well as decreased spinal nerve conduction velocity
[30]. In that study the effects of autologous nucleus
pulposus were compared to the effects of autologous
retroperitoneal fat in a blinded experimental set-up.
These original observations have subsequently been
reproduced by other non-related research groups
[2, 14, 17, 34]. A series of experimental investigations
The Role of Cytokines
in the Degenerative Spine
Björn Rydevik and Helena Brisby
B. Rydevik (*)
Department of Orthopaedics, Sahlgrenska University Hospital,
e-mail: bjorn.rydevik@gu.se
1.3

18 B. Rydevik and H. Brisby
have shown that TNF seems to be an important compo-
nent of the nucleus pulposus in causing the nerve root
irritation which renders the nerve root sensitive to
mechanic compression, leading to nerve root pain [26,
29, 31]. These pronounced biologic effects of nucleus
pulposus are related to the cells of the nucleus pulpo-
sus [20]. Local application of exogenous TNF on nerve
roots mimics nucleus pulposus induced nerve injury
[17]. In a series of investigations it has also been dem-
onstrated that local application of nucleus pulposus or
constriction of nerve roots, together with experimental
treatment of the animal with anti-TNF substances such
as etanercept (a soluble receptor) of infliximab (a chi-
meric monoclonal antibody), can prevent the nerve
root injury effects [29, 32, 39]. Moreover, it has been
shown that local application of autologous nucleus
pulposus on spinal nerve roots in rats can induce pain
behavioural changes and that such pain behavioural
changes can be prevented by anti-TNF treatment [28].
Further, in a neurophysiological experimental set-up,
nucleus pulposus application onto the dorsal root gan-
glion has been demonstrated to increase afferent fibre
evoked responses in the thalamus within a few min-
utes, suggesting that nucleus pulposus itself can affect
sensory transmitting pathways [5].
Other Cytokines and Disc Herniation
In a disc herniation rabbit model, intervertebral disc
cells in the created disc herniation have been demon-
strated to produce not only tumour necrosis factor, but
interleukin-1beta as well, at day 1 after the disc injury
[38]. mRNA expressions of different cytokines have
also been investigated in human herniated disc speci-
mens from patients undergoing surgery [1]. IL-8, TNF-
alpha, TGF-beta and IL-1alpha were the most
frequently expressed cytokines of those investigated in
this study, and were found in 70%, 65%, 50% and
39%, respectively, of the specimens. IL-8 mRNA
expression was associated with short symptom dura-
tion (average 3.8 weeks) and also associated with
provocation of the radiating pain by back extension.
The expression of IL-1alpha was found more fre-
quently in transligamentous herniations than in sub-
ligamentous herniations.
Further, patients with lumbar disc herniation and
sciatica of short duration have been shown to have
increased concentration of IL-8 in the cerebrospinal
fluid [3, 6]. These findings support the concept that
several inflammatory substances are involved when a
disc herniation occurs (see Fig. 1.3.1).
Cytokines and Intervertebral Disc
and Facet Joint Degeneration
The cells of the intervertebral disc are biologically
active, as well as responsive, and increase their pro-
duction of interleukin-6, prostaglandin E2 and matrix
metalloproteinases when stimulated with interleu-
kin-1 [22]. These findings are of particular interest in
view of the increased levels of interleukin-1 found in
degenerated intervertebral discs [22]. Disc specimens
from patients with discogenic low back pain have fur-
ther been shown to express increased levels of inter-
leukin-6, interleukin-8 and TNF compared to controls
[7, 36]. Recently the concentration of TNF in blood
samples also was demonstrated to be increased in
patients with chronic low back pain compared to con-
trols [35].
Regarding facet joints it has been shown in a rat
model that experimentally induced lumbar facet
joint inflammation causes mechanical allodynia in
the ipsilateral limb and that the number of TNF-alpha
Cytokines
Nerve root
dysfunction
Ab
Pain
NP
cell
Compression
CSF
serum TNF
IL-8Macrophages
Fig. 1.3.1 Schematic presentation of various events regarding
nerve root involvement in conjunction with disc herniation.
Nerve root compression and application of nucleus pulposus
cause nerve root dysfunction and pain (sciatica). There is evi-
dence for involvement of inflammatory components and activa-
tion of the immune system in this process. Biomarkers for
inflammation, e.g. IL-8 in CSF and TNF in serum, can be
detected. Adapted from Brisby 2000 [3]

191.3 The Role of Cytokines in the Degenerative Spine
immunoreactive cells in the epidural space was
significantly increased compared to controls [33].
Clinical studies have shown increased levels of
interleukin-1b in human facet joint tissue from
patients undergoing surgery for lumbar spinal steno-
sis and disc herniation [16]. These studies also dem-
onstrated that the concentrations of interleukin-1b
correlated with leg pain, and the authors suggested
that interleukin-1b may leak from facet joints to the
nerve roots, and thus induce radiating sciatic pain.
Another inflammatory substance that is closely
related to the presence of cytokines, NO, has recently
been demonstrated to be elevated in facet joints in
patients with chronic low back pain and facet joint
arthrosis when compared to healthy controls [4].
Interestingly, chronic low back pain patients who
responded to facet corticosteroid injection with a
temporary pain reduction, had higher concentrations
of NO in their facet joints than patients who did not
respond positively.
Clinical Studies on Anti-TNF Treatment
for Disc Herniation Induced Sciatica
Based on the basic science research studies regarding
the pathophysiology of sciatic pain related to cytokine
activation, for example, TNF, clinical research has
been conducted investigating these novel therapeutic
strategies. The first study to evaluate the use of
Infliximab (a TNF-alpha monoclonal antibody) to
treat sciatica was published by Karppinen et al. in
2003 [19]. In this study the authors evaluated the
effects in 10 patients with severe sciatic pain due to
lumbar disc herniation, confirmed by MRI, who were
on the waiting list for surgical treatment of the disc
herniation. The results were compared to historical
controls and comprised 62 patients who received
saline in a randomized controlled trial of periradicu-
lar infiltration for sciatica. In this study, Karppinen
and co-workers showed a statistically significant
improvement of leg pain as well as significantly
decreased disability up to 12 weeks after treatment.
Furthermore, they showed that in the study group
there were significantly more patients who were pain
free, defined as more than 75% decrease of leg pain
from baseline, compared to the controls. Also at four
weeks, all of the four patients who were off work in
the treated group had returned to work, while in the
control group about 40% of the patients were still off
work. Genevay and co-workers evaluated the efficacy
of etanercept in the treatment of acute severe sciatica
in a pilot study in which ten patients received three
subcutaneous injections of etanercept (25 mg) every
three days [11]. The results were compared to ten
historical control patients who received intravenous
methylprednisolone for treatment of the same condi-
tion. Visual Analogue Scale for leg pain and back
pain was evaluated at ten days and 6 weeks. The
authors conclude that leg and back pain decrease sig-
nificantly more with anti-TNF treatment than with
intravenous cortisone. Korhonen et al. performed a
randomized controlled trial with 1-year follow-up of
the treatment effects using infliximab for manage-
ment of disc herniation induced sciatica [21]. In this
study no positive effect was seen when comparing
the two groups. However, the authors concluded that
“Although the long-term results of this randomized
trial do not support the use of infliximab compared to
placebo for lumbar radicular pain in patients with
disc herniation induced sciatica, further study in a
sub-group of patients appears to be warranted”. In
particular, the authors noted that at 2 weeks, 33% of
the infliximab treated patients reported more than
75% reduction in leg pain by VAS, while only 17% of
the control patients reported such reduction in leg
pain. Thus, initial clinical studies indicate a possible
role of anti-TNF treatment in disc herniation, but
clinical studies have provided contradictory results. A
recent study by Cohen and co-workers [9] evalutated
the effects of epidural etanercept for the treatment of
sciatica in a RCT in 24 patients. The study showed
positive results of epidural etanercept over a 6 month
follow-up period as compared to placebo control
(saline).
Cytokines and Spine Surgery
It has been shown that patients undergoing micro endo-
scopic surgery for lumbar disc herniation had less sys-
temic cytokine response as compared to patients who
underwent open discectomy [8, 15]. Serum levels of
TNF-alpha, IL-1beta, IL-6, IL-8 and CRP were mea-
sured before surgery and up to 24 h post-operatively

20 B. Rydevik and H. Brisby
[15]. Serum IL-6 and CRP increased less significantly
following microendoscopic surgery than after open
discectomy. The authors conclude that microsurgical
approaches are less traumatic to the patients than open
discectomy. However, both surgical techniques lead to
good clinical results.
Conclusions
Experimental and clinical research performed mainly
during the last 15 years has provided evidence that
cytokines such as TNF and interleukins are involved in
the pathophysiology of various spinal pain conditions
and that these substances may also be activated by spi-
nal surgery. Moreover, a research-based concept that the
intervertebral disc is biologically active and not merely
a biomechanically important structure in the spine has
gradually evolved during the same period of time.
These developments may lead to a better understand-
ing of back pain pathogenesis as well as provide a plat-
formforthedevelopmentofnoveltreatmentapproaches
for certain subgroups of patients with back pain.
Acknowledgements This review is partly based on research
supported by the Swedish Research Council, Project number
K2008-53X-20627-01-3,andMarianneandMarcusWallenberg’s
Foundation.
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