SCIATICA.

STUDIES OF
SYMPTOMS, GENETIC
FACTORS, AND TREATMENT
WITH PERIRADICULAR
INFILTRATION

JARO
KAR PPINEN
Department of Physical Medicine and
Rehabilitation, University of Oulu

O UL U 2 0 0 1

JARO KARPPINEN

SCIATICA. STUDIES OF SYMPTOMS,

GENETIC FACTORS, AND
TREATMENT WITH PERIRADICULAR
INFILTRATION

Academic Dissertation to be presented with the assent of

the Faculty of Medicine, University of Oulu, for public
discussion in the Auditorium 5 of the University Hospital
of Oulu, on September 28th, 2001, at 12 noon.

O U LU N Y LI O P IS TO, O U L U 2 0 0 1

Copyright 2001
University of Oulu, 2001

Manuscript received 24 August 2001

Manuscript accepted 30 August 2001

Communicated by
Docent Ilkka Kiviranta
Professor Kjell Olmarker

ISBN 951-42-6480-0

(URL: http://herkules.oulu.fi/isbn9514264800/)

ALSO AVAILABLE IN PRINTED FORMAT

ISBN 951-42-6479-7
ISSN 0355-3221
(URL: http://herkules.oulu.fi/issn03553221/)
OULU UNIVERSITY PRESS
OULU 2001

Karppinen, Jaro, Sciatica. Studies of symptoms, genetic factors, and treatment with
periradicular infiltration
Department of Physical Medicine and Rehabilitation, University of Oulu, P.O.Box 5000, FIN90014 University of Oulu, Finland
2001
Oulu, Finland
(Manuscript received 24 August 2001)

Abstract
The nature of symptoms and signs of sciatica, genetic factors, and efficacy of periradicular infiltration
were studied in 160 nonoperated patients with unilateral sciatica of 3 to 28 weeks duration.
Back and leg pain (100-mm VAS), disability (Oswestry), and quality-of-life (NHP) were
evaluated. ENMG and 1.5-T MRI were performed on every patient. Presence of the Trp2 and Trp3
alleles of collagen IX was determined from blood samples. After informed consent, patients were
randomized for periradicular infiltration with either methylprednisolonebupivacaine, or saline. The
final follow-up assessment was 1 year after the intervention. Economic analysis was based on data
gathered from the patients, medical records and the National Insurance Register.
At baseline, symptoms of sciatica did not correlate with the type of displacement of the
symptomatic disc in MRI, or the presence of the Trp2 or Trp3 alleles. In the case of the Trp2 allele,
there was a non-significant tendency for the presence of a radial tear at the L45 level. A significant
genotype-phenotype association was found for the Trp3 allele: 15 of 34 (44%) patients with the Trp3
allele were positive for thoracolumbar Scheuermanns disease in MRI compared to 19% for sciatic
patients without the allele (p = 0.003).
Periradicular infiltration with methylprednisolonebupivacaine produced a significant treatment
effect compared to saline at 2 weeks for leg pain, straight leg raising, lumbar flexion and patient
satisfaction. At 6 months, saline was superior to steroid in back and leg pain. By 1 year, 18 patients
in the methylprednisolone group and 15 in the saline group had received surgical treatment.
Subgroup analysis revealed that the short-term effect of the steroid treatment was most
pronounced for contained herniations and symptomatic lesions situated at the L45 (or L34) disc
level. Patients with a contained herniation were less likely to undergo back surgery when receiving
the steroid treatment and they also had significantly fewer days on sick leave from 3 to 6 months.
Counter-effectiveness was most pronounced for extrusions.
The results indicate that disability among sciatic patients may be present even when MRI findings
are minor; and vice versa, prominent MRI findings may not associate with any symptoms. However,
MRI seems to be useful for identifying patients with the Trp3 allele. On the basis of the treatment
intervention results, periradicular infiltration with a combination of steroid and anaesthetic may be
recommended for sciatica as it offers at least short-term pain relief. Furthermore, in the case of
contained herniations the steroid injection is cost-effective and may also prevent surgery. However,
this subgroup analysis calls for a verification study.

Keywords: phenotype, magnetic resonance imaging, collagen IX, conservative treatment,

randomized controlled trials

Acknowledgements
This work was carried out at the Department of Physical Medicine and Rehabilitation,
University Hospital of Oulu, from 1996 to 2001.
Firstly, I am thankful to my teacher and a great innovator, former head of our department, Professor Heikki Vanharanta, who introduced my to the topic of periradicular infiltration, and taught me all I know about intervertebral discs. Throughout these years he has
supported me unfailingly and guided me on the path to fullfilling my dream.
My other official advisor was Docent Antti Malmivaara, without whom this thesis
would not have materialized; he steered me safely through all kinds of hazards and taught
me the secrets of back research. I could always count on him to check my literary efforts.
If only every rookie could have someone like him as their advisor. Thank you Antti.
Docent Leena Ala-Kokko has been my advisor in basic science over the last few years.
We have coworked on several papers, and Leena has taught me much about scientific writing and thinking. In addition to being an outstanding expert, and not merely in collagen
research, she is also a delightful person and true friend. I hope our research efforts together will continue.
The radiologic expertise of Docent Osmo Tervonen proved a crucial factor in the current studies, and he taught me all I know about the interpretation of MRI scans. He is a
visionary, and I am sure we are destined to achieve further interesting findings together.
I want to express my gratitude to the official examiners of this thesis, Docent Ilkka
Kiviranta and Professor Kjell Olmarker. Their constructive criticism improved the quality of the thesis considerably.
Sincere thanks are due to all my coauthors: Mauno Kurunlahti, M.D., Eero Kyllnen,
M.D., Ph.D., Jaana Lohiniva, M.C., Docent Pentti Nieminen, Docent Arto Ohinmaa, Petteri Paassilta, M.D., Tuomo Pienimki, M.D., Ph.D., Docent Eija Pkk, Susanna Rin
(former Annunen), M.D., Pirjo Syrjl, M.D. and Pekka Vasari, M.Sc. Without them, this
thesis would not have been completed.
I am grateful to the staff at the departments of physical medicine and rehabilitation
(especially Mrs. Marjatta Ollikainen, Mrs. Irja Ksm, Mrs. Raija Jalopaasi and Mrs.
Marjatta Riihimki) and radiology for their valuable help during the trial.
I wish to thank Professor Esa Lr for helping me to conduct the trial, and Mr.
Richard Burton for revising the language of the manuscript.

Finally, I want to aknowledge that without the support of my loving wife Kirsi and my
son Mikael, this thesis could even have been attempted. Their patience and support
throughout these long years has been crucial. Because I spent far less at home than I
wanted, Kirsi ran the household as I pursued my scientific activities. The care of our
dogs, Angela and Mika (may their souls rest in peace) and our newcomer Zin, has been
in Kirsis capable hands. Thank you Kirsi!
Financial support was gratefully received from the Yrj Jahnsson Foundation, the Finnish Office for Health Technology Assessment, and the Finnish Work Environment Fund.
Oulu, August 2001

Jaro Karppinen

Abbreviations
AF
AUC
CI
CGRP
CT
CSGE
DRG
EMG
ENMG
FIM
Gd-DTPA
HNP
IL
INOS
MRI
NSAID
NHP
NO
NP
PCR
PG
PLA2
RCT
SLR
SP
TE
TLS
TNF
TR
Trp2 allele

anulus fibrosus
area-under-the-curve
confidence interval
calcitonin gene related peptide
computed tomography
conformation sensitive gel electrophoresis
dorsal root ganglion
needle electromyography
electroneuromyography
Finnish marks
Gadolinium-diethylenetriamine pentaacetic acid
herniated nucleus pulposus
interleukin
inducible nitric oxide synthase
magnetic resonance imaging
nonsteroidal anti-inflammatory drug
Nottingham Health Profile
nitric oxide
nucleus pulposus
polymerase chain reaction
proteoglycan
phospholipase A2
randomized controlled trial
straight leg raising
substance P
echo time
thoracolumbar Scheuermanns disease
tumor necrosis factor
repetition time
sequence variation in the COL9A2 gene changing a codon for glutamine
to one for tryptophan in the 2 chain of collagen IX

Trp3 allele
VAS
VIP

sequence variation in the COL9A3 gene changing a codon for arginine

to one for tryptophan in the 3 chain of collagen IX
visual analog scale
vasoactive intestinal peptide

List of original publications

This thesis is based on the following articles referred to in the text by their Roman
numerals:
I

Karppinen J, Malmivaara A, Tervonen O, Pkk E, Kurunlahti M, Syrjl P,

Vasari P & Vanharanta H (2001) Severity of symptoms and signs in relation to
magnetic resonance imaging finding among sciatic patients. Spine 26: E149-153.

II

Karppinen J, Pkk E, Rin S, Tervonen O, Kurunlahti M, Nieminen P,

Malmivaara A, Ala-Kokko L & Vanharanta H. Magnetic Resonance Imaging
findings in relation to the COL9A2 tryptophan allele among sciatic patients. Spine
In Press.

III

Karppinen J, Pkk E, Paassilta P, Lohiniva J, Kurunlahti M, Tervonen O,

Nieminen P, Malmivaara A, Vanharanta H & Ala-Kokko L. Importance of MRI in
phenotypic evaluation of lumbar disc disease. Association between thoracolumbar
Scheuermanns disease and COL9A3 tryptophan allele. Submitted for publication.

IV

Karppinen J, Malmivaara A, Kurunlahti M, Kyllnen E, Pienimki T, Nieminen P,

Ohinmaa A, Tervonen O & Vanharanta H (2001) Periradicular infiltration for
sciatica. A randomized controlled trial. Spine 26:1059-1067

Karppinen J, Ohinmaa A, Malmivaara A, Kurunlahti M, Kyllnen E, Pienimki T,

Nieminen P, Tervonen O & Vanharanta H. Cost-effectiveness of periradicular
infiltration for sciatica. Subgroup analysis of a randomized controlled trial. Spine In
Press.

Contents
Abstract
Acknowledgements
Abbreviations
List of original publications
1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2 Review of the literature . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.1 Pathogenesis of sciatic pain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.1.1 Intervertebral disc herniation (HNP) . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.1.1.1 Intervertebral disc . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.1.1.2 Mechanisms of disc herniation . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.1.1.3 Nerve root compromise by the HNP . . . . . . . . . . . . . . . . . . . . . . .
2.1.2 Other causes of sciatica . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.2 Pathophysiological mechanisms of sciatica . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.2.1 Compression of nerve roots . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.2.1.1 Chronic compression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.2.1.2 Compression of the dorsal root ganglia (DRG) . . . . . . . . . . . . . . .
2.2.2 Inflammation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.2.2.1 Inflammatory mechanism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.2.2.2 Inflammatory mediators . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.2.3 Combination of compression and inflammation . . . . . . . . . . . . . . . . . . . .
2.2.4 Pain sensitization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.2.5 Effect of methylprednisolone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.3 Etiognosis of sciatica . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.3.1 Constitutional factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.3.2 Environmental and behavioural factors . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.3.3 Genetic factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.4 Diagnosis of sciatica . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.4.1 Medical history . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.4.2 Physical signs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.4.3 Imaging and other diagnostic tests . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.4.4 Associations of symptoms and clinical signs with MRI findings . . . . . . .
2.5 Treatment of sciatica . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.5.1 Natural history . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

15
17
17
17
17
18
19
21
21
21
22
22
23
23
24
26
27
28
28
28
29
30
32
32
32
33
34
35
35

3
4

2.5.2 Conservative treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2.5.2.1 Epidural steroids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.5.2.2 Periradicular infiltration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.5.3 Surgical treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Aims of the study . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Subjects and methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.1 Study population . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.2 Evaluation of patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.2.1 Demographics and clinical symptoms (IV) . . . . . . . . . . . . . . . . . . . . . . .
4.2.2 Genetic analysis (II and III) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.2.3 Diagnostic evaluation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.2.3.1 Clinical examination (IV) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.2.3.2 Magnetic Resonance Imaging (MRI) (IV) . . . . . . . . . . . . . . . . . .
4.2.3.3 Electroneuromyography (ENMG) (I, IV and V) . . . . . . . . . . . . . .
4.3 Patient information and randomization (IV and V) . . . . . . . . . . . . . . . . . . . . . . .
4.4 Periradicular infiltration (IV and V) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.5 Other interventions (IV and V) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.6 Follow-ups and outcome assessment (IV and V) . . . . . . . . . . . . . . . . . . . . . . . .
4.7 Economic analysis (IV and V) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.8 Statistical analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.8.1 Calculation of sample size (IV) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.8.2 Reliability of MRI findings (IV) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.8.3 Associations of MRI findings, clinical tests and symptoms (I) . . . . . . . . .
4.8.4 Evaluation of patients with the Trp2 and Trp3 alleles (II and III) . . . . . . .
4.8.5 Estimation of treatment efficacy and cost-effectiveness (IV and V) . . . . .
4.8.6 Subgroup analysis (V) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.1 Baseline characteristics of the patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.2 Correlations of symptoms and signs to MRI findings (I) . . . . . . . . . . . . . . . . . .
5.3 Evaluation of patients with the Trp2 and Trp3 alleles (II and III) . . . . . . . . . . .
5.3.1 Demographic and clinical characteristics . . . . . . . . . . . . . . . . . . . . . . . . . .
5.3.2 MRI findings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.3.3 Thoracolumbar Scheuermanns disease (TLS) . . . . . . . . . . . . . . . . . . . . .
5.4 Clinical efficacy of periradicular infiltration.
Intention-to-treat analysis (IV) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.5 Clinical efficacy of periradicular infiltration. Subgroup analysis (V) . . . . . . . . .
5.5.1 Contained herniations vs. extrusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.5.2 Disc level . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.6 Cost-effectiveness of the treatments in subgroups (V) . . . . . . . . . . . . . . . . . . . .
5.6.1 Contained herniations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.6.2 Extrusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.6.3 Disc level . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6.1 Study population . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6.2 Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6.3 MRI findings versus symptoms and signs of sciatica (I) . . . . . . . . . . . . . . . . . .

35
36
37
37
39
40
40
40
40
41
41
41
42
43
43
43
44
45
45
45
45
46
46
46
47
48
49
49
51
52
52
53
53
55
60
60
61
61
61
62
64
65
65
66
67

6.4 Phenotype of patients with the Trp2 allele (II) . . . . . . . . . . . . . . . . . . . . . . . . . .

6.5 Phenotype of patients with the Trp3 allele (III) . . . . . . . . . . . . . . . . . . . . . . . . .
6.6 Intention-to-treat analysis of periradicular infiltration (IV) . . . . . . . . . . . . . . . .
6.7 Subgroup analysis of periradicular infiltration (V) . . . . . . . . . . . . . . . . . . . . . . .
7 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

67
68
70
71
73
74

1 Introduction
Sciatic pain is classified as radicular pain pain radiating from the back into the
dermatome of the affected nerve root along the femoral or sciatic nerve trunk, or as
nonradicular pain pain radiating in the leg in a nondermatomal pattern (van
Akkerveeken 1996). True radiculopathy is defined as radicular pain in the presence of a
neurological deficit (Bogduk 1997a).
Various surveys have found the prevalence of sciatic pain in the adult population to be
between 1 and 40 % (Frymoyer 1991). The prevalence of lumbar disc syndrome
(herniated disc or typical sciatica) was studied as part of the Mini-Finland Health Survey
(Helivaara et al. 1987a). A diagnosis of lumbar disc syndrome was made for 5.1% of the
men and 3.7% of the women aged 30 years or over. In a Finnish longitudinal cohort study,
symptomatic lumbar disc disease (herniated nucleus pulposus (HNP) or sciatica)
appeared around the age of 15 years, and the incidence rose more sharply from the age of
19 (Zitting et al. 1998). In Finland, the prevalence of age-adjusted work disability in
sciatica has been reported to be over 14 % (Helivaara et al. 1989). In 1999,
compensation was paid for almost 600 000 days of sick leave because of some ICD-10
M51-diagnosis (e.g. radiculopathy M51.1, and disc displacement M51.2, but not low back
pain M54.5). According to the National Insurance Register, the reimbursement cost of
these sick leaves was FIM 112 million ($22 million) in 1999.
Surgery is traditionally regarded as the only effective treatment for sciatica (Mixter &
Barr 1934, Weber 1983). Knowledge of the pathophysiology of sciatica has, however,
increased greatly during the last decade. It was observed that disc herniations are common
in asymptomatics (Boden et al. 1990, Jensen et al. 1994), and that disc ruptures without a
herniation can induce similar sciatic symptoms to HNP (Ohnmeiss et al. 1997, Ohnmeiss
et al. 1999). The concept of inflammation underlying sciatica was presented (McCarron et
al. 1987, Olmarker et al. 1993, Olmarker et al. 1995, Saal 1995). Furthermore, the genetic
background of sciatica is also being resolved (Annunen et al. 1999, Paassilta et al. 2001).
In this thesis, the study population consisted of consecutive sciatic patients. Patients
were thoroughly examined clinically and by MRI in order to describe the determinants of
sciatic symptoms and signs, and the phenotypes of the different Trp alleles of collagen IX.

16
Patients were randomized to receive periradicular infiltration with either a combination of
steroid and anaesthetic, or saline. Theoretically, in view of the inflammatory concept,
steroid treatment could be a cost-effective treatment option for sciatica.

2 Review of the literature

2.1 Pathogenesis of sciatic pain

The tissue origin of sciatic pain has been studied during decompression operations
performed with local anaesthesia. In these studies, sciatic pain could be produced only by
pressure on the compressed, swollen nerve root, or on the dorsal root ganglion (DRG).
Pressure on normal nerve roots or on other tissue did not produce sciatica (Smyth &
Wright 1958, Kuslich et al. 1991). The most common cause of nerve root compression is
HNP (Mixter & Barr 1934).

2.1.1 Intervertebral disc herniation (HNP)

2.1.1.1 Intervertebral disc

Intervertebral disc is composed of lamellar anulus fibrosus (AF) encircling the central
gelatinous nucleus pulposus (NP), and thin vertebral endplates. Collagens and
proteoglycans (PG) are the primary structural components of the intervertebral disc
macromolecular framework (Eyre & Muir 1976, Buckwalter 1995, Antoniou et al. 1996).
The NP consists of a central core of a well-hydrated PG matrix entrapped in a loose,
irregular meshwork of collagen fibers. The PGs consist of sulphated glycosaminoglycan
side-chains (chondroitin and keratan sulphates) covalently bound to a protein core. The
negatively charged sulphate and carboxyl groups attract cations (Na+, H+). Indeed, in
children and young adults, water accounts for over 80% of the weight of the NP.
Hyaluronic acid, long, nonsulphated glycosaminoglycan, binds multiple aggrecan
molecules stabilized by a link protein, to form large PG aggregates (Eyre 1979). PGs

18
account for 50 % of the dry weight of the NP from a child, whereas collagens account for
about 20 % (Buckwalter 1995). Collagen II is the major collagen of human NP (~80 %),
but collagen VI (~15 %), collagen IX (12%), collagen XI (3%) and traces of collagen III
can also be found (Hukins 1988, Eyre et al. 1989, Buckwalter 1995).
The AF consists of 1020 concentric lamellae of collagen fibres. The lamellae of the
outer part of the AF are attached to the ring apophysis of the upper and lower vertebrae.
The inner lamellae are attached to the end-plates. The content of collagen I increases (up
to 80 %) towards the outer part of the AF and the content of collagen II towards the NP.
Minor collagens of the AF include type V (3%), type VI (10%), type IX (12%) and
traces of type III collagen (Eyre et al. 1989, Buckwalter 1995).
The end-plates consist of hyaline cartilage, which is approximately 1 mm thick. In
contrast to articular cartilage, there are no collagenous connections directly anchoring the
end-plates to the bone of the underlying vertebral bodies. The collagen fibers of the inner
AF are attached to the end-plates. The cells of the cartilaginous end-plate are
chondrocytic cells. The end-plate has a lower PG and water content, and a higher collagen
content than do adjacent regions of the disc (Roberts et al. 1989). Its function is to serve
as a semipermeable membrane to facilitate diffusion of solutes from the vertebra to the
disc (Eyre 1979).
Human intervertebral discs undergo age-related degenerative changes, potential causes
of which include declining nutrition, loss of viable cells, cell senescence, posttranslational modification of matrix proteins, accumulation of degraded matrix proteins,
and fatigue failure of the matrix (Buckwalter 1995). The onset of disc degeneration is not
possible to observe in humans, but the process has been studied thoroughly in animal
models. After incision of rabbit AF, acute herniation of the NP was produced, followed by
progressive dehydration of the NP with a concomitant decrease in total uronic acid
content (constituent of PGs) (Lipson & Muir 1981a, Lipson & Muir 1981b). Similar
results (decrease of PG and water content in the NP) have been obtained in a pig model
(Karppinen et al. 1995). The phenotype of the chondrocytes also seems to change after
the injury; instead of producing collagen II, the chondrocytes begin to produce collagens
I, III, IV and VI (Kp et al. 1994, Kp et al. 1995).

2.1.1.2 Mechanisms of disc herniation

Mechanisms of disc injuries have been studied in animal and cadaver models. After the
injury, progressive water and PG loss in the NP occurs (Karppinen et al 1995). In postmortem analysis of human spine samples, three types of anular tears have been shown:
concentric, transverse and radial tears (Yu et al. 1988b). Of these, concentric tears are not
seen in MRI. Transverse, or rim lesions are suggested to be due to trauma rather than
biochemical degradation, and they develop independently of nuclear degeneration (Osti et
al. 1992). High-intensity zone (HIZ) lesions, which seem to associate with typical pain in
discography, represent a combination of radial and circumferential tears (Aprill &
Bogduk 1992).

19
Tears of the anulus are suggested to play an important role in the degeneration of the
intervertebral joint complex (Osti et al. 1990). Radial ruptures are especially interesting
as they precede disc degeneration (Yu et al. 1988a, Osti et al. 1992). Radial tears
extending from the NP into the middle layers of the AF are associated with subjective
pain in discography (Vanharanta et al. 1988a, Vanharanta et al. 1989, Moneta et al. 1994),
and are also known to cause sciatic pain (Ohnmeiss et al. 1997).
Biomechanisms of disc herniation have been studied in cadaver spine segments.
Hyperflexion injury caused an anular tear either centrally or on the side opposite the
component of lateral bending where the AF was stretched the most (Adams & Hutton
1982). The fissure through which the nuclear pulp was extruded usually occurred at the
boundary between the AF and the end-plate. Large central nuclear extrusions ruptured the
posterior longitudinal ligament, whereas smaller extrusions either formed a bulge behind
it or were deflected sideways and appeared on one or both posterior lateral margins of the
disc (Adams & Hutton 1982). In the same study it was shown that the susceptibility of a
disc to prolapse depends on age, degree of disc degeneration and spinal level. Slightly
degenerated lower lumbar discs of people aged between 40 and 50 seemed particularly
vulnerable (Adams & Hutton 1982). The same authors showed that even young discs can
prolapse slowly over days or months by fatigue compressive loading of a flexed disc
(Adams & Hutton 1985). Disc deterioration occurred gradually. Distortion of the
posterior lamellae is first observed, then breaking through the lamellae, and thereafter
gradual nuclear extrusion through posteriolateral anular fissures and disruption of anular
lamellae (Adams & Hutton 1985). This gradual disc prolapse mechanism probably
accounts for the non-dramatic disc herniation cases.

2.1.1.3 Nerve root compromise by the HNP

Nuclear extrusion usually occurs posterolaterally, at the weak point of the dorsal AF
(Farfan et al. 1970, Adams & Hutton 1985). At this point, the structures prone to
irritation by the HNP are nerve roots. At each lumbar level, a pair of dorsal and a pair of
ventral nerve roots leave the dural sac just above the level of each intervertebral foramen,
taking with them an extension of dura and arachnoid mater called the dural sleeve (Figure
1A). Later, dorsal and ventral roots at both sides converge at the outlet of the root canal,
giving rise to a spinal nerve (Olmarker 1991, Bogduk 1997a).
The dorsal root transmits sensory fibres from the spinal nerve to the spinal cord,
whereas the ventral root largely transmits motor fibres, along with some sensory fibres,
from the cord to the spinal nerves. The diameter of large myelinated axons (A and A
fibers) ranges between 1.5 and 16 m, while the unmyelinated nociceptor axons (C
fibres) range between 0.4 and 1.6 m (Olmarker 1991, Bogduk 1997a). The soma of
ventral roots lie in the ventral horn of the spinal cord, whereas the soma of the afferent
dorsal roots lie in the dorsal root ganglia (DRG). A DRG typically lies at the distal end of
the dorsal root inside the apex of the dural sleeve, directly inferior to the pedicle and close
to the nerve root axilla (Cohen et al. 1990).

20
The nerve roots differ from peripheral nerves as they are enclosed by the thin root
sheath, cerebrospinal fluid and meninges. The axons of the peripheral nerves, on the other
hand, areenclosed by the epineurium and the perineurium (Olmarker 1991). Moreover,
the arteriolar and venular networks are less developed in the nerve roots (Figure 1B), and
there is no regional blood supply to the intrinsic vasculature, as in peripheral nerves.
These anatomical circumstances make nerve roots more vulnerable to mechanical stress
than peripheral nerves. The findings in the porcine model indicate that diffusion from the
cerebrospinal fluid can not compensate completely for compression-induced effects on
the blood flow in the intrinsic vessels (Olmarker et al. 1990). DRG is an exceptional
neural tissue as it is covered by a tight capsule with a blood-nerve barrier less well
developed than in the nerve root vessels (Seitz et al. 1985), which makes it more prone to
the closed compartment syndrome (Rydevik et al. 1989).

A
D

DR

SN
DRG
VR
CSF
RS

B
GP

SA
NRA

Fig. 1. A) Cross-section of the spinal cord with a ventral (VR) and dorsal (DR) spinal nerve root.
The cell bodies of the motor axons are located in the anterior horn of the gray matter of the
spinal cord, whereas the cell bodies of the sensory axons of the dorsal root are located in the
dorsal root ganglion (DRG). The ventral and dorsal nerve roots blend just caudal to the DRG,
and form the spinal nerve (SN). Nerve roots are covered with root sheath (RS), a continuation
of the pia mater covering the spinal cord. The spinal cord and nerve roots are floating freely in
the cerebrospinal fluid (CSF) in the subarachnoid space. D=dura. B) Schematic drawing of
vascular supply to the spinal cord and nerve roots. The nervous system branch of the segmental
artery (SA) joins the nerve root and forms a ganglionic plexus (GP) in the DRG and caudal
nerve root arteries (NRA) running in cranial direction. From the vaso corona of the spinal cord,
cranial arteries run in caudal direction in the nerve roots. (Reproduced with permission from,
Olmarker K, Thesis, Gothenburg 1990).

21

2.1.2 Other causes of sciatica

Other causes of sciatica can be divided into intraspinal or extraspinal. Intraspinal causes
include spondylosis and osteoarthritis with encroachment upon the intervertebral
foramina (Schellinger et al. 1987). Lateral lumbar spinal canal stenosis due to
osteoarthritis can be divided into entrance zone, mid zone and exit zone stenosis (Lee et
al. 1988). The most common cause of entrance zone stenosis is hypertrophic
osteoarthritis of the facet joint, particularly involving the superior articular process,
whereas exit zone stenosis is caused typically by a subluxed facet joint or by an
osteophytic ridge along the superior margin of the disc. However, mid zone stenosis is
clinically the most important entity, because the DRG occupies a large part of the mid
zone. Two common causes are osteophyte formation under the pars interarticularis where
the ligamentum flavum is attached, and fibrocartilagenous or bursal tissue hypertrophic at
a spondylolytic defect (Lee et al. 1988). Spondylolisthesis is occasionally responsible for
sciatica, and symptoms are usually bilateral (Kikuchi & Hasue 1988). Zygoapophyseal
joint cyst, on the other hand, produces unilateral symptoms (Reust et al. 1988). Other
intraspinal processes causing sciatica include tumors, abscesses and tuberculosis (Elliott
& Schutta 1971).
Extraspinal causes can be differentiated into diseases of the lumbosacral plexus and
lesions of the sciatic nerve or its branches. Lesions of the lumbosacral plexus usually
produce symptoms of more than one segment, and often the pelvic condition responsible
for lumbosacral pain overshadows sciatica. In disease of the sciatic nerve, pain is not
usually a prominent symptom (Elliott & Schutta 1971). Diseases of the lumbosacral
plexus include pelvic tumors (Bickels et al. 1999), intrapelvic aneurysm (Dudeney et al.
1998), and endometriosis (Dhote et al. 1996). Disease of the sciatic nerve can be caused
by compression of the nerve as in hamstring (Puranen & Orava 1991) and piriformis
syndromes (Hanania & Kitain 1998), or by vascular compromise as in diabetes (Naftulin
et al. 1993). A rare cause of sciatica is cervical and thoracic spinal cord compression (Ito
et al. 1999).
Physicians have to recognize nondermatomal pain which is synonymous with referred
pain from the mesenchymal structures (bones, joints, ligaments and bursae) of the
lumbosacral spine, the pelvis and the lower extremity. Referred pain is deep, dull, boring
and aching. It follows the distribution of the myotomes and sclerotomes (Elliott & Schutta
1971, Bogduk 1997a), as opposed to dermatomally distributed radicular pain.

2.2 Pathophysiological mechanisms of sciatica

2.2.1 Compression of nerve roots
Traditionally, compression of nerve roots or DRGs by the HNP has been regarded as the
cause of sciatica, although HNP can be found in 20% to 36%, depending on the age, of
asymptomatic subjects (Wiesel et al. 1984, Boden et al. 1990, Jensen et al. 1994).

22
Similarly, internal disc ruptures (without HNP) may also induce disabling radicular pain,
indicating the existence of an alternative mechanism to neural compression (Ohnmeiss et
al. 1997, Ohnmeiss et al. 1999).
The effect of compression on the nerve roots has been studied extensively in animal
models. Rapid onset (0.050.1 s) compression of porcine nerve roots induced intraneural
oedema after 2 minutes compression at 50 mmHg, whereas following slow onset (15
20 s) compression, oedema occurred after 2 hours (Olmarker 1991). Significant reduction
(2030 %) of nutrition was already observed at 10 mmHg compression, probably due to
impairment of cerebrospinal fluid flow (Olmarker 1991). Intraneural oedema may
increase the endoneural fluid pressure and lead to impairment of intraneural blood flow as
in the closed compartment syndrome (Rydevik et al. 1989). In dogs, compression induced
a marked extravasation of protein tracers; electron microscopy showed the tight junctions
of the intraneural capillaries opened and vesicular transport increased, indicating
disruption of the blood-nerve barrier (Kobayashi et al. 1993). In MRI, this was reflected
as enhancement of the compressed nerve roots.

2.2.1.1 Chronic compression

When normal feline dorsal roots were compressed with chromic gut ligatures, only a brief
discharge of maximally 20 impulses was observed (Howe et al. 1977). Chronic injury,
however, greatly increased their mechanical sensitivity. When chronic compression of
canine nerve roots was studied with a silastic tube model, impairment of the blood-nerve
barrier (thickening of the dura and arachnoid membrane around the affected nerve root)
was observed after 1 month, suggesting that the most important factor in nerve root
dysfunction due to chronic compression is intraradicular oedema induced by increased
local vascular permeability (Yoshizawa et al. 1995). Similar nerve root enhancement and
axonal degeneration, along with marked inflammatory cell infiltration, were also found in
baboons (Nguyen et al. 1995). Destruction of large myelinated fibers was observed after
1 week of gradual chronic compression of porcine nerve roots (Cornefjord et al. 1997).
Endoneural bleeding and signs of inflammation in the compressed nerve roots were more
common after 1 than 4 weeks.

2.2.1.2 Compression of the dorsal root ganglia (DRG)

In contrast to nerve roots, even normal noninjured DRGs were very sensitive to
compression, gentle pressure producing prolonged repetitive firing in single afferent
fibers (Howe et al. 1977). This was confirmed by measuring the responses in dorsal horn
wide dynamic range neurons to compression of dorsal root or DRG (Hanai et al. 1996).
Compression of the DRG, but not the dorsal root, produced prolonged repetitive firing.
Hypoxia further increased sensitivity to mechanical stimuli and even evoked spontaneous
firing in an in vitro model (Sugawara et al. 1996). The relevance of DRGs in the

23
pathophysiology of sciatica is supported by observations that the DRG is the most likely
site of compression from a herniated disc (Lindblom & Rexed 1948, Rydevik et al.
1984).

2.2.2 Inflammation
The extruded nuclear material of the disc is chemically inflammatory and neurotoxic
(McCarron et al. 1987). When in contact with the nerve roots, the nuclear material
(without any compression) induces structural and functional changes in porcine nerve
roots (Olmarker et al. 1993). The functional changes include focal degeneration of
myelinated fibers and focal Schwann cell damage in nondegenerated axons. The damage
to the Schwann cells resulted in a disintegration of Schmidt-Lanterman incisures
(Olmarker et al. 1996). These incisures connect the cytoplasm of the Schwann cells
situated outside the myelin sheath to the part on its inner side, the external parts of the
Schwann cells being essential for the normal impulse conduction properties of the axons.
These studies were performed by applying a large amount of NP on the nerve roots, but
similar functional nerve root damage was also observed in pigs after experimental disc
herniation (Kayama et al. 1996).

2.2.2.1 Inflammatory mechanism

The nerve fiber damage induced by the NP could be due to its toxicity. In fact, many
substances, including hydrogen ions and glycoproteins, has been suspected to cause
chemical radiculitis (Nachemson 1969, Marshall et al. 1977). However, NP is also
chemotactic, attracting leukocytes, and it may also induce macromolecular leakage and
spontaneous firing of axons in vitro (Olmarker et al. 1995). In chronic compression
studies, inflammatory cell infiltrates, mainly macrophages, have been observed
(Yoshizawa et al. 1995, Nguyen et al. 1995). Furthermore, in a rat model of mechanical
hyperalgesia induced by application of NP to nerve roots, depletion of leukocytes
inhibited the generation of hyperalgesia (Kawakami et al. 2000b). This indicated that
leukotactic properties of the HNP are important in the production of pain-related
behaviour. The cells first appearing in and around the herniated NP on nerve root were
polymorphonuclear leukocytes, whereas macrophages, originating from monocytes, did
not predominate until after a few days and then remained in the affected region until the
inflammation subsided (Kawakami et al. 2000b).
The observed decrease in nerve conduction velocity may be due to impaired ion
exchange following changes in Schmidt-Lanterman incisures (Olmarker et al. 1996) or to
ischaemia (Kayama et al. 1996). The latter mechanism is supported by the finding that
autologous NP increased endoneural pressure and reduced blood flow (assessed with a
laser Doppler flow probe) by 10 % to 20 % in the DRG (Yabuki et al. 1998a). Irritation of
a nerve root thus caused a compartment syndrome in the DRG. Interestingly, blood flow

24
in the ipsilateral hind paw was reduced, too (Yabuki et al. 2000). Also after experimental
herniation, blood flow in canine nerve root was reduced, correlating with the decrease in
nerve conduction velocity (Otani et al. 1999). The decrease in blood flow was maximal at
1 week, recovering within 1 month. In the DRG, however, there was a statistically
significant decrease in blood flow only at 1 week, and no reduction/recovery pattern was
observed (Otani et al. 1999).

2.2.2.2 Inflammatory mediators

The neurotoxicity of the NP seems to be associated with disc cells, as freezing prevented
the neuronal damage (Olmarker et al. 1997, Kayama et al. 1998). In the following, the
possible inflammatory candidates in the NP are discussed.
Phospholipase A2. Phospholipase A2 (PLA2) is the rate-limiting enzyme in the
synthesis of proinflammatory lipid mediators (prostaglandins, leukotrienes, lipoxenies,
and platelet-activating factor). The enzyme liberates arachidonic acid from the membrane
phospholipids, and is secreted extracellularly by activated phagocytes in response to
cytokines (Vadas & Pruzanski 1986). Additionally, it is released from rabbit chondrocytes
by IL-1 (Chang et al. 1986). PLA2 is found in extraordinarily high concentrations in
herniated and painful discs (Saal et al. 1990b), and the enzyme is also itself inflammatory
(Franson et al. 1992). PLA2 is calcium-dependent, adsorbing tightly to plasma
membranes and intact cells (Vadas & Pruzanski 1986).
When PLA2 was injected into the nerve receptive fields of isolated rabbit facet joints,
it produced sensitization of the nerves and recruitment of silent neural units.
Histologically, inflammation was observed in the samples 2 hours after the injection
(zaktay et al. 1998). This resembled the observed neuroexitatory effect of NP (multiunit
discharge lasting for several minutes) (Cavanaugh 1995). Furthermore, when PLA2 was
injected epidurally, motor weakness, demyelinisation, and increased sensitivity of dorsal
roots to mechanical stimulation were observed after 3 days, but not beyond 3 weeks
(Chen et al. 1997). This could explain the finding of low phospholipase activities in
herniated tissue samples (Grnblad et al. 1996), because surgery is usually undertaken
several weeks after the onset of symptoms. In fact, phospholipase A2 activity was found
to be maximal 1 week after chromic gut ligature, whereas thermal hyperalgesia was
maximal 3 weeks after surgery (Lee et al. 1998). In a rat model, NP-induced mechanical
hyperalgesia was abolished by mepacrine, a selective inhibitor of phospholipase A2
(Kawakami et al. 1998). Interestingly, anulus or a combination of anulus and NP induced
mechanical hyperalgesia only after addition of a selective inhibitor of inducible nitric
oxide synthase (iNOS), indicating a role for nitric oxide (NO) in reducing mechanical
hyperalgesia in this model (Kawakami et al. 1998).
Tumor necrosis factor (TNF-). TNF- is a cytokine produced mainly by activated
macrophages and T cells in response to inflammation, and by mast cells and Schwann
cells in response to peripheral nerve injury (Wagner & Myers 1996b, Bemelmans et al.
1996). It activates the transcription factors NF-B and AP-1 by binding to its p55 TNF
receptor (TNFRI), thereby inducing the production of proinflammatory and

25
immunomodulatory genes (Darnay & Aggarwal 1997). Endoneurial TNF- causes
demyelinisation, axonal degeneration, and hyperalgesic pain states (Wagner & Myers
1996a), while anti-inflammatory IL-10 treatment in chronic constriction injury to
peripheral nerves decreases thermal hyperalgesia, macrophage recruitment and
endoneurial TNF- expression (Wagner et al. 1998). However, TNF- also has an
important role in the resorption of disc herniation (Haro et al. 2000). Macrophages secrete
matrilysin-enzyme (MMP-7), which liberates soluble TNF- from macrophage cell
membranes. Soluble TNF- induced disc chondrocytes to secrete stromelysin-1 enzyme
(MMP-3), which was required for the release of a macrophage chemoattractant and
subsequent macrophage infiltration of the disc (Haro et al. 2000).
In thermal hyperalgesia, two peaks have been associated with Wallerian degeneration,
and can be reproduced in chronic injury to peripheral nerves (Shubayev & Myers 2000).
These peaks are also related to changes in TNF- expression. It seems that the first TNF peak, 6 hours after the peripheral nerve injury, is due to the local expression of the
cytotoxic transmembrane 26 kDa TNF- protein released by the resident Schwann cell,
mast cells and macrophages. This peak in TNF- expression corresponds to an increase
in activity of gelatinase B (MMP-9), which is already greatly upregulated 3 hours after
the injury. The second peak occurs 5 days after the injury, and may represent TNF-
protein released by haematogenously recruited macrophages. The second peak
corresponds to an increase in soluble 17 kDa TNF- and gelatinase A (MMP-2)
upregulation (Shubayev & Myers 2000). When degenerated and normal human articular
cartilage were compared, TNF- (and IL-1) was expressed only in the superficial zone
of degenerated cartilage. However, the phenotype of chondrocytes varied widely even in
degenerated cartilage, 5 to 40 % of cells expressing these cytokines (Tetlow et al. 2001).
Recently it was found immunohistochemically that TNF- was expressed in the NP
(Olmarker & Larsson 1998); in fact, 17 kDa cytokine was expressed at a concentration of
approximately 0.5 ng per disc (Igarashi et al. 2000). Consistent with the results of Haro
and co-workers (Haro et al. 2000), TNF- (and other cytokines) was produced in
protrusion type herniations by chondrocytes, but in extrusions by histiocytes, fibroblasts,
and endothelial cells constituting granulation tissue (Takahashi et al. 1996).
Exogenous TNF- produced neuropathological and behavioural changes (Wallerian
degeneration of nerve fibers, macrophage recruitment to phagocytoze the debris, splitting
of the myelin sheath) that mimicked those of the NP (Igarashi et al. 2000). Later, in a
chronic peripheral nerve injury model, remyelinisation and reactive changes in
endothelial cells (collagen deposition in response to fibroblast activation) have been
observed after intraneural injection of TNF- (Redford et al. 1995). In herniated disc
tissues similar changes, such as endothelial proliferation, vascular activation and collagen
proliferation have been observed (Cooper et al. 1995). Treatment with doxycycline, a
nonspecific TNF- antagonist, blocked the NP-induced reduction of nerve conduction
velocity (Olmarker & Larsson 1998). More recently, both soluble TNF- receptor
(Embrel) and TNF- antibodies (Remicade) reversed NP-induced nerve conduction
block (Olmarker & Rydevik 2001). Furthermore, these antagonists also specifically
blocked the NP-induced oedema and thrombus formation, indicating that these vascular
changes were TNF- mediated. In another study, topical pentoxifylline, an inhibitor of

26
TNF- synthesis, prevented the NP-induced compartment syndrome in the DRG (Yabuki
et al. 2001). In conclusion, it seems that TNF- exerts a crucial role in NP-induced nerve
root damage.
Other inflammatory mediators. IL-1 plays an important role in experimental allergic
radiculitis induced in rats, since IL-1 receptor antagonist ameliorated the symptoms
(Wehling et al. 1996). In fact, IL-1 and IFN act synergistically with TNF- and are more
or less neurotoxic (Chao et al. 1995). In vitro, herniated discs spontaneously produce
nitric oxide, matrix metalloproteinases, IL-6 and PgE2 (Kang et al. 1997). Even control
discs synthetized these substances when the tissue samples were exposed to IL-1 (but
not without). In herniated discs, IL-1 further increased the production of NO, IL-6 and
PgE2 (Kang et al. 1997).
In a canine model, PgE2 produced ectopic firing of nerve roots, which was suppressed
with steroid (Muramoto et al. 1997). PgE2 production in vitro could also be blocked with
inducible cyclo-oxygenase enzyme (COX-2) inhibitor (Miyamoto et al. 2000).
NO seems to play an important role in radicular pain. In a disc herniation sample,
iNOS was produced by cells in the granulation tissue around the extruded anulus fibrosus
(Hashizume et al. 1997). Autologous epidurally applied AF (but not NP) produced
thermal hyperalgesia in a rat model (Kawakami et al. 1998). Thermal hyperalgesia was
abated with epidural saline and abolished with a specific inhibitor of iNOS. In pigs, a
specific inhibitor of iNOS, aminoguanidine, prevented the formation of NP-induced
oedema and a negative effect on the nerve conduction velocity (Brisby et al. 2000), but in
the rat model NO reduced mechanical hyperalgesia (Kawakami et al. 1998). NO seems
thus to have a dual action on the nerve roots, both negative and positive, similar to
articular cartilage where it is involved in both the catabolism and synthesis of PGs
(Stefanovic-Racic et al. 1996).

2.2.3 Combination of compression and inflammation

When the effects of the NP, compression by silk ligature, and the combination of these
two were compared in rats, thermal hyperalgesia was induced only by the combination of
compression and NP (Kawakami et al. 2000a). Even though silk ligature did not effect
thermal withdrawal latency, histologically there were fewer large and more smalldiameter fibers than with the combination of silk and NP (Kawakami et al. 2000a).
Similar results were observed in a study where three experimental procedures (either NP
applied on the rat L4 nerve root, nerve root displacement with a needle, or a combination)
were compared in a rat model (Olmarker & Myers 1998). There was a significant
reduction in mechanical threshold at days 2, 4, 16 and 18, and significant thermal
hyperalgesia from day 2 until day 14 post-operatively in the combination protocol
animals. Histologically, a significant cellular injury by 21 days post-operatively was
noticeable. Oedema and fibrotic reactions were observed in the subperitoneal/root sheath
area and in the endoneural space. There was also perivascular oedema and indications of
reactive endothelial cells, axonal demyelination, myelin splitting, and Schwann cell
hypertrophy (Olmarker & Myers 1998). On the basis of these studies, the probable

27
scenario is that the ruptured intervertebral disc with leaking nucleus sensitizes the nerve
root(s), and in the presence of mechanical deformation, pain-related behaviour is induced.
This accords with observations that stimulation of nerve root in contact with herniated
disc tissue reproduces sciatic pain (Smyth & Wright 1958, Kuslich et al. 1991). In these
animal models, autologous NP has mainly been used. However, in articular cartilage,
TNF- expression was confined only to the degenerated samples, and even in
degenerated cartilage 540 % of cells expressed the cytokine (Tetlow et al. 2001).
Nondegenerated animal disc tissue may, thus, not be fully comparable with degenerated
tissue. This explains the discrepancy between these animal results and the clinical
situation where prolonged sciatica is encountered without disc herniation.

2.2.4 Pain sensitization

Peripheral nerve endings become sensitized by chemical mediators that are released
during tissue damage and inflammation. These include neurogenic mediators, such as
substance P, and non-neurogenic mediators, such as bradykinin, histamine and
prostaglandins (Cavanaugh 1995). In addition to local increase in the excitability of C
fibers, spinal mechanisms are important in the production and maintenance of
hyperalgesia. Thermal hyperalgesia requires the activation of N-methyl-D-aspartate
(NMDA) receptors and is primarily mediated by production of nitric oxide, whereas
mechanical hyperalgesia requires -amino-3-hydroxy-5-methylisoxazole-5-propionate
(AMPA) and metabotropic glutamate receptor coactivation, and is primarily mediated by
cyclooxygenase products and PLA2 activation (Meller & Gebhart 1994).
In rats, compression of nerve roots by loose chromic gut ligatures induced prolonged
thermal hyperalgesia (related to neuropathic pain), and initial transient motor dysfunction
and mechanical hypoalgesia (Kawakami et al. 1994a). Pain-related behaviour correlated
with increased dorsal horn c-fos and dorsal ganglion VIP amounts. Similarly, DRG
irritation generated thermal hyperalgesia, which was accompanied by increased c-fos
expression and spontaneous pain-related behaviour (Chatani et al. 1995).
Epidural betamethasone, but not bupivacaine, inhibited thermal hyperalgesia generated
by ligating rat nerve roots with chromic gut ligatures (Hayashi et al. 1998). However, in
this model the positive effect of steroid did not correlate with the changes in SP, CGRP,
and c-fos expression. Histological nerve fiber damage did not correlate with pain-related
behaviour, which indicates that rather than mechanical compression, a chemical irritant
released from chromic gut is responsible for thermal hyperalgesia (Kawakami et al.
1994b). Interestingly, in the rat model PLA2 was involved in mechanical hyperalgesia
induced by the NP, and NO in thermal hyperalgesia induced by the AF (Kawakami et al.
1998).
In a rat model, astrocytic activation demonstrated a direct relationship with the
mechanical allodynia for the first 7 days. Simultaneously, spinal cord IL-1 secretion was
increased, indicating a neuroimmune component in lumbar radiculopathy (Hashizume et
al. 2000). Similarly, one week after relocation of autologous NP on rat L4 and L5 nerve

28
roots, nerve root and DRG IL-1 expression were increased. In the same study, IL-6
expression was observed in these tissues over the whole 4-week period (Kawakami et al.
1999).

2.2.5 Effect of methylprednisolone

Methylprednisolone injected within 48 hours after the application of the NP inhibited the
NP-induced vascular permeability and functional impairment (decrease of nerve
conduction velocity) (Olmarker et al. 1994). Histologically, no differences between the
NP and NP + methylprednisolone groups were observed. The nerve loss was, however,
focal (Olmarker et al. 1994). Methylprednisolone also inhibited the NP-induced increase
of vascular permeability (Byrd et al. 2000).
In the rat model, PLA2 activity was found to be maximal 1 week after chromic gut
ligature, whereas thermal hyperalgesia was maximal 3 weeks after surgery (Lee et al.
1998). Epidural steroid decreased PLA2 activity and reduced thermal hyperalgesia.
Interestingly, steroid at different time points (1 day before, 1 day after, or 3 days after
surgery) had a similar effect on thermal withdrawal latency (Lee et al. 1998).

2.3 Etiognosis of sciatica

Data on the determinants are largely based on cross-sectional studies, although
longitudinal cohort studies potentially yield more relevant information. In the following
chapters, determinants of lumbar disc disease (herniated disc or typical sciatica) are
reviewed in three parts: constitutional factors such as body height, age, gender and
obesity; environmental and behavioural factors such as occupation, smoking, leisure time
activities and psychological factors; and finally genetic factors, knowledge of which is
increasing constantly.

2.3.1 Constitutional factors

Sciatica and risk of undergoing surgery is highest during the fourth and fifth decades of
life (Kelsey & Ostfeld 1975, Frymoyer 1988). This age-related vulnerability is also
supported by findings from cadaver studies (Adams & Hutton 1982), and it may be
related to greater prevalence of disc ruptures. The reduced incidence of disc herniation in
old persons may be related to the loss of turgor and elasticity of discs with age.
Male predominance of HNP has been observed among patients hospitalized for
sciatica (Spangfort 1972, Naylor 1974, Thomas et al. 1983). On the other hand, in one
study prevalence of sciatic symptoms did not differ between males and females (Kelsey &
Ostfeld 1975). In the mid-1980s the prevalence of lumbar disc syndrome in Finland was

29
5.1% for men and 3.7% for women aged 30 years or over (Helivaara et al. 1987a). The
diagnosis was based on medical history, symptoms and physical examination. In a recent
longitudinal Finnish cohort study, the incidence of disc disease (HNP or sciatica) at the
age of 28 was 12.8 per 1000 for men and 6.6 per 1000 for women (Zitting et al. 1998),
concordant with the earlier observations of male predominance.
Body height seems to predispose to sciatica (Hrubec & Nashold 1975, Weir 1979,
Merriam et al. 1983), although in some studies no association was found (Kelsey &
Ostfeld 1975, Kelsey et al. 1984). In a Finnish survey, body height was a significant risk
factor for HNP in both sexes (Helivaara 1987a). The relative risk increased on average
by 5 % among men and 4 % among women per one centimetre increase in body height.
The risk was evident above heights of 180 cm for men and 170 cm for women
(Helivaara 1987a).
Obesity measured as body mass index has been found to be a significant predictor of
disc disease only in men (Helivaara 1987a). Herniations are often found in
asymptomatic subjects (Boden et al. 1990, Jensen et al. 1994), but narrowing of the
lumbar canal may predispose to symtomatic disc lesions and sciatica as the space is
limited (Porter et al. 1978, Helivaara et al. 1986).

2.3.2 Environmental and behavioural factors

Heavy physical loading and materials handling, including lifting, bending, twisting,
sitting and sustained nonneutral postures predispose to low back pain (Magora 1973).
Similarly, hard physical jobs and, in particular, frequent lifting and postural stress are
known to increase the risk of sciatica (Helivaara 1989, Riihimki et al. 1989). Motor
vehicle driving is also positively associated with HNP and sciatica (Kelsey & Hardy
1975, Kelsey et al. 1984, Helivaara 1987b). The incidence of sciatica during a 3-year
follow-up period was 22% for machine operators, 24% for carpenters and 14% for office
workers (Riihimki et al. 1994). However, lifetime loading is more relevant than current
conditions (Videman & Battie 1999). Moreover, many occupations are also associated
with various lifestyle factors that can act as confounding factors in attempts to determine
occupational effects (Ilmarinen et al. 1991). When lumbar disc degeneration among
Finnish twins was studied, heavier lifetime occupational and leisure physical loading was
associated with greater disc degeneration at the upper lumbar levels, whereas sedentary
work was associated with lesser degeneration (Battie et al. 1995).
Accident-related trauma has also been suspected of causing structural damage and
accelerating degenerative changes (Videman et al. 1990). The risk of sciatic pain has
indeed been reported to be increased among workers who had earlier had back accidents
(Riihimki 1985, Riihimki et al. 1989, Helivaara et al. 1991).
Self-assessed stenuousness of work was a significant risk factor for sciatica in women
(Helivaara 1987b). In a Finnish follow-up study, distress symptoms predicted hospital
admissions for HNP or sciatica among women who reported no severe back trouble at
entry (Helivaara et al. 1987b, Helivaara et al. 1991). The findings are in agreement
with a recent experimental study where the influence of psychosocial stress, gender and

30
personality on mechanical loading of the lumbar spine was evaluated (Marras et al.
2000). Psychosocial stress increased spine compression and lateral shear on the basis of
differences in muscle coactivation. Women's anterior-posterior shear forces increased in
response to stress, whereas men's decreased. Certain personality traits (e.g. introverts and
thinkers) were associated with increased spine loading compared with those with an
opposing personality trait, and explained loading differences between subjects (Marras et
al. 2000).
The effect of smoking on the incidence of sciatica is controversial. In a Finnish followup study, smokers and ex-smokers had a similar increased risk of sciatica (Manninen et
al. 1995), whereas in other studies smoking was of borderline or no significance
(Helivaara et al. 1987b, Riihimki et al. 1994).

2.3.3 Genetic factors

Findings of a study with Finnish identical twin pairs indicated that environmental factors
account for more than 80 % of the aetiology of sciatica, whereas genetic factors were
more significant in individuals under 40 years (Heikkil et al. 1989). In the same study
population, determinants of lumbar disc degeneration were also studied (Battie et al.
1995). In multivariate analyses, the mean job code and age together explained only 16 %
of the variability in degeneration at the upper levels, whereas addition of familial
aggregation improved the model so that 77 % of the variability was explained (Battie et
al. 1995). At the lower levels, the model explained only 43 % of the variability, but here
also familial aggregation, including both genetic influences and early childhood
environment, was the most important determinant. In concordance with the twin studies,
several authors have reported the association of a positive family history of low back
pain, sciatica or herniated disc in adolescents with herniated discs (Nelson et al. 1972,
Zamani & MacEwen 1982, Gunzburg et al. 1990, Varlotta et al. 1991). When adolescent
patients with disc herniation were compared with matched controls, 32% of patients had
first-degree relatives with a history of severe back pain, sciatica or herniated disc
compared with 7% in the control group (Varlotta et al. 1991). It was estimated that the
risk of developing a herniated lumbar disc before the age of 21 years was four to five
times greater in adolescents with a positive family history.
The search for candidate genes is ongoing. Recently, two intragenic polymorphisms of
the vitamin D receptor gene revealed an association with disc degeneration and anular
tears (Videman et al. 1998, Videman et al. 2001). However, the role of vitamin D receptor
gene polymorphism in disc disease is somewhat unclear because the receptor is not found
in the discs. Aggrecan, on the other hand, is a major constituent of the disc. The coding
region of the aggrecan gene contains a highly conserved repeat region. A total of 13
alleles differing by the number of nucleotide repeats have so far been observed. As the
result of this polymorphism, aggrecan core proteins of different lengths are expressed.
Multilevel and severe disc degeneration was found to be present in the individuals with a
shorter tandem repeat length of aggrecan gene (Kawaguchi et al. 1999). In mice,
homozygotes for a deletion mutation of aggrecan died shortly after birth because of

31
respiratory failure (Watanabe et al. 1997). The phenotype of heterozygotes included slight
dwarfism and a delayed onset spinal disorder. Within 19 months of age, the mice
exhibited spastic gait due to misalignment of cervical spine. Histological examination
revealed a high incidence of disc herniations and disc degeneration (Watanabe et al.
1997).
Collagen IX is a heterotrimeric protein consisting of three genetically distinct
chains, 1(IX), 2(IX) and 3(IX), encoded by the COL9A1, COL9A2 and COL9A3
genes (Shaw & Olsen 1991, Brewton & Mayne 1994, Pihlajamaa et al. 1999, Paassilta et
al. 1999). Collagen IX is covalently cross-linked to the surface of the collagen II fibril,
and a portion of the molecule projects away from the fibril surface (Wu & Eyre 1989,
Brewton & Mayne 1994). Collagen IX is believed to function as a bridge between
collagen fibril structure and other matrix molecules (Figure 2). Its role in intervertebral
disc disease is supported by the findings of transgenic mice expressing mutant 1(IX)
chain (Kimura et al. 1996). These mice developed accelerated intervertebral disc
degeneration with partial disruption of endplates and fissures in the anulus. A sequence
variation in the COL9A2 gene that changes a codon for glutamine to one for tryptophan
in the 2 chain of collagen IX (Trp2 allele) has been found to associate with dominantly
inherited disc disease characterized by sciatica in about 4 % of Finnish patients (Annunen
et al. 1999). This allele was not detected in the controls. Recently, a similar sequence
variation changing a codon for arginine to one for tryptophan was found in the COL9A3
gene coding for the 3 chain of collagen IX (Trp3 allele) (Paassilta et al. 2001). The Trp3
allele was observed in 24.4% of the sciatic patients, but in only 9.3% of the controls. The
allele was found to increase the risk of lumbar disc disease almost threefold, representing
the first common genetic risk factor for the disease (Paassilta et al. 2001). Since
tryptophan is not normally found in collagen IX it is possible that, as the most
hydrophobic amino acid, it may render intervertebral discs fragile by disturbing the
collagen triple helix or interfering with the molecular interactions (Annunen et al. 1999,
Paassilta et al. 2001).
Globular domain
Helical domain
GAG

Type IX collagen

Type II collagen fibril

Crosslinks between type IX and type II collagen

Fig. 2. A schematic presentation of collagen IX. It is covalently cross-linked to the surface of collagen II fibril, but a portion of the molecule projects from the fibril surface. Collagen IX is a
heterotrimeric protein consisting of three genetically distinct chains, 1(IX), 2(IX) and
3(IX). Helical domains are interrupted with globular domains (circles). The glycosaminoglycan (GAG) chain is attached to an 3-chain. The defect in 2(IX) leads to a change of codon for
glutamine to that for tryptophan, which may interrupt the covalent binding of collagen IX with
collagen II.

32

2.4 Diagnosis of sciatica

2.4.1 Medical history
Typically, patients with sciatica due to lumbar disc herniation will present with a sharp,
burning, stabbing pain radiating below the knee. The pain is superficial and localized,
band-like (Andersson & Deyo 1996, Bogduk 1997a). It is often associated with
numbness or tingling (paresthesia) and is aggravated by increased intradiscal pressure or
specific movements. There is usually substantial, but incomplete relief with rest. Initially,
pain may be felt only in the low back and the buttock(s), but as the disease progresses
pain is felt distally along the dermatome. The extent of radiation of pain appears to
depend on the severity of the pathologic process affecting the nerve roots (Smyth &
Wright 1958). In clinical practice, the physician mostly encounters sciatica caused by
irritation of lumbosacral nerve roots L4, L5 or S1. The upper roots (L1-L3) are involved
in less than 5% of surgical patients (Andersson & Deyo 1996). Patients with central or
lateral lumbar spinal stenosis present typically with leg pain during or after walking
(neurogenic claudication). Pain is often bilateral and in contrast to arterial ischemic
claudication, neurogenic claudication is more likely to occur on standing alone without
ambulation (Deyo et al. 1992).
Pain may be distributed along the whole segment, or confined to certain circumscribed
areas. Thus, disease of the L4 nerve root can cause localized pain just below the knee
anteriorly and down the shin. L5 nerve root lesion may present with pain in the large toe
or over a relatively small area on the anteromedial aspect of the foot and along the fibula.
Pain due to S1 nerve root lesions may be felt in the heel or the lateral border of the foot
and also in the middle of the calf (Norlen 1944, Agency for Health Care Policy and
Research (AHCPR) 1994). There is, however, considerable overlapping between the
dermatomes (Nitta et al. 1993). A medical history of current sciatica per se has a high
sensitivity for lumbar nerve root compression (AHCPR 1994). The level of disc
herniation can be correctly predicted in over 90% of the cases by the pain location alone
or supplemented by neurological signs (Kortelainen et al. 1985, Albeck 1996).

2.4.2 Physical signs

The physical examination of sciatic patients should include observation, palpation,
determination of the range of motion of the spine, a root tension test and evaluation of the
neurological status of the lower limbs. The straight leg raising test stretches the L5 and
S1 roots, and this test is regarded positive if leg pain is aggravated when the affected leg
(SLR) or the contralateral leg (crossed SLR) is raised (Andersson & Deyo 1996). Root
tension tests are sensitive but unspecific as to the location and cause of nerve root
irritation. SLR is sensitive, but unspecific, whereas crossed SLR is very specific, but its
sensitivity is low (Hakelius & Hindmarsh 1972, Spangfort 1972). L4 root lesions may be
accompanied by reduction of the knee jerk whereas impaired ankle reflex is fairly

33
pathognomic for the S1 root (Norlen 1944, Knuttson 1961, Hakelius & Hindmarsh 1972,
Spangfort 1972). Reflex testing is less useful in recurrent sciatica, and the lower
extremity reflexes often diminish with advancing age (Andersson & Deyo 1996).
The most important muscle strength test involves the extensor hallucis longus,
primarily innervated by L5 (Knuttson 1961, Andersson & Deyo 1996). Sensory defects
are almost always confined to the periphery of the dermatome. Thus, in L4 root disorders
diminished sensation may be present over the medial part of the lower leg, in L5 root
lesions over the first three or four toes on the dorsum of the foot, and in S1 root disease
along the lateral border and the sole of the foot (Nitta et al. 1993, Bogduk 1997a ).
However, the area of sensory loss is a poor predictor of the level of herniation (Blower
1981, Kortelainen et al. 1985). When small nerve fibers were studied using tests for
thermal thresholds and the large myelinated fibers by vibrametry, it was found that the
adjacent nerve roots are also involved in the pathophysiology of sciatica in patients with
lumbar disc herniation (Nygaard & Mellgren 1998).
Clinical examination is recommended to include: 1) testing of dorsiflexion strength of
the ankle and the big toe, with weakness suggesting mainly L5 dysfunction; 2) testing of
ankle reflexes to evaluate S1 root dysfunction; 3) testing of light touch sensation in the
medial (L4), dorsal (L5) and lateral (S1) aspects of the foot; and 4) SLR (Deyo et al.
1992). However, history preselects patients already very likely to have disk herniation,
and clinical examination increases the confidence in a positive diagnosis by only two
percentage points (Bogduk 1997b); most of the relevant information can be obtained by
listening to the patient (Vucetic et al. 1999). The accuracy of neurological tests can,
however, be improved by combining the tests (parallel testing) (Andersson & Deyo
1996).

2.4.3 Imaging and other diagnostic tests

The anatomic level of imaging study findings must correspond to the side and the level of
lesion detected via the history, physical examination or other methods. CT (with or
without myelography) and MRI should be used only when there exist sciatica and
clinically specific detectable nerve root compromise, or history of neurogenic
claudication with symptoms severe enough to consider surgical intervention, or clinical
findings or other tests suggesting other serious conditions affecting the spine (Agency for
Health Care Policy and Research (AHCPR) 1994). Physicians treating sciatic patients
should, however, remember that abnormal findings are common among asymptomatic
subjects in CT (Wiesel et al. 1984) and MRI (Powell et al. 1986, Paajanen et al. 1989a,
Boden et al. 1990, Jensen et al. 1994). There seem not to be clinically important
differences between CT, CT-myelography and MRI in terms of their true positive and true
negative rates for diagnosing lumbar disc herniation, although all these tests are better
than plain myelography (AHCPR 1994). MRI is nowadays regarded as the best imaging
mode (Herzog 1996), but in the diagnosis of internal disc ruptures pain provocation is
needed. Therefore, a combination of CT and discography is recommended (Vanharanta et
al. 1987, Vanharanta et al. 1988a, Vanharanta et al. 1988b, Vanharanta et al. 1989,

34
Moneta et al. 1994). However, discography is an invasive method with possible
complications (Guyer & Ohnmeiss 1995), but it can be replaced with the bony vibration
test (Yrjm & Vanharanta 1994). This test, combined with MRI (Yrjm et al. 1997) or
diagnostic ultrasound (Yrjm et al. 1996), was a sensitive method compared to
discography, although the specificity was lower in both studies. Transabdominal
ultrasound alone also proved a sensitive screening test for intradiscal abnormalities
(Tervonen et al. 1991), but the method depends on the experience of the radiologist
performing the analysis.
The diagnostic objectives of electrophysiologic tests are to assess myelopathy
(dysfunction of the spinal cord), radiculopathy (dysfunction of a nerve root), neuropathy
(dysfunction of a peripheral nerve distal to the nerve root), and myopathy (muscle
abnormalities). EMG is used to assess acute and chronic nerve root dysfunction,
myelopathy, and myopathy. H-reflex and F-wave response are tests measuring sensory
conduction through nerve roots, used mostly to assess S1 radiculopathies and proximal
neuropathies, respectively. The results of EMG are, however, unreliable until sciatic pain
has persisted for over 3 weeks (Agency for Health Care Policy and Research (AHCPR)
1994) and greater accuracy will be achieved if the EMG results are combined with
information from imaging and clinical findings (Spengler et al. 1990).
Pain drawing is independent of language, and correlates with spinal pathology in
myelography (Uden & Landin 1987) and in CT/discography (Ohnmeiss et al. 1995).
Patients with discogenic pain seem to use more symbols of burning pain and aching pain
than patients with nondiscogenic pain (Ohnmeiss et al. 1999b). Pain drawing can also be
used in the level diagnosis of lumbar disc pathology (Vuceticn et al. 1995, Ohnmeiss et
al. 1999a) and in the qualitative estimation of the hernia type (Vucetic et al. 1995).

2.4.4 Associations of symptoms and clinical signs with MRI findings

The pathophysiological mechanisms of sciatica have recently been the subject of
extensive study. On the basis of clinical experiments, it is known that only irritated nerve
roots produce pain when compressed (Smyth & Wright 1958, Kuslich et al. 1991). On the
other hand, abnormalities are common in asymptomatics (Boden et al. 1990, Jensen et al.
1994). Certain determinants are known to predispose to sciatica and HNP (Helivaara et
al. 1991). The asymptomatic populations in the afore mentioned studies might have been
biased with respect to these determinants. However, when symptomatic patients were
compared with risk factor-matched controls, disc herniations were common in both
groups (Boos et al. 1995). Symptomatic patients could be differentiated only on the basis
of neural compromise. Nerve compression and disc extrusion also seem to predict distal
leg pain reliably (Beattie et al. 2000).
An association has been observed between the severity of sciatica and the size of
lumbar disc herniations on computed tomography adjusted for the size of the spinal canal
(Thelander et al. 1994). In addition, impaired walking capacity, pain upon coughing,
restriction in SLR and use of analgesics were more common in patients with extruded/
sequestered disc herniation than in those with a contained herniation/bulge (Jnsson &

35
Strmqvist 1996). Furthermore, extrusions are uncommon in asymptomatics (Jensen et al.
1994, Weishaupt et al. 1998). The similarity of symptoms in patients with or without disc
herniation has been observed (Modic et al. 1995). Although the number of patients in the
study was very limited, the results indicate that disc ruptures can be as painful as HNPs.
The amount of inflammatory cells in disc samples does not correlate with the
symptoms and signs of sciatica (Grnblad et al. 2000, Rothoerl et al. 1998). The
association of nerve root enhancement with sciatic symptoms is far from clear (Toyone et
al. 1993, Crisi et al. 1993, Taneichi et al. 1994), whereas SLR restriction seems to
correlate with disability (Thelander et al. 1992, Jnsson & Strmqvist 1995).

2.5 Treatment of sciatica

2.5.1 Natural history
There is a high remission rate in acute non-specific LBP, with approximately 90 %
resolving within 6 weeks (Frymoyer 1988, Carey et al. 1995). The recovery rate from
sciatica is not as rapid as for patients with LBP (Andersson et al. 1983). In a recent study,
most sciatic symptoms and signs had cleared within the first 3 months (Balague et al.
1999). At the 1-year follow-up, one third of the patients had recovered fully, and one
third had undergone surgery. In another study, only 11.4% of conservatively treated
sciatic patients reported that the predominant pain had completely disappeared at the 1year follow-up assessment (Atlas et al. 1996).
However, the long-term prognosis of sciatica and lumbar herniations seems to be good
(Hakelius 1970, Weber 1983, Saal et al. 1990a, Weber et al. 1993). Large disc herniations
will resorb without treatment more quickly than smaller herniations (Maigne et al. 1992,
Ito et al. 1996, Ahn et al. 2000). Return to work is usually governed by extraspinal
factors, being closely linked in industrialized countries to the legal framework of social
insurance (Waddell et al. 1986). Female sex, longer duration of symptoms, litigation or
compensation pending, poor psychosocial circumstances and comorbidities have been
shown to be associated with poor outcomes (Hurme & Alaranta 1987, Junge et al. 1995,
Carragee & Kim 1997).

2.5.2 Conservative treatment

Recommendations about conservative (or surgical) treatment of sciatica are handicapped
by the limited number of randomized controlled trials (RCT). A recent systematic review
found only 19 RCTs, of which 8 met the three major requirements (comparability of
groups, observer blinding, and intention-to-treat analysis) (Vroomen et al. 2000). In the
1980s, the treatment of sciatica consisted of 2 weeks bed rest, and thereafter gradual
mobilization combined with anti-inflammatory drugs (NSAIDs) (Bell & Rothman 1984).

36
Nowadays, bed rest for sciatica is no more recommended (Vroomen et al. 1999). On the
basis of this systematic review, no significant effect was demonstrated for NSAIDs,
traction, or intramuscular steroids; only epidural steroids were possibly shown to have
some benefit (Vroomen et al. 2000). In the following sections, epidural steroids and
periradicular infiltration are discussed further.

2.5.2.1 Epidural steroids

Epidural injection of medication allows a concentrated amount of the treatment agents to
be deposited and retained, exposing the nerve roots to the medication for a prolonged
period of time. When a combination of epidural steroid and anaesthetic was compared
with local anaesthetic at a tender spot over the sacrum, epidural steroid was superior at 3
months, but not at the 1, 6, or 12-month follow-up assessments (Mathews et al. 1987). A
combination of epidural steroid and anaesthetic was found to give better short-term (34
weeks) leg pain relief than epidural saline (two injections 2 weeks apart) (Bush & Hillier
1991), than epidural anaesthetic (bupivacaine) (Breivik et al. 1976), and than interspinous
injections (Dilke et al. 1973, Ridley et al.1988). No long-term effect of this combination
has been observed (Dilke et al. 1973, Snoek et al. 1977, Klenerman et al. 1984, Bush &
Hillier 1991), although the return to work rate was better in the steroid group in one study
(Dilke et al. 1973). In some studies, not even short-term relief was found (Snoek et al.
1977, Klenerman et al. 1984, Cuckler et al. 1985). In a recent study, up to three epidural
injections of methylprednisolone acetate were compared with saline among patients with
sciatica due to HNP (Carette et al. 1997). In the steroid group, significant improvements
were found in finger-to-floor distance and sensory deficits at 3 weeks, and leg pain at 6
weeks. At three months, there were no significant differences between the groups and the
cumulative probability of back surgery was similar (around 25 %). As a conclusion the
authors stated that despite the short-term improvement in leg pain and sensory deficits,
epidural steroid injection offers no significant functional benefit, nor does it reduce the
need for surgery (Carette et al. 1997). Two meta-analyses of epidural corticosteroids have
been conducted. One found no, or at most a short-term effect of epidural steroids in LBP
and sciatica (Koes et al. 1995), whereas the other found epidural steroid effective in
radicular pain in both the short- and long-term (Watts & Silagy 1995). Epidural
corticosteroid injections can be recommended as additional therapy, especially in the
acute phase of the conservative management of sciatica (Buchner et al. 2000, Vroomen et
al. 2000).

2.5.2.2 Periradicular infiltration

Periradicular (transforamimal) infiltration was developed in the late 1960s by Ian Macnab
(Macnab 1971). It has since been used for diagnostic purposes mostly when surgery is
considered (Krempen & Smith 1974, Wilppula & Jussila 1977, Herron 1989, Stanley et

37
al. 1990). In the procedure, the pharmaceutical agents are injected between the nerve root
and the epiradicular sheath, depicting the nerve root in tubular fashion (Hasue & Kikuchi
1997), which permits precise application of steroids into the vicinity of the irritated nerve
root resulting in a massive concentration of the agent at the site (Derby et al. 1992,
Weinstein et al. 1995). An accuracy of 85% to 94% in identifying a single symptomatic
root, sensitivity of 100%, and positive predictive value of 93% to 95% have been
presented for periradicular infiltration (Haueisen et al. 1985, Dooley et al. 1988, van
Akkerveeken 1996, Hasue & Kikuchi 1997). Indications for periradicular infiltration
include radicular pain and/or intermittent claudication without neurologic findings,
atypical leg pain, multiple nerve root signs, radicular pain and/or intermittent claudication
associated with other types of pain, multilevel abnormalities on imaging studies,
discrepancy between imaging studies and clinical findings, nerve root and/or spine
anomalies, failed back syndrome, and intra- and extraforaminal lesions (Hasue & Kikuchi
1997). The mechanism of periradicular infiltration may be blocking of afferent impulses
from the periphery (Hasue & Kikuchi 1997), or increased intraradicular blood flow
(similar to after symphathetic ganglion block) (Yabuki & Kikuchi 1995).
Patients with lumbar spinal stenosis due to spondylosis or degenerative
spondylolisthesis had more therapeutic benefit than those with disc herniation and
spondylolytic spondylolisthesis (Kikuchi et al. 1984, Hasue & Kikuchi 1997). Recent
uncontrolled studies confirm these observations of a therapeutic effect (Weiner & Fraser
1997, Lutz et al. 1998). In HNP induced radiculopathy, there was a 75 % long-term
recovery after on average of 1.8 transforaminal injections per patient of betamethasone
acetate combined with xylocaine. The outcome was better, with symptom duration of less
than 36 weeks (Lutz et al. 1998). Nerve root injection is also effective in sciatica due to
lateral disc herniations, which are difficult to treat by other therapeutic means (Weiner &
Fraser 1997). For postoperative radicular pain, however, the technique seems not to have
therapeutic effect, and CT-guided injection seems to be superior to fluoroscope-assisted
for both its visualization and a longer-lasting effect (Lutze et al. 1997). An MRI-guided
procedure can be recommended for S1-infiltrations (Ojala et al. 2000).

2.5.3 Surgical treatment

The outcome of patients operated for disc herniation has been reported to be superior to
that of conservatively treated patients (Nykvist et al. 1989, Atlas et al. 1996), but for mild
symptoms the benefits of surgical and conservative treatments are similar (Atlas et al.
1996). Only one RCT compared standard discectomy with conservative therapy (Weber
1983). At the 1-year follow-up there were significantly more patients with good or fair
results in the surgery group (90% vs. 61% in non-surgery group), but at the 4- and 10year follow-ups the results were similar in both groups. During the first year, 26% of the
nonsurgery group demanded discectomy because of unrelieved sciatic pain (Weber 1983).
It has been estimated that 5 to 20 % of patients with symptomatic HNP require surgery
(Helivaara et al. 1987, Deyo et al. 1990, Frymoyer 1992), but even higher figures have
been obtained (Balague et al. 1999). According to the Mini-Finland survey, 32 % of

38
sciatic patients had been in hospital and 21% operated on for a low-back condition
(Helivaara et al. 1989). In 1995, the overall rate of lumbar disc surgery in Finland was
nearly 78 per 100 000 (Keskimki et al. 2000). The clinician should consider referral to a
specialist for disc herniation surgery when all of the following conditions are met: 1)
sciatica is both severe and disabling, 2) symptoms of sciatica persist without
improvement or with progression, and 3) there is clinical evidence of nerve root
compromise (Agency for Health Care Policy and Research (AHCPR) 1994).

3 Aims of the study

The objectives of this study of a sciatic population were:
1. To assess the extent to which self-reported symptoms and clinical findings can be
interpreted by the degree of disc displacement in MRI (I)
2. To evaluate the clinical and radiological phenotype of patients with the Trp2 and Trp3
alleles (II and III)
3. To compare the efficacy and costs of periradicular infiltration with either a
combination of methylprednisolone and bupivacaine, or saline in an intervention
prognostic study, in the whole study population (IV) or in subgroups (V)

4 Subjects and methods

4.1 Study population
The study population consisted of consecutive, eligible sciatic patients with unilateral
symptoms to below the knee that had lasted 3 to 28 weeks. Leg pain had to be at least
comparable with that of back pain. A positive dural tension sign (limited straight leg
raising) was not a prerequisite for entry. The exclusion criteria were an earlier back
operation, an application for early retirement, clinical depression anticoagulation
treatment, unstable diabetes, epidural injection during the preceding three months,
pregnancy, allergy to any ingredients of the treatment agents, and rare causes of sciatica
such as synovial cysts and non-degenerative spondylolisthesis. The patients had been
referred by general practitioners in the catchment area of Oulu University Hospital
(population 360 000). The study protocol was approved by the ethics committee of the
Oulu University Hospital.
There were 160 sciatic patients in studies I, IV and V, 159 patients in the study II
(blood sample not obtained from one patient), and 153 patients in the study III (6 patients
with the Trp2 allele excluded).

4.2 Evaluation of patients

4.2.1 Demographics and clinical symptoms (IV)
The self-administered questionnaire items included education, estimation of physical
workload, mental job stress, days on sick leave (only sick leaves related to the current
sciatic episode), smoking, medical history (including back pain and sciatica) and history
of current episode. Job status of those patients currently employed was characterized by a
3-scale classification (sedentary job, mixed job and physical job) (Ilmarinen et al. 1985).
Every patient recorded his/her back pain and leg pain on 100-mm VAS scales and

41
disability with the Oswestry Low Back Disability Questionnaire (Fairbank et al. 1980,
Grnblad et al. 1993). The patients also estimated their quality-of-life on the Nottingham
Health Profile (NHP), using its scale options ranging from 0 (best) to 100 (worst)
(Koivukangas et al. 1995). In addition, every patient produced a pain drawing (Uden &
Landin 1987).

4.2.2 Genetic analysis (II and III)

Blood samples had been collected previously for genomic DNA extraction and analysed
for sequence variations in the human COL9A1, COL9A2 and COL9A3 genes (Annunen
et al. 1999, Paassilta et al. 1999, Pihlajamaa et al. 1999, Paassilta et al. 2001). The
analysis consisted of PCR amplification of all exons and exon boundaries of the genes.
The PCR products were subjected to CSGE analysis (Krkk et al. 1998). Sequence
variations observed in CSGE analysis as heteroduplexes were identified by automated
sequencing (ABI PRISM 377 Sequencer and dRhod Dye Terminator Cycle Sequencing
Kit, Perkin Elmer).
Mutation analysis of the 159 sciatic patients revealed 6 Trp2 allele positive cases (4
%), and 34 Trp3 allele positive cases among the remaining 153 sciatic patients (22%).
Two of the Trp3 allele positive patients were homozygous for the allele.

4.2.3 Diagnostic evaluation

4.2.3.1 Clinical examination (IV)
The clinical examination took place within the week prior to MRI. The straight leg
raising test of the ipsilateral (SLR) and contralateral legs (crossed SLR) was performed in
the standard way, and the position where back or leg pain prevented further elevation was
recorded with a goniometer to the nearest 5. Lumbar flexion was measured by the
modified Schober procedure (the difference between a 15-cm distance marked on the
back of the patient in a standing position and the distance with the patient in full flexion).
Sensory and motor defects, and tendon reflexes were examined. The dermatomal
distribution of pain radiation was evaluated as normal: For L4 an area centred on the
medial aspect of the lower leg; For L5 an area from the medial aspect of the foot across
the dorsum of the foot and onto the lateral aspect of the lower leg; For S1 a band from the
posterior sacrum along the entire posterior length of the lower limb and to the lateral
aspect of the foot (Keegan & Garret 1948, Bogduk 1997a). Big toe extension weakness
was used as an L5 root-specific test, abnormal patellar reflex as an L4 root-specific test,
and missing ankle reflex as a S1 root-specific test (Agency for Health Care Policy and
Research (AHCPR) 1994, Andersson & Deyo 1996).

42

4.2.3.2 Magnetic Resonance Imaging (MRI) (IV)

MRI scans were obtained with a 1.5-T imaging system (Signa, General Electric,
Milwaukee, Wisconsin) consisting of sagittal images with a repetition time (TR) of 4000
msec and echo time (TE) of 95 msec (T2-weighted) and axial images with a TR/TE of
640/14 msec (T1-weighted) before and immediately after intravenous injection of
gadolinium-diethylenetriamine pentaacetic acid (0.1 mmol/kg Gd-DTPA, Magnevist,
Schering, Berlin, Germany). Frequency-selected fat saturation was used for the
postcontrast axial images. The technical specifications included a slice thickness of 4 mm
with interslice gaps of 1.0 and 0.5 mm, a field of view of 30 and 20 cm for sagittal and
axial images, respectively, and a matrix of 192 by 256/ two excitations (NEX). All
images were read by two experienced MRI -radiologists blinded to the clinical status of
the patients. In the case of any discrepancies between the radiologists, a consensus was
reached before the final grading.
Disc displacement was graded as normal (grade 1); bulge (grade 2: a symmetrical
extension of the peripheral annulus beyond the margins of the vertebral endplates);
contained herniation (grade 3: a focal extrusion of disc material through the annulus but
not through the posterior longitudinal ligament (PLL)); noncontained herniation (grade 4:
an extrusion of disc material through the PLL); and sequester (grade 5: a disc fragment
not in contact with the parent disc). Postcontrast enhancement of the nerve roots was
regarded as positive if there was clear intraneural or perineural enhancement (compared
to the contralateral asymptomatic root) distinct from the rim enhancement around the disc
herniation. The extent of neural compromise was graded as none, minor (dislocation of
the nerve root by disc herniation), or major (compression of the nerve root by disc
herniation against the bony structures) according to Boos and co-workers (1995).
Intervertebral disc degeneration was graded normal (no signal changes); grade 1
(slight decrease in signal intensity of the nucleus on T2-weighted images); grade 2
(hypointense nucleus pulposus on T2-weighted images with normal disc height); and
grade 3 (hypointense nucleus with disc space narrowing) (Stadnik et al. 1998). The endplates and adjacent bone marrow were evaluated by Modics criteria (Modic et al. 1988).
Schmorls nodes were evaluated from the sagittal scans (Takahashi et al. 1995).
Intervertebral disc tears were evaluated from the posterior anulus fibrosus according Yus
criteria (1989). A radial tear extended as a hyperintense line from the nucleus to the outer
part of anulus fibrosus on T2-sequences, and with Gd-DTPA no enhancement was
observed. Radial tears were evaluated only from nonherniated discs. A transverse tear was
located in the outer part of anulus near either end-plate (Stadnik et al. 1998). Highintensity zone (HIZ) lesions were bright spots in the dorsal annulus on T2-weighted
sagittal scans (Aprill & Bogduk 1992). The presence of thoracolumbar Scheuermanns
disease (TLS) was evaluated from the T2-weighted sagittal scans: disc space narrowing,
disc dehydration, end-plate irregularities, wedging of anterior vertebral body margins, and
Schmorls nodes in the thoracolumbar region. Either end-plate irregularities or Schmorls
nodes and two of the other criteria at three or more disc levels from T10-11 to L3-4 had to
be present for thoracolumbar Scheuermann (Heithoff et al. 1994).

43

4.2.3.3 Electroneuromyography (ENMG) (I, IV and V)

ENMG was performed on every patient. H-reflexes of the tibialis posterior nerve and Fresponses of the peroneus profundus nerve were measured on both sides. Muscles
corresponding to root levels LIII-SI (vastus lateralis, tensor fasciae latae, semitendinosus,
tibialis anterior, flexor hallucis longus, medial gastrocnemius, short head of biceps
femori, and gluteus maximus) in the affected leg and paravertebral muscles down to
multifidus were examined. The criteria for myelin damage were asymmetry of F-response
of the peroneus profundus nerve and abnormality of H-reflex of the tibialis posterior
nerve, in L5 and S1 nerve root irritation, respectively.
The symptomatic disc of each patient was evaluated in terms of clinical and ENMG
findings. If no abnormalities were thereby detected, the symptomatic disc was evaluated
solely on the basis of pain distribution (van Akkerveeken 1996). In addition, the
neurophysiologist evaluated on the basis of pain drawing and ENMG if the sciatic pain
experienced by each patient was radicular or nonradicular. Radicular pain is here defined
as band-like dermatomal pain below the knee (Bogduk 1997a).

4.3 Patient information and randomization (IV and V)

Patients meeting the criteria for inclusion were requested to read through preliminary
information about the infiltration procedure and the trial. Patients were informed of the
trial option both orally and with a written description of its content and purpose. Where
written consent was obtained, patients underwent the investigations and completed the
questionnaires. The randomization process took place immediately before the
intervention, and was based on a published list of random permutations (Cohran & Cox
1957) with a block size of 16. A person uninvolved in the study placed the assignments in
sealed envelopes with running numbers. The envelopes were used in the order provided.
On their way to the infiltration procedure, each patient took an envelope to the
Department of Radiology, where an authorized nurse filled a tape-covered syringe with
the treatment agent indicated therein. The assignments were thus masked to the patient,
the physicians and the radiologist giving the injection.

4.4 Periradicular infiltration (IV and V)

Periradicular infiltration was performed by an experienced radiologist (M.K.) using
conventional technique (Derby et al. 1992) under repeated fluoroscopic screening (Carm) with a 22- to 25-G spinal needle. For the L4 and L5 roots the needle was advanced
obliquely toward the base of the corresponding pedicle. For the S1 root the needle was
aimed in a medial and cephalad direction relative to the corresponding sacral foramen.
After the injection of 0.5 to 1 ml contrast medium to produce a neurogram that identified
the nerve root in question, either Solomet (methylprednisolone 40 mg/ml)-bupivacaine (5

44
mg/ml) or isotonic (0.9%) sodium chloride solution was injected (Figure 3). The volume
of the injection was 2 ml for L4 and L5 blocks and 3 ml for S1 based on anatomic
differences.

Fig. 3. A) Needle placement in the L5 periradicular infiltration. B) Contrast medium extension

(neurogram) around the L5 nerve root. C) Needle placement in the S1 infiltration. D) S1
neurogram.

4.5 Other interventions (IV and V)

Every patient was given back school instructions by the physiotherapist at the 2-week
follow-up assessment. In cases of persisting sciatic pain, the patients received pain
medication and traditional physiotherapy. In the case of severe sciatic pain from disc
herniation and pronounced disability, the patient was referred to a neurosurgeon for
discectomy evaluation. Each additional treatment and its cost to the patient were
documented in the follow-up questionnaires.

45

4.6 Follow-ups and outcome assessment (IV and V)

Immediately after the injection, each patient recorded his/her back and leg pain on a
paper questionnaire, which was filed separately from the other data. At the follow-up
checks (2 weeks, 1 month, 3 months, 6 months, and 1 year after the intervention) the
same questionnaires as those at the baseline were completed (NHP was not recorded at 2
weeks). Usually, the same physician performed the patients clinical examinations were
throughout the follow up assessments. The managing physician decided possible future
interventions and documented the clinical status on separate forms filed with the rest of
the patient data.
At the 2-week follow-up assessment, the attending physicians were asked to judge
which of the two interventions had been used. Their determination was correct in 59% of
the saline and 65% of the methylprednisolone-bupivacaine injection cases.

4.7 Economic analysis (IV and V)

The economic analysis, which concerned the use and costs of health care services and
help at home, was based on the responses to the 4-week, 3-month, 6-month and 1-year
follow-up questionnaires. The cost of the infiltration procedure itself ($200) was not
included in the saline group. The charge of MRI ($550) was included in the costs for both
groups. Data on days of sick leave and costs of medication were obtained from the
National Insurance Register. Because of the controversy over human capital and friction
cost analysis, the monetary value of sick leaves was not assessed (Hutubessy et al. 1999).
All additional treatments and visits to physiotherapists, osteopaths and physicians were
estimated from the data entered on the questionnaires and from medical records. For the
costs of physician and physiotherapist visits, the charges of the University Hospital were
used ($55 for a physician visit and $38 for a physiotherapist visit). Data on back
operations were gathered from the questionnaires and from medical records. The cost of a
discectomy at the University Hospital ($3215) includes three inpatient postoperative
days, with additional days costing $205. Home help was defined as help from the
patients spouse, children, relatives or friends. The monetary value of 1 hour of home
help was taken as the hourly wage of a munipical home helper ($9). Dollar costs were
calculated at the 1998 exchange rate ($1=5.096 Finnish marks).

4.8 Statistical analysis

4.8.1 Calculation of sample size (IV)
Preliminary calculations showed a need for 68 patients in both (steroid and saline)
treatment groups (=0.90, two-sided =0.05). The calculations were made for leg pain
(the primary outcome) on the VAS scale, using a clinically significant difference between

46
the groups with a rating of 15 mm and assuming a standard deviation of 15%. After
adjusting for a 20 % loss to follow-up evaluation, 80 persons were enrolled for both
groups.

4.8.2 Reliability of MRI findings (IV)

Kappa statistics were used to establish interobserver (reader 1 vs. reader 2) and
intraobserver (reader 1 vs. reread of reader 1) reliabilities of the various MRI findings
(Altman 1991). Interobserver and intraobserver kappa values for the various MRI
findings showed mostly moderate to substantial agreement (I, table 1). The interobserver
kappa value for TLS was 0.71 (substantial agreement) and the intraobserver value 1.0
(perfect agreement)

4.8.3 Associations of MRI findings, clinical tests and symptoms (I)

The intercorrelations of the different diagnostic tests (clinical tests and MRI findings),
demographic characteristics, and sciatic symptoms were investigated by Spearman
correlation analysis. The significances were tested with the Pearson chi-square and
Fishers exact test (2x2 tables) for nominal and ordinal variables or with Students t-test
and Kruskal-Wallis ANOVA (depending on the skewness of the variable in question) for
quantitative variables. For stepwise regression analysis of clinical symptoms and signs,
the most significant characteristics (duration of symptoms, age, gender, education,
physical work load) and the MRI classification were selected for the evaluated outcomes
(back pain, disability and SLR). Because of skewed distributions, a square root
transfomation was applied to the scores of each outcome before the regression analysis.

4.8.4 Evaluation of patients with the Trp2 and Trp3 alleles (II and III)
Demographic variables, symptoms and clinical signs of the patients with sciatica were
analyzed by the presence of the Trp2 allele and the significancies were tested with the
chi-square or Fishers exact test (2x2 tables) for nominal and ordinal variables, and the
Students t-test or Kruskal-Wallis test for quantitative variables. Three controls of similar
age and occupation, and from the same gender were selected for each of the patients with
the Trp2 allele. MRI findings of the patients with the Trp2 allele and their controls, and
family members with and without the Trp2 allele were investigated by contingency tables
and chi-square or Fishers exact test.

47
The presence of TLS was analyzed by presence of the Trp3 allele, and the statistical
significance evaluated with Fishers exact test. Logistic regression analysis was
performed to clarify the determinants of TLS; these included the Trp3 allele, gender, age,
duration of symptoms, occupational load, sciatic and back pain history, smoking, body
mass index and height.
Demographic variables, symptoms and clinical signs of the patients with sciatica were
analyzed by presence of the Trp3 allele, and the significances were tested with the
Pearson chi-square or Fishers exact test (2x2 tables) for nominal and ordinal variables
and the Students t-test or Kruskal-Wallis test for quantitative variables.
In the evaluation of intervertebral disc degeneration, end-plate degeneration, dorsal
transverse tears, high-intensity zone lesions, and Schmorls nodes by Trp3 allele presence,
for each of the Trp3 allele positive patients, a control matched for age, gender and
occupation was selected from the patients without the allele. Matched pair analysis was
warranted because determinants such as age affect disc degeneration (Miller et al 1988).
The mean age of the Trp3 allele positive patients was 42.6 years compared to 42.7 years
for their matched pairs. Nineteen of the total 34 pairs were concordant for occupation.
The discordant pairs differed by only one category (sedentary job vs. mixed job, or mixed
job vs. physical job). For the statistical analyses, end-plates were graded as normal or
degenerated. The statistical significance of the differences in the MRI findings between
patients with the Trp3 allele and their matched controls was investigated by the marginal
homogeneity test (extension of the McNemar test) for intervertebral disc degeneration
and by the McNemar test for the other MRI findings. P-values less than 0.05 were
considered significant.

4.8.5 Estimation of treatment efficacy and cost-effectiveness (IV and V)

Analysis of covariance was performed to compare the treatments. The adjusted change in
scores for the different outcomes between adjacent follow-up assessments and baseline
were calculated with 95% confidence intervals. Treatment effects were determined by
reducing the adjusted scores of the saline group from those of the methylprednisolone
group. Additionally, the percentage of painless patients (=responders, 75% decrease of
leg pain from the baseline scores) for both methylprednisolone-bupivacaine and saline
groups were evaluated at every follow-up assessment. Operated patients were always
regarded as nonresponders. The statistical significance of difference was evaluated with
Fishers exact test. Repeated measures analysis of variance was used for the estimation of
within-groups changes over time. Between-groups treatment difference over time
(efficacy) was analyzed with the AUC-method (Altman 1991). The AUC-scores were
adjusted, in addition to symptomatic disc level and days of sick leave before the
intervention, with the baseline value of the respective outcome (except for medical costs)
and duration of symptoms. The AUC-scores of selected outcomes were calculated
separately from baseline to 3 months, and from 3 months to 1 year. The AUC-scores for
different outcomes were adjusted also for the baseline values of the respective outcome
(except for medical costs).

48
In order to get a cost-effectiveness estimate for the treatments, total costs by 3 and 12
months were divided by the number of treatment responders at the respective time point.
The obtained figures for the steroid and saline treatments were compared by Students ttest.

4.8.6 Subgroup analysis (V)

The efficacy and cost-effectiveness were evaluated with respect to the duration of
symptoms, age, the symptomatic disc level, and the MRI classification. For MRI
classification, noncontained herniations and sequesters were combined as extrusions. Age
of patients did not have any significant effect on the treatment differences. Duration of
symptoms modified the total costs at 6 months so that the patients with shorter symptom
duration ( 2 months) before the intervention had greater monetary savings with the
steroid injection. Therefore the AUC-scores for medical costs have been adjusted also for
symptom duration. The rate of operations in different subgroups was evaluated by
Kaplan-Meier curves and log-rank tests (Altman 1991). P-values less than 0.05 were
considered statistically significant. For the statistical analysis, SPSS version 8.0 (SPSS
Corp., Chicago, IL) was used.

5 Results
5.1 Baseline characteristics of the patients
A total of 277 trial candidates were contacted by the principal author from January 1997
to May 1998. Of the 171 eligible patients, 8 refused to take participate. None specified
the reason for refusal. Of the remaining 163 patients, 3 were withdrawn by the radiologist
(envelopes unsealed) because typical neurograms were not produced. Of the final study
population (160 patients), 97 were men and 63 women. The mean age of the patients was
43.7 years (range 1978 years), and the mean duration of symptoms 2.5 months. Their
clinical signs and symptoms are presented in Table 1.
Five patients had L4, 89 had L5, and 66 had S1 radiculopathy. MRI identified a disc
herniation corresponding to the symptoms in 131 (82 %) patients, as well as nerve root
enhancement in 3 patients with a non-herniated symptomatic disc. The degree of disc
displacement was graded bulge (or normal) in 29 (18%), as contained herniation in 50
(31%), as noncontained herniation in 68 (43%) and as sequester in 13 (8%) patients.

50
Table 1. Baseline characteristics of 160 patients with sciatica randomly assigned to
receive periradicular infiltration either with methylprednisolone-bupivacaine or saline.*
Characteristic

Methylprednisolonebupivacaine
(n = 80)
43.813
64
15

Saline

Total

(n = 80)
(n = 160)
Age (year)
43.713
43.713
Male gender (%)
58
61
High school graduates (%)
16
16
Work-related features
Employed (%)
73
78
75
Retired (%)
11
11
11
Others (unemployed, students)
16
11
14
Duration of sciatica (months)
2.41.5
2.61.5
2.51.5
First or second episode of sciatica (%)
59
47
53
Level affected on MRI (%)
L3-L4
3
5
4
L4-L5
61
40
51
L5-S1
36
55
45
MRI-classification of the symptomatic disc (%)
Bulge or normal
22
14
18
Contained herniation
30
32
31
Extrusion
48
54
51
Leg pain intensity (100-mm VAS)
71 18
75 19
73 18
Back pain intensity (100-mm VAS)
53 25
60 25
56 25
Oswestry score (%)
43 16
44 15
43 15
Nottingham Health Profile
Dimension of energy
21 28
17 25
19 27
Dimension of emotional reactions
11 15
10 13
10 14
Dimension of sleep
28 32
31 31
29 31
Dimension of pain
66 26
72 25
69 26
Dimension of mobility
33 19
34 17
34 18
Dimension of social isolation
49
28
38
Mean duration of sick leave (days)
14 18
22 26
18 23
Physical measures
Straight leg raising test ()
58 18
60 19
59 19
Lumbar flexion (cm)
4.81.5
4.91.5
4.81.5
Motor deficit (% )
24
20
22
* Mean SD values shown unless otherwise stated.
The scores of the Nottingham Health Profile range from 0 to 100, with higher scores indicating worse healthrelated quality in each dimension.

Measured by the modified Schober method (the difference between a 15-cm distance marked on the back of

the patient in a standing position and distance with the patient in full flexion).

51

5.2 Correlations of symptoms and signs to MRI findings (I)

Symptoms of sciatica (back and leg pain, disability, days of sick leave) were not
associated with the degree of disc displacement in MRI, whereas SLR restriction
(p<0.01), and nerve root enhancement (p < 0.001) were strongly associated with MRI
classification (Figure 4). The results were similar when patients with non-radicular pain
radiation into the leg were excluded; only associations with SLR and neural enhancement
were weaker. The associations of root level, nerve root enhancement by Gd-DTPA, and
degree of neural compromise were also analyzed with the symptoms of sciatica. There
were no correlations except that pain upon coughing was more frequent in S1 irritation (p
< 0.01). Among the physical measures, SLR restriction correlated with almost all of the
symptoms (Spearman coefficients 0.190.27). The correlations for lumbar flexion were
similar, but weaker. Analyzed by stepwise regression analysis with SLR restriction as the
outcome, MRI classification of non-herniations versus herniations explained 20.4% of the
variance in SLR restriction. MRI classification did not explain any of the variance in the
Oswestry index, or back pain.

Fig. 4. Boxplots comparing low-back specific disability measured by Oswestry Index (upper
scale) and straight leg raising (SLR, lower scale, shaded boxes) with MRI classification. Note
that disability is not associated with the degree of disc displacement, whereas SLR is. The
boxplots show the median (50th percentile) and the interquartile (25th to 75th percentile) range.
Vertical bars show the minimum and maximum scores. Cont. HNP=contained herniation,
noncont HNP=noncontained herniation.

52

5.3 Evaluation of patients with the Trp2 and Trp3 alleles (II and III)
Mutation analysis revealed 6 Trp2 and 34 Trp3 allele positive cases among the 159 sciatic
patients (prevalences 4 % and 22 %, respectively). Two of the Trp3 positive patients were
homozygous for the allele, whereas none of the Trp2 positive patients were homozygous.

5.3.1 Demographic and clinical characteristics

The medical history and demographic characteristics of the patients with the Trp2 allele
did not differ from the other 153 sciatic patients, except that they had significantly more
often sedentary job (p < 0.05; Table 2). Patients with the Trp3 allele had generally higher
education (chi-square p < 0.05), but otherwise they did not differ from the patients
without the allele on the basis of age, gender, height or sciatic history. They had,
however, significantly longer symptom duration before the index visit (3.0 months vs. 2.4
months, p < 0.05; Table 2).
Table 2. Characteristics of patients with the Trp2 (Trp2 allele +) and Trp3 (Trp3 allele +)
alleles compared to patients without the alleles. MeansSD shown unless otherwise
stated.
Characteristic

Trp2 allele +
(n=6)

Trp3 allele +
(n=34)

Negatives
(n=119)

Age (years)

45 13

43 13

4413

Symptom duration (months)

2.9 1.7

3.0 1.8 (p<0.05)

2.41.3

Height (cm)

175 6

172 8

1719

Female (%)

41

41

Primary school or less (%)

Sedentary job (%)
Sciatica >6 mo/last year (%)
Recurrent sciatica (%)
Back pain (100-mm VAS)

17

21 (p<0.05)

41

80 (p<0.05)

35

38

17

15

18

18

40 29

57 23

5726

Leg pain (100-mm VAS)

73 8

72 17

7319

Disability Index (Oswestry%)

33 12

39 14

4515

5.9 1.1 (p<0.05)

5.0 1.9

4.81.4

70 15

60 20

5818

Lumbar flexion (cm)

Straight leg raising test ()

A 3-scale job classification (sedentary job, mixed job, or physically demanding job) for the
patients currently employed was used.
Percentage of patients with over 5 sciatic episodes during lifetime.

Patients with the Trp2 allele were significantly more flexible by the modified Schober
measure than the others (p < 0.05), but otherwise their symptoms and signs did not differ

53
significantly from the other sciatic patients. Likewise, patients with the Trp3 allele did not
differ from the other sciatic patients on the basis of clinical symptoms and findings (Table
2). Both two patients homozygous for the allele were male (39 and 50 years of age). The
clinical symptoms and findings of the homozygous did not differ significantly from those
heterozygous for the allele.

5.3.2 MRI findings

With respect to the Trp2 allele, no significant differences were detected in intervertebral
disc degeneration, end-plate degeneration, Schmorls nodes, dorsal transverse tears and
HIZ lesions at any lumbar level. Three of the patients (3 of 6) with the Trp2 allele had
radial rupture in nonherniated disc at the L4-5 level, but not at other levels. The controls
had no radial ruptures in nonherniated discs (0 of 18). The difference at the L4-5 level did
not, however, reach statistical significance (p = 0.055). Two of the three patients with a
radial tear in nonherniated disc had also oedema in the symptomatic nerve root. Family
members with the Trp2 allele were slightly (but not significantly) older than members
without the Trp allele. They had significantly more intervertebral disc and end-plate
degeneration at the L5-S1 level (p < 0.05 for both), but not at any other level. Otherwise,
the MRI findings did not differ significantly. Interestingly, three of the family members
with the Trp2 allele (3 of 11) had a radial tear in a nonherniated disc, and none of the
family members without the Trp2 allele (0 of 11). Two of the family members with a
radial tear at the L4-5 level, were symptomatic at the time of the investigation. The third
family member was asymptomatic and had a radial tear at the L3-4 level.
Comparison of patients with the Trp3 allele with their matched controls revealed no
differences in end-plate degeneration, dorsal transverse tears, or HIZ-lesions. Patients
with the Trp3 allele had, however, significantly more disc degeneration at the L4-5 level
compared to the matched controls (P = 0.007). Disc degeneration at the other levels was
similar in both groups. The number of Schmorls nodes tended to be higher at the L1-2
level in the Trp3 allele positive patients (5 of 34 vs. 0 of 34; P = 0.06).

5.3.3 Thoracolumbar Scheuermanns disease (TLS)

Fifteen of 34 (44%) patients with the Trp3 allele were positive for TLS compared to 23 of
119 (19%) sciatic patients without the allele. This difference was highly significant
(p=0.003). Two of the patients with the Trp2 allele were also positive for TLS, but this
difference was not statistically significant. Other determinants significantly associated
with TLS included gender (p=0.001), occupational load (p=0.009) and body mass index
(p=0.04). Analyzed by stepwise logistic regression analysis, the final model for the
presence of TLS contained three significant determinants: male sex (OR 4.7; 95% CI,
1.812.2; p<0.001), the Trp3 allele (OR 4.7; 95% CI, 1.812.1; p=0.001) and physical job
(OR 7.1; 95% CI, 2.123.6; p=0.04; Table 3). Both individuals homozygous for the Trp3

54
allele had TLS in MRI. Otherwise, their MRI scans were similar to those of the
heterozygous patients (Figure 5).
Table 3. Significant determinants of thoracolumbar Scheuermanns disease in MRI
analyzed by stepwise logistic regression analysis. Odds ratios (OR) with 95% Confidence
Intervals (CI) and p-values presented.
Characteristic

OR (95% CI)

P-values to remove

Gender
Female (reference)
Male

1.0
4.7 (1.812.2)

<0.001

Trp3 allele
Negative (reference)
positive

1.0
4.7 (1.812.1)

0.001

Occupational load
Sedentary job (reference)

1.0

Mixed job

2.7 (1.07.5)

Physical job

7.1 (2.123.6)

0.04

Other variables (age, height, body mass index, sciatic history, smoking, duration of symptoms) did not improve
significantly logistic regression model.

55

Fig. 5. Magnetic resonance imaging scans of a 50-year old storeman with right-sided sciatica for
1.5 months. He is homozygous for the Trp3 allele. Left, T1-weighted sagittal scan, right, T2weighted sagittal scan. Schmorls nodes at the L1-2, L2-3, L3-4 and L4-5 levels. Grade 3 disc
degeneration at the L1-2, L2-3 and L4-5 levels. Contained herniation at the L4-5 level. He has
thoracolumbar Scheuermanns disease with multiple Schmorls nodes and disc degeneration in
the thoracolumbar region.

5.4 Clinical efficacy of periradicular infiltration.

Intention-to-treat analysis (IV)
In the final study population, 80 patients received saline and 80 received
methylprednisolone-bupivacaine injection. The affected level on MRI was more often the
L4-L5 disc in the methylprednisolone group and the L5-S1 disc in the saline group (p =
0.03). Days on sick leave before the intervention were significantly more in the saline
group (p = 0.03), although number of patients on sick leave was similar between the
groups. These differences were considered clinically important confounders, and the
scores of the treatment effects were adjusted accordingly. For the days on sick leave, a

56
categorical staging was used: 0 days, 130 days and over 30 days. For disc level, the L3L4 discs were combined with the L4-L5 discs.
In each treatment group, follow-up information was obtained at 2 weeks for 79
patients, 4 weeks for 80 patients and 3 months for 79 patients. At the 6-month and 1-year
follow-up assessments, information was obtained for 99% of the patients (n=158). Two
drop-outs occurred in the steroid group: One patient moved away and the other lived in
the remote countryside. A retroperitoneal hematoma developed in one patient on
anticoagulant therapy as a complication of the injection (steroid group). The extra costs of
the complication were not included in the economic analysis, and no further
complications were encountered.
Information on the immediate effects of the intervention on leg and back pain was
obtained for 78 patients in the saline group and 79 patients in the methylprednisolonebupivacaine group. In the saline group, leg pain decreased by 44% and back pain by 53%,
as compared with 61% and 52%, respectively, in the steroid group. The treatment effect in
leg pain was significantly better in the steroid group (11.9; 95% CI, 2.021.8; p = 0.02),
whereas no difference was observed for its effect on back pain (p = 0.36).
At the 2-week follow-up assessment, in both treatment groups, a significant
improvement from baseline was observed in every outcome parameter except lumbar
flexion (within-group data not shown). There was a significant between-group treatment
effect in favor of methylprednisolone-bupivacaine for leg pain, SLR and lumbar flexion
(Table 4). Leg pain decreased on the average by 24 % in the saline group and by 45 % in
the steroid group (Figure 6A, p < 0.01). Patient satisfaction also was significantly greater
in the steroid group (12.1; 95% CI, 1.223; p = 0.03). At the 4-week follow-up, there was
no significant between-group treatment differences in favor of either treatment. At the 3month follow-up assessment, a significant treatment effect in favor of the saline treatment
for back pain was observed, whereas at 6 months, the treatment effects for both leg pain
and back pain favored the saline treatment (Table 4). At the 1-year follow-up assessment,
there were no treatment effects in favor of either treatment. Leg pain had decreased on
average by 65% in both groups. No differences between the two treatments in the AUCscores of evaluated outcomes were found.

MRI-classification

Disc level

Difference (95% CI)

NS

NS

0.006

6 (10 to 22)

6 (3 to 15)

8 (0.4 to 16)

11 (5 to 26)

Difference (95% CI)

NS

NS

NS

NS

NS

NS

13 (3 to 29)

9 (1 to 17)

20 (5 to 35)

9 (0.3 to 18)

10 (2 to 17)

25 (10 to 40)

Difference (95% CI)

NS

0.027

0.008

0.043

0.009

0.002

1 (12 to 11)

2 (4 to 7)

2 (9 to 13)

6 (1 to 12)

5 (0.3 to 10)

13 (2 to 23)

Difference (95% CI)

NS

NS

NS

0.03

NS

0.02

Total

Table 4. Between-groups treatment differences following periradicular infiltration with steroid or saline in the whole study population
(total), and in subgroups of contained herniations, extrusions and disc levels L345. Positive treatment difference values indicate that the
steroid treatment was superior to saline.
Characteristic

24 (8 to 41)

0.023

6 (10 to 21)

9 (0.4 to 18)

L34/L45

Leg pain (100-mm VAS)

7 (1 to 16)

8 (0.3 to 16)

NS

Extrusions

Disability (Oswestry %)

19 (3 to 36)
NS

Contained herniations

Straight leg raising ()

3 (5 to 10)

Two weeks

Leg pain (100-mm VAS)

13 (9 to 35)

Four weeks
Disability (Oswestry %)

Straight leg raising ()

NHP emotional reactions

2 (13 to 9)

1 (20 to 23)

9 (2 to 19)

5 (6 to 16)

NS

NS

NS

NS

NS

3 (8 to 13)

2 (9 to 5)

0 (18 to 17)

3 (8 to 14)

3 (19 to 12)

5 (5 to 14)

5 (5 to 14)

NS

NS

NS

NS

NS

NS

NS

6 (4 to 15)

5 (0.6 to 14)

0 (19 to 19)

3 (7 to 13)

3 (14 to 19)

8 (4 to 22)

7 (2 to 16)

NS

NS

NS

NS

NS

0.006

NS

2 (5 to 9)

3 (2 to 8)

5 (18 to 7)

1 (9 to 6)

1 (12 to 11)

5 (1 to 11)

2 (4 to 8)

NS

NS

NS

NS

NS

NS

NS

Leg pain (100-mm VAS)

22 (43 to 0.3)

14 (24 to 3)

23 (40 to 5)

0.047

0.01

0.014

8 (25 to 9)

1 (11 to 9)

17 (32 to 1)

NS

NS

0.033

7 (23 to 9)

2 (10 to 7)

8 (23 to 6)

NS

NS

NS

12 (24 to 0.03)

6 (12 to 1)

16 (27 to 6)

NS

NS

0.003

57

Leg pain (100-mm VAS)

5 (27 to 17)

NS

0.008

NHP pain

Disability (Oswestry %)

13 (4 to 23)

Three months

NHP pain

2 (12 to 10)

NHP emotional reactions

Straight leg raising ()

Disability (Oswestry %)

Six months

NHP pain

Disc level

3 (5 to 10)

Difference (95% CI)

NS

NS

1 (9 to 10)

3 (4 to 10)

Difference (95% CI)

NS

NS

2 (9 to 5)

2 (7 to 3)

Difference (95% CI)

NS

NS

Total

p
1 (11 to 8)

Table 4. Continued.
MRI-classification
DifferLence (95% CI)
NS

NS

L34/L45

9 (21 to 3)

3 (13 to 7)

Extrusions

NHP emotional reactions

Contained herniations

Straight leg raising ()

Leg pain (100-mm VAS)

0 (16 to 16)

NS

8 (22 to 7)

NS

4 (4 to 13)

7 (7 to 20)

NS

NS

NS

4 (16 to 8)

0 (7 to 6)

5 (16 to 5)

NS

NS

NS

One year

1 (17 to 15)

NS

NS

NS

5 (2 to 11)

2 (7 to 4)

NS

NS

NS

4 (6 to 13)

2 (4 to 8)

5 (21 to 11)

7 (2 to 16)

NS

NS

NS

NS

3 (5 to 10)

0 (22 to 22)

1 (10 to 8)

1 (12 to 9)

NS

NS

Disability (Oswestry %)

4 (7 to 16)

3 (13 to 7)

NHP pain
NHP emotional reactions
Straight leg raising ()

Numbers of patients at the 2-week, 4-week, 3-month, 6-month and 1-year follow-ups were 24/26, 23/26, 24/25, 24/25 and 24/25 (saline/steroid) for contained herniations;
38/43, 37/43, 38/42, 38/42 and 38/42; and 51/36, 51/36, 51/35, 51/35 and 51/35, respectively, for the combined L34 & L45 levels.
The between-group mean values of present the difference between the adjusted change from baseline in the methylprednisolonebupivacaine and saline groups (95% CI and
p-values are also presented). The values are adjusted to the level of the symptomatic disc and days on sick leave before the intervention.
VAS = visual analog scale, MRI = magnetic resonance imaging, CI = confidence interval, NHP = Nottingham Health Profile, NS = not significant.

58

59

A
100

80 79 80

79

80

Saline

80

80 79 80

79

78

Steroid

78

90
80

Leg pain (m m )

70
60
50
40
30

*
**

20
10
0

0 2 4

12

26

52

Follow-up tim e (weeks)

B
100

24 23 24

24

24

Saline

24

26 26 26

25

25

Steroid

25

90

Contained herniations

80

Leg pain (m m )

70
60
50

**
*

40
30

20
10
0

0 2 4

12

26

52

Follow-up tim e (weeks)

Fig. 6. Leg pain (mm on VAS, standard deviations indicated with vertical bars) at baseline and
at each follow-up assessment after the nerve root infiltration with either methylprednisolone
bupivacaine ( ) or saline ( ). The upper box presents the number of patients at each
follow-up assessment. A) intention-to-treat analysis, B) subgroup of contained herniations, C)
subgroup of extrusions. * P-value of between-group treatment difference at the respective
follow-up <0.05, **p<0.01.

60
C
100

38 38 38

37

38

43 43 43

43

42

Saline
Steroid

38
42

90

Extrusions

80

Leg pain (m m )

70
60
50
40
30

20
10
0

0 2 4

12

26

52

Follow-up tim e (weeks)

Fig. 6. Continued.

5.5 Clinical efficacy of periradicular infiltration.

Subgroup analysis (V)
For bulges, at 12 months, NHP emotional reactions were in favor of the saline injection
(p<0.05) and SLR in favor of the steroid treatment (p < 0.05). No differences between the
treatments in the AUC-scores of evaluated outcomes or number of painless patients were
observed.

5.5.1 Contained herniations vs. extrusions

In the case of contained herniations, the methylprednisolone-bupivacaine injection
produced significant treatment effects for leg pain at 2 and 4 weeks, and for NHP
emotional reactions at 3 months (Table 4). At 6 months, leg pain, disability and NHP
emotional reactions were in favor of saline (Table 4; Leg pain Fig. 6B). The AUC-scores
indicated that the steroid option was superior to saline in leg pain and in NHP emotional
reactions from baseline to 3 months (for both p < 0.05). In accordance with the
aforementioned efficacy in leg pain, the number of painless patients at 2 weeks was
significantly in favor of the steroid treatment. For extrusions, leg pain was in favor of
saline at 6 months (p < 0.05; Table 4; Figure 6C).

61

5.5.2 Disc level

For symptomatic lesions situated at the L3-4-5 levels, the steroid treatment was superior
to the saline with respect to leg pain, disability, and SLR at 2 and 4 weeks (Table 4).
Similarly, the AUC-score these outcomes from baseline to 3 months, and the number of
painless patients at 4 weeks favored significantly the steroid option (P<0.05 for both).
The treatment difference in NHP emotional reactions almost reached statistical
significance in favor of the steroid group. At the L5-S1 level, between-group treatment
difference at 1 year (P= 0.031) and the AUC-score score from 3 to 12 months (P= 0.006)
for NHP emotional reactions were in favor of saline but otherwise the treatments were
similar.

5.6 Cost-effectiveness of the treatments in subgroups (V)

After adjustment for baseline differences and duration of symptoms, the total costs during
the 1 year follow-up period did not differ between the two treatment groups. At the 4week follow-up assessment, therapy visits (physiotherapists and osteopaths; P<0.05) and
drug cost (P = 0.005) were significantly less in the methylprednisolone group. From the
4-week follow-up onward, no significant cost differences between the treatments
emerged at any time point. At 1 year, the mean cumulative cost per patient was $2195
(95% CI 17292661) in the steroid group and $2180 (95% CI 16942666) in the saline
group. No differences in cost-effectiveness between the treatments were observed. After
1 month only, one patient in the saline group underwent surgery, and by 1 year 18 patients
in the methylprednisolone group and 15 in the saline group received surgical treatment.
For bulges, no differences between the treatments in the medical costs or sick leaves
were observed. Cost-effectiveness of the treatments was likewise similar: to obtain one
painless patient at 1 year cost with steroid $3740 vs. $3629 with saline (Table 5).

5.6.1 Contained herniations

For contained herniations, the steroid intervention produced savings in the need for
homecare ($200 per patient; 95% CI, $46 to $355, P = 0.013) at 4 weeks and for total
costs at 6 months ($1795; 95% CI, $1069 to $2521, P < 0.001). Medical costs at each
follow-up are presented in Figure 7A. By 1 year, 42 % of patients were operated in the
saline group vs. 20 % in the steroid group (p = 0.1). When the rate of operations was
evaluated by Kaplan-Meier curves and log-rank tests, p-value of 0.1 was obtained (Figure
8). Because of the different operation rate, days on sick leave by 6 months (7.4 days per
month per patient; 95% CI, 2.312.5 days, p = 0.006) and cumulative costs at 12 months
($1969 per patient; 95% CI, $590 to $2914, P = 0.007) were in favor of steroid. The
AUC-scores of medical costs from 3 to 12 months were also in favor of the steroid
treatment (p < 0.001) in accordance with the other data.

62
No significant short-term differences were observed in cost-effectiveness, but by 12
months to obtain one painless patient cost $12666 less per patient in the steroid group (p
< 0.01; Table 5).
Table 5. Mean cumulative costs ($) of periradicular infiltration per one responder ( 75%
decrease of leg pain) according to MRI-classification*.
Timepoint

Bulges

Contained herniations

Extrusions

Steroid

Saline

Steroid

Saline

Steroid

Saline

Three months

2640

2116

NS

5850

6360

NS

4081

2230

NS

Twelve
months

3740

3629

NS

4432

17098

0.0073

7165

2484

0.0058

* Operated patients were always regarded as non-responders. Statistical significance evaluated by Students t-test.
MRI = magnetic resonance imaging, NS = not significant.

5.6.2 Extrusions
For extrusions, cost of therapy visits at 4 weeks was significantly less with the steroid
injection ($182; 95% CI, $79 to $285, P = 0.001). Medical costs at each follow-up
assessment are presented in Figure 7B. By 1 year, 13 % underwent surgery in the saline
group vs. 32 % in the steroid group (chi-square value 3.9, df 1, p = 0.05). By KaplanMeier analysis, p-value was 0.1 (Figure 8). Because of the higher operation rate in the
steroid group, the area-under-the-curve scores of medical costs from 3 to 12 months were
significantly (P = 0.004) in favor of saline, whereas for cumulative costs at 12 monts only
a trend (P = 0.08) in favor of saline existed. No significant differences in sick leaves were
observed.
No significant short-term differences were observed in cost-effectiveness, but by 12
months the steroid treatment was more expensive: $4445 more per one painless patient
(P<0.01; Table 5).

63
A
3500

24

24

24

24

Saline

24

26

26

25

25

Steroid

25

Contained herniations

Medical costs ($)

3000
2500
2000
1500
1000

**

500

12

26

52

Follow-up tim e (weeks)

B
3500

38

38

37

38

43

43

43

42

Medical costs (%)

3000

Saline
Steroid

38
42

Extrusions

2500
2000
1500
1000
500

12

26

52

Follow-up time (weeks)

Fig. 7. Medical costs ($, standard deviations indicated with vertical bars) at each follow-up
assessment after the periradicular infiltration with either methylprednisolonebupivacaine
( ) or saline ( ). The upper box presents the number of patients at each follow-up
assessment. A) Subgroups of contained herniations, B) extrusions. * P-value of the betweengroup treatment difference at the respective follow-up <0.05, **p<0.01.

64
Extrusions/Steroid

Num ber of operated patients

14
12
10
Contained herniations/Saline

Extrusions/Saline

6
4
2

Contained herniations/Steroid

0
0

10

20

30

40

50

Follow-up tim e (weeks)

Fig. 8. Kaplan-Meier curves for the number of operated patients versus time of operation in
weeks after the periradicular infiltration in subgroups of contained herniations and extrusions.
Curves are presented separately for both treatments in each subgroup.

5.6.3 Disc level

Steroid treatment was superior to the saline at the 4-week follow-up assessment with
respect to need for homecare at the L345 level ($120; 95% CI, $31 to $209, P = 0.01).
No significant differences with respect to cumulative medical costs, rate of operations or
work absenteism or cost-effectiveness were observed between the treatments.

6 Discussion
6.1 Study population
In order to obtain a homogenous study population and avoid chronicity, the inclusion
criteria included dermatomal unilateral pain below the knee (dermatomes LIV to SI) with
symptom duration from 3 to 28 weeks. Depressed patients and those applying for early
retirement were excluded, because it was anticipitated that their treatment responses
could be confounded. Patients who had undergone back surgery were excluded for the
same reason. The physicians working in the University Hospital catchment area were
thoroughly informed about the trial and most of the patients were referred directly from
primary care, which means that the findings of these studies can be generalized to an
unoperated sciatic population with a limited symptom duration. The final study
population was in fact similar to other sciatic populations with respect to age and gender
(Jnsson & Strmqvist 1993, Carette et al. 1997). Selection bias was probably
insignificant because consecutive eligible patients were enrolled, and of the eligible
patients only 8 refused to take part in the study. The recruitment of 160 patients was
based on power calculations with an assumption of 15 % clinical effect and 10 % dropout rate. Only two patients were lost during the follow-up period, which means that the
treatment effects could be calculated reliably. However, even this study population was
not large enough to reliably characterize the phenotype of the Trp2 allele. The study
population was, however, comparatively homogenous. Most of the patients had
experienced a disc herniation, and the mean disability and leg pain scores indicated a
severe disease. Of the final population, only 29 had sciatica due to a non-herniated disc.
Exclusion of these patients would have rendered the study population more homogenous,
but then valuable information about intercorrelations between different types of disc
displacement and clinical signs and symptoms would not have been obtained.

66

6.2 Methods
In this study, sciatic patients were characterized using validated questionnaires (VAS,
Oswestry, NHP), clinical examination, ENMG and MRI. Clinical examinations and
ENMG at baseline were performed by experienced physicians. The patients clinical
examinations during the follow-up period were usually performed by one and the same
physician, who was familiar with the study protocol. Sequence variations in the human
COL9A1, COL9A2 and COL9A3 genes were analysed with advanced methods in an
experienced laboratory (Krkk et al. 1998).
The MRI scans were obtained with a high-resolution 1.5-T imaging system and read
by two experienced radiologists blinded to the patients clinical status. The intertester and
intratester reliabilities were moderate to substantial. The most common disagreement in
the degree of disc displacement was for contained herniation versus noncontained
herniation, but in study I the scores in these subgroups were similar (whereas they
differed significantly in study V) . The major weakness in our MRI protocol was the lack
of proton density-weighted sagittal images, which visualize well the disruption of the
posterior longitudinal ligament. However, contrast-enhancement compensated somewhat
for this shortcoming. The periradicular infiltrations were performed by an experienced
radiologist using a conventional technique (Derby et al. 1992). Only one complication
was encountered during the trial.
Randomization (studies IV and V) was done with random number tables, and resulted
in only minor imbalances in baseline characteristics between the treatment groups.
Adjustments were made for these imbalances in the multivariate analyses. One important
component of validity in experimental studies is adherence to study protocol (i.e.
compliance). Poor adherence is a major source of bias in randomized controlled trials
(Malmivaara 1997). In this RCT, the compliance was excellent because every patient
received the treatment immediately after randomization, and no further interventions were
undertaken. In addition, cointerventions, including booster injections, were avoided to
optimize the treatment standardization. The study was conducted in a double-blind
manner. Patients were not asked to guess the treatment they received, but the responses of
the physicians at 2 weeks indicated that the nature of the intervention remained masked.
The radiologist giving the injections was also blinded, and he did not attend the treatment
of the patients after the injection. In conclusion, the current RCT fulfilled all three major
requirements (comparability of groups, observer blinding, and intention-to-treat analysis)
requested of an intervention prognostic study (Vroomen et al. 2000). Subgroup analysis
of intention-to-treat studies is controversial. It has been stated that it is essential to
identify homogenous groups of low back pain patients, and that the efficacy of
interventions in these subgroups should be studied in randomized controlled trials (Bouter
et al 1998). However, subdividing sciatic patients into homogenous strata has the
disadvantage of poorer generalizability of results to heterogenous populations (Bloch
1987).
One problem in comparing studies on sciatica and low back pain is the diversity of
outcome measures. There is an urgent need to standardize outcome measures and include
health-related quality-of-life (HRQOL) measures in economic assessment studies (Deyo
et al 1998). Economic analysis is a necessary input before a choice is made between two

67
or more competing treatments for the same illness. A cost-effectiveness analysis (CEA) is
basically a ratio, where changes in health due to an intervention are captured in the
denominator and changes in resource use, valued in monetary terms, in the numerator,
both being compared with a specific alternative (Conrad & Deyo 1994, Russell et al.
1996). In this thesis, only validated questionnaires were used, and a cost-effectiveness
estimate for the intervention was obtained.

6.3 MRI findings versus symptoms and signs of sciatica (I)

The findings of this study indicate that MRI is unable to distinguish sciatic patients in
terms of the severity of their symptoms, in contrast to results of some earlier studies
(Thelander et al. 1994, Jnssn & Strmqvist 1996). This suggests that pain mechanisms
other than the extent of disc herniation in MRI generate the subjective symptoms, and
accords with the results of Modic et al. (1995), who showed that patients with or without
disc herniation had similar disability. The lack of association between imaging and
clinical findings was also observed in the study of Balague and co-workers (1999). Our
result is further supported by the high prevalence of false-positive MRI findings among
asymptomatic subjects (Boden et al. 1990, Jensen et al. 1994).
In a study population including symptomatics and asymptomatics, herniations were as
common in both groups (Boos et al. 1995). The best predictor of symptoms was the
extent of neural compromise. In the present study, neural compromise was not associated
with the symptoms, but most of the patients had major neural compromise. Straight leg
raising restriction was a good measure of nerve root entrapment, but it could not
differentiate the subclasses of disc herniations. The association of SLR restriction and
disability has also been observed by others (Thelander et al. 1992, Jnsson & Strmqvist
1995).
These findings are similar to those of a study in which patients with painful disc
disruption but without deformation of the outer anular wall had similar leg pain to
patients with more severe disruption deforming the outer wall (Ohnmeiss et al. 1997).
Thus, an organic cause, like anular tear, of disability among sciatic patients may be
present, even when MRI findings are minor; and vice versa, prominent MRI findings may
not associate with any symptoms.

6.4 Phenotype of patients with the Trp2 allele (II)

This is the first report of the phenotype of patients with the Trp2 allele, a gene mutation
that is strongly associated with intervertebral disc disease (Annunen et al. 1999). Patients
with the Trp2 allele were significantly more flexible than patients without the allele,
which may be related to altered interactions between collagen IX and other matrix
molecules. Their clinical symptoms, however, did not differ from those without the allele.
Analysis of the radiological (MRI) phenotype revealed that radial tears in nonherniated

68
discs seem to be more common in patients with the allele. Patients with and without the
Trp2 allele did not differ with respect to end-plate or intervertebral disc degeneration,
HIZ-lesions or dorsal transverse tears.
Tears of the anulus are suggested to play an important role in the degeneration of the
intervertebral joint complex (Osti et al. 1990). Anular tears can be classified into
concentric, transverse and radial tears, of which MRI can demonstrate the transverse and
radial tears (Yu et al. 1988b). HIZ-lesions, on the other hand, represent a combination of
radial and circumferential tears (Aprill & Bogduk 1992). Radial ruptures are interesting
as they precede disc degeneration (Yu et al. 1988a, Osti et al. 1992), and are associated
with subjective pain in discography (Moneta et al. 1994). Radial tears are also known to
cause sciatic pain (Ohnmeiss et al. 1997). In the current study, patients with the Trp2
allele were mostly in sedentary jobs and relatively young, yet three of them, and none of
the other patients, had a radial tear in a nonherniated disc in MRI. Moreover, two of them
had nerve root oedema at the same level, which ensures the presence of a radial tear.
Consistent with this finding, 3 family members with the Trp2 allele, and none of those
without it, had a radial tear. The occurrence of radial ruptures at the most mobile lumbar
disc, i.e. the L4-5 level, may relate to mechanical factors. In accordance, intervertebral
disc degeneration is also most prominent at the L4-5 and L3-4 levels (Miller et al. 1988).
Transverse tears and HIZ-lesions were comparable in patients with or without the Trp2
allele. Indeed, histological analysis of post-mortem lumbar spines has indicated that
transverse tears are due to trauma rather than biochemical degradation (Osti et al. 1992).
The patients with the Trp2 allele did not differ from their controls with respect to
intervertebral disc degeneration, but the patients (and their controls) had mostly sedentary
work. A hard physical job, and, particulararly frequent lifting and postural stress, increase
the risk of sciatica (Helivaara 1989, Riihimki et al. 1989), whereas a sedentary job may
decrease the risk of both sciatica (Riihimki et al. 1994) and intervertebral disc
degeneration (Battie et al. 1995). Interestingly, family members with the Trp2 allele had
significantly more disc degeneration at the L5-S1 level than those without the amino acid
substitution. They were, however, slightly older and there might also exist some
difference in occupational load, i.e. these two populations are not fully comparable.
The possible association of radial tears and the Trp2 allele should be verified by
discography with a larger patient population. Recently, a German population of patients
operated for an intervertebral disc herniation was screened for the presence of the Trp2
allele (Wrocklage et al. 2000). Three patients of 250 (1.2%) had this sequence variation.
The patients with the Trp2 allele were older than the others, but their radiologic
phenotype was not characterized. The role of collagen IX in intervertebral disc disease is
supported by the findings in transgenic mice expressing mutant 1(IX) chain: there was
accelerated intervertebral disc degeneration with partial disruption of end-plates and
fissures in the anulus (Kimura et al. 1996).

6.5 Phenotype of patients with the Trp3 allele (III)

The results of this study suggest that the Trp3 allele is strongly associated with TLS in
sciatic patients. On the basis of the matched pair analysis, the Trp3 allele also enhances

69
the likelihood of intervertebral disc degeneration at the L4-5 level, but other MRI and
clinical characteristics were similar in patients with or without the allele. These and our
previous findings emphasise the importance of collagen IX for end-plate and
intervertebral disc integrity (Annunen et al. 1999, Paassilta et al. 2001).
Scheuermanns disease already presents typically as rigid kyphosis of the thoracic or
thoracolumbar spine in adolescence (Lowe 1999). The association of the Trp3 allele with
TLS is a clinically important finding, because TLS predisposes to low back pain (Lings &
Mikkelsen 1982, Greene et al 1985, Lowe 1999). Its incidence reportedly ranges from 4
% to 8 % among patients with low back pain, although it is probably underestimated
through being missed or attributed to poor posture (Lowe 1999). A Danish study among
patients with low back pain found considerably higher prevalences of both high
(=thoracic; 28%) and low (=thoracolumbar; 26%) Scheuermanns disease (Lings &
Mikkelsen 1982).
TLS may also associate with lower lumbar discogenic disease. In one study 9 % of
1419 patients with TLS also had lower lumbar disc disease, and since 81 % were under 40
years and 9 % younger than 21 years, the authors proposed the term juvenile discogenic
disease (Heithoff et al. 1994). The association of the two diseases and the early onset
also led them to suggest that an intrinsic defect of the disc and/or end-plate, principally in
proteoglycan or collagen, could be responsible for the structural weakness (Heithoff et al.
1994). The co-occurrence of Scheuermann-type changes with discogenic disease is also
supported by findings from a Finnish long-term follow-up study. Children and
adolescents with intervertebral disc degeneration and Scheuermanns disease had an
increased risk of recurrent low back pain at this age, and also a long-term risk of recurrent
pain up to early adulthood (Paajanen et al. 1989b, Tertti et al. 1991, Salminen et al.
1999).
The aetiology of TLS is obscure. Our observation that it appears significantly more
often in sciatic patients with the Trp3 allele (44 %) than without it (19 %) emphasises the
importance of genetic factors. Further support comes from reports suggesting that TLS is
inherited autosomally dominantly with incomplete penetrance and variable expression
(Lowe 1999). In addition, histologic findings suggest that abnormal collagen matrix may
be an aetiologic factor in the disease (Aufdermaur 1981). The importance of intact
collagen IX for the development of TLS is also highlighted by the present finding that
both individuals who were homozygous for the allele had the disease. Moreover, the
finding that collagen IX defect is associated with TLS accords with the the presence of
the protein in both the intervertebral disc and endplate. Thus, a defect in collagen IX,
especially combined with other risk factors like physical job and male sex, may
predispose to recurrent low back pain problems. The role of other risk factors is supported
by findings that TLS is associated with repetitive trauma, and tends to occur primarily in
adolescent boys engaged in heavy physical activity (Lowe 1999).
Patients with the Trp3 allele had significantly more disc degeneration on T2-weighted
scans at the L4-5 level than those without the allele. Intervertebral disc degeneration has
multifactorial aetiology (Battie et al. 1995). Among identical twins disc degeneration may
be explained primarily by genetic influences and unidentified factors, which may include
complex, unpredictable interactions (Battie et al. 1995). Involvement of genetic factors in
intervertebral disc degeneration is strengthened by recent reports of an association

70
between the disease and both vitamin D receptor gene polymorphism (Videman et al.
1998) and aggrecan gene polymorphism (Kawaguchi et al. 1999).

6.6 Intention-to-treat analysis of periradicular infiltration (IV)

This is the first randomized controlled trial comparing the efficacy of periradicular steroid
with that of saline for unilateral discogenic sciatica. The findings of the study indicate
that both treatments had already induced clinical improvements at the 2-week follow-up.
Periradicular infiltration with a combination of methylprednisolone and bupivacaine was
superior to saline injection for leg pain, straight leg raising and lumbar flexion (in
addition to patient satisfaction) according to findings at 2 weeks, but not at later followup assessments. The saline injection was more effective for back pain at the 3- and 6month follow up assessments, and for leg pain as shown at 6 months. The economic
analysis showed that the methylprednisolone treatment had produced savings in costs of
therapy visits and medications at 4 weeks, but other uses of resources and their respective
costs and mean duration of sick leave were more or less equal in the two groups
throughout the follow-up period. The total number of operations did not differ
significantly between the treatment groups. The 21 % overall rate of operations was
similar to that of other studies (Dilke et al. 1973, Bush & Hillier 1991, Carette et al.
1997).
Some controlled studies suggest that epidural corticosteroids may be beneficial for
sciatica (Dilke et al. 1973, Bush & Hillier 1991), but negative results also exist
(Klenerman et al. 1984, Cuckler et al. 1985, Mathews et al. 1987, Carette et al. 1997).
Two meta-analyses suggest some benefit of epidural steroids for sciatica (Watts & Silagy
1995, Vroomen et al. 2000). Basically, epidural steroids could be effective in sciatica
because a rapid direct transport from the epidural space to the axons of the spinal nerves
in pigs was observed following application of Evans-blue-labelled albumin (Byrd et al
1995). It has been found, however, that even in experienced hands up to 25 % of epidural
needle placements may be incorrect (White 1983), and additionally, there is a possibility
that epidural corticosteroids might be effective in a subgroup that is overlooked because
of heterogeneity in the study populations, follow-up times and intervention methods
(Weinstein et al. 1995).
Periradicular injections have been recommended, but unfortunately only two
uncontrolled prospective series have been published (Weiner & Fraser 1997, Lutz et al.
1998). Both studies suggest that such injections might have a beneficial effect on
discogenic sciatic pain. Recently, multiple periradicular infiltrations with either
bupivacaine or a combination of bupivacaine and betamethasone were compared (Riew et
al. 2000). The combination of steroid and anaesthetic significantly reduced the need for
operative treatment during the follow-up period (13 to 28 months). Eight patients of 28 in
the steroid surgery underwent surgery compared to 18 of 27 in the bupivacaine group.
Periradicular injection of a corticosteroid anaesthetic combination was found to have
only a short-term, but clinically meaningful, effect compared with saline injection. This
was a single-injection study, and repeated injections could possibly produce a more

71
sustainable effect. Decisive clinical improvement had already occurred in both treatment
groups at 2 weeks. Interestingly, in a rat model, thermal hyperalgesia was abated with
epidural saline and abolished with a specific inhibitor of iNOS (Kawakami et al. 1998).
This indicates that saline might have some clinical efficacy, maybe by blocking the NOmediated cascade. However, the data as such does not allow any inference that saline
injection has an effect superior to that of a genuine placebo.

6.7 Subgroup analysis of periradicular infiltration (V)

The present subgroup analysis revealed that the short-term effect of the steroid treatment
was most pronounced for contained herniations and symptomatic lesions situated at the
L45 (or L34) disc level. Patients with a contained herniation were less likely to
undergo back surgery when receiving the steroid treatment and they also had significantly
fewer days on sick leave from 3 to 6 months. Counter-effectiveness of the steroid
treatment was most pronounced for extrusions, where the steroid injection generated
significantly higher medical costs and a greater likelihood of surgery. The authors are not
aware of any other studies where the response to epidural or periradicular epidural
steroids was analyzed according to the type of disc displacement.
Outcome measures in low back research can be divided into disease-specific and
generic functional status, or quality-of-life questionnaires (Deyo et al. 1994). The shortterm efficacy of the methylprednisolonebupivacaine injection compared to saline at the
L4-5 disc level was evident in disease-specific measures (leg pain, disability by Oswestry,
and straight leg raising restriction), whereas in the case of contained herniations efficacy
was seen in leg pain and one dimension of the generic questionnaire (NHP). The
Oswestry and Million scales have often been employed as outcomes in longitudinal prepost studies (Kopec & Esdaile 1995), yet the Oswestry disability questionnaire may be
less sensitive than the Roland-Morris questionnaire (Bouter et al. 1998). Another possible
explanation for the lesser disease-specific effect in the case of contained herniations is the
smaller patient number in this subgroup. This could also explain why we found no
difference between the treatments in the case of bulges, although an uncontrolled study
suggested that foraminal steroids could be effective in this subgroup (Shackleford &
Mulholland 1994).
Periradicular infiltration with steroid seemed to prevent surgery in contained
herniations, suggesting the effectiveness of steroid treatment in this subgroup.
Corticosteroids may calm the inflammatory process in many ways (Cupps & Fauci 1982,
Arantes et al 2000). Betamethasone clearly inhibits the secretion of cytokines (IL-1, IL1, IL-6 and TNF) and PgE2 from harvested disc herniation tissues in vitro (Takahashi
et al. 1996). Local anaesthetic might also exert some beneficial effect, as in the porcine
model lidocaine appeared to have an anti-inflammatory effect (Yabuki et al. 1998b). In
this study, 42 % of patients with contained herniation underwent surgery after the saline
injection, contrasted with 20% after the steroid injection. The operated patients were
almost entirely painless after surgery, which may explain the between-group differences
in favour of saline at 6 months. For contained herniations repeated steroid injections

72
could be recommended, maybe 2 to 4 weeks after the index injection, as the steroid
treatment does not increase the rate of disc operations and is effective in diminishing leg
pain.
Macrophages are found in abundance in disc herniations, and are thought to play a role
in the resorption of herniations (Ikeda et al. 1996, Haro et al. 1997, Habtemariam et al.
1998). Macrophages are more prominent in extrusions than in non-extruded herniations
(Grnblad et al 1994, Haro et al 1996, Matsui et al. 1998, Arai et al. 2000). When
extrusions were compared with non-extruded herniations, they exhibited more vascularity
(Yasuma et al 1993, Haro et al. 1996, Ikeda et al. 1996) and monocyte chemotactic
protein-1 positive cells (Haro et al. 1996). Mononuclear cells infiltrate along the margins
of extruded discs, expressing inflammatory mediators. In co-cultures with endothelial
cells, disc cells from extrusions enhanced the proliferation of endothelial cells and
fibroblasts significantly more than disc cells from protrusions (Doita et al. 1996). It is
speculated that the extrusion of herniated nucleus pulposus causes damage to the anulus
fibrosus and epidural vessels, inducing fibroblasts and endothelial cells to produce
chemokines, which may recruit macrophages in the initiation of the resorption process of
disc herniation (Haro et al. 1996). The vascularized granulation tissue can be detected
with contrast media (e.g. Gd-DTPA) as rim enhancement along the edges of extrusions
(Yamashita et al. 1994). Enhancement is most pronounced in the case of sequesters, and
histologically macrophages and small amounts of T-lymphocytes are found (Ikeda et al.
1996). It may be that corticosteroids have some detrimental effect on the function of
macrophages. In fact, in a rabbit model high-dose steroid suppressed the replacement of
grafted intervertebral disc tissue, in accordance with our results (Minamide et al. 1998).
Our subgroup analysis revealed that the steroid injection seemed more harmful for
extrusions, which accords with the observation that macrophages are more abundant in
extruded disc fragments. While inhibiting the secretion of cytokines (including TNF-)
(Takahashi et al. 1996), steroids may interfere with the resorption of HNP, in which TNF plays an important role (Haro et al. 2000). This was clearly seen in our study: steroid
and saline were both effective in relieving leg pain, but at approximately 3 months
patients in the steroid group were more likely to be operated compared to those in the
saline group.
The steroid intervention already produced some monetary savings for contained
herniations by 4 weeks, but by 1 year it had saved $1969 per treated patient. The disparity
of operation rates in these two subgroups explains the significant differences in medical
costs, as well as the decrease in days on sick leave at 6 months among the contained
herniation cases treated with steroid. The cost-effectiveness analysis indicates that for
contained herniations the steroid treatment was decisively more cost-effective than saline,
with a difference of over $12 600 per one painless patient. The contrast might have been
even greater with dry-needling as placebo. For extrusions, on the other hand, the costeffectiveness analysis suggests that a better alternative to saline than steroid needs to be
sought, one possibility being a TNF- antagonist (Olmarker & Larsson 1998). We did not
include indirect costs in our economic analysis, because return to work is less responsive
to clinical treatment than symptoms or daily functioning, although it is of utmost social
and personal importance (Deyo et al. 1998). Moreover, the monetary assessment of work
absenteism is controversial (Hutubessy et al. 1999).

7 Conclusions
The findings of this thesis indicate that MRI is unable to distinguish sciatic patients in
terms of the severity of their symptoms. Symptoms and signs of sciatica should receive
the major emphasis when assessing the severity of the disorder and in subsequent clinical
decision making.
In this sciatic patient population it was impossible to differentiate the genotypes (Trp2
and Trp3 alleles) on the basis of symptoms or clinical signs, whereas MRI has greater
potential in this respect. A radial tear in a nonherniated disc may indicate the presence of
the Trp2 allele, and the findings of TLS may indicate the presence of the Trp3 allele. The
Trp2 allele is a rare gene defect, but the Trp3 allele is more common. In fact, in this study
almost every fourth patient with sciatica had the Trp3 allele. These associations are
important for physicians treating back pain patients with or without sciatica, as MRI
findings may provide some estimates of the phenotype, and thus about the heredity of the
lumbar disc disease to the offspring of the patients.
The present double-blind, controlled trial indicated that periradicular infiltration with a
combination of methylprednisolone and bupivacaine offers only short-term clinical and
economic benefit for sciatica compared to saline. On the basis of the subgroup analysis,
however, steroid is clearly superior to saline in the case of contained herniations at the
symptomatic level, in terms of both leg pain and medical costs, and possibly also in the
need for operative treatment. In addition, if the lesion is located at the L34 or L45 level,
steroid treatment is more likely to achieve good results in terms of disease-specific
outcomes, but not in medical costs. In the case of extrusions steroid seems to be countereffective. However, subgroup analyses carry a high risk of bias and the promising results
in our subgroup analyses call for a verification study, which might be achievable using
oral steroid medication. Consistent findings would provide us with an easily available,
cost-effective, non-operative treatment for a large subgroup of sciatic patients.

8 References
Adams MA & Hutton WC (1982) Prolapsed intervertebral disc. A hyperflexion injury. 1981 Volvo
Award in Basic Science. Spine 7: 184191.
Adams MA & Hutton WC (1985) Gradual disc prolapse. Spine 10: 524531.
Agency for Health Care Policy and Research (AHCPR) (1994) Acute low back problems in adults:
Clinical Practice Guidelines 14. U.S. Department of Health and Human Services, Rockville, MD.
Ahn SH, Ahn MW & Byun WM (2000) Effect of the transligamentous extension of lumbar disc
herniations on their regression and the clinical outcome of sciatica. Spine 25: 475480.
Albeck MJ (1996) A critical assessment of clinical diagnosis of disc herniation in patients with
monoradicular sciatica. Acta Neurochir 138: 4044.
Altman DG (1991) Practical Statistics for Medical Research. Chapman and Hall, London.
Andersson GB & Deyo RA (1996) History and physical examination in patients with herniated
lumbar discs. Spine 21: S1018.
Andersson GB, Svensson HO, & Oden A (1983) The intensity of work recovery in low back pain.
Spine 8: 880884.
Annunen S, Paassilta P, Lohiniva J, Perl M, Pihlajamaa T, Karppinen J, Tervonen O, Krger H,
Lhde S, Vanharanta H, Ryhnen L, Gring HH, Ott J, Prockop DJ & Ala-Kokko L (1999) An
allele of COL9A2 associated with intervertebral disc disease. Science 285: 409412.
Antoniou J, Steffen T, Nelson F, Winterbottom N, Hollander AP, Poole RA, Aebi M & Alini M
(1996) The human lumbar intervertebral disc: evidence for changes in the biosynthesis and
denaturation of the extracellular matrix with growth, maturation, ageing, and degeneration. J Clin
Invest 98: 9961003.
Aprill C & Bogduk N (1992) High-intensity zone: a diagnostic sign of painful lumbar disc on
magnetic resonance imaging. Br J Radiol 65: 361369.
Arai Y, Yasuma T, Shitoto K, Yamauchi Y & Suzuki F (2000) Immunohistological study of
intervertebral disc herniation of lumbar spine. J Orthop Sci 5: 229231.
Arantes RM, Lourenssen S, Machado CR & Blennerhassett MG (2000) Early damage of sympathetic
neurons after co-culture with macrophages: a model of neuronal injury in vitro . Neuroreport 11:
177181.
Atlas SJ, Deyo RA, Keller RB, Chapin AM, Patrick DL, Long JM & Singer DE (1996) The Main
Lumbar Spine Study, Part II. 1-year outcomes of surgical and nonsurgical management of sciatica.
Spine 21: 17771786.
Aufdermaur M (1981) Juvenile kyphosis (Scheuermann's disease): radiography, histology, and
pathogenesis. Clin Orthop 154: 166174.

75
Balague F, Nordin M, Sheikhzadeh A, Echegoyen AC, Brisby H, Hoogewoud HM, Fredman P &
Skovron ML (1999) Recovery of severe sciatica. Spine 24: 25162524.
Battie MC, Videman T, Gibbons LE, Fisher LD, Manninen H & Gill K (1995) 1995 Volvo Award in
clinical sciences. Determinants of lumbar disc degeneration. A study relating lifetime exposures
and magnetic resonance imaging findings in identical twins. Spine 20: 26012612.
Beattie PF, Meyers SP, Stratford P, Millard RW & Hollenberg GM (2000) Associations between
patient report of symptoms and anatomic impairment visible on lumbar magnetic resonance
imaging. Spine 25: 819828.
Bell GR & Rothman RH (1984) The conservative treatment of sciatica. Spine 9: 5456.
Bemelmans MH, van Tits LJ & Buurman WA (1996) Tumor necrosis factor: function, release and
clearance. Crit Rev Immunol 16: 111.
Bickels J, Kahanovitz N, Rubert CK, Henshaw RM, Moss DP, Meller I & Malawer MM (1999)
Extraspinal bone and soft-tissue tumors as a cause of sciatica. Clinical diagnosis and
recommendations: analysis of 32 cases. Spine 24: 16111616.
Bloch R (1987) Methodology in clinical back pain trials. Spine 12: 430432.
Blower PW (1981) Neurologic patterns in unilateral sciatica. A prospective study of 100 new cases.
Spine 6: 175179.
Boden SD, Davis DO, Dina TS, Patronas NJ & Wiesel SW (1990) Abnormal magnetic-resonance
scans of the lumbar spine in asymptomatic subjects. A prospective investigation. J Bone Joint
Surg [Am] 72: 403408.
Bogduk N (1997a) Clinical anatomy of the lumbar spine and sacrum. New York: Churchill
Livingstone.
Bogduk N (1997b) Musculosceletal pain: toward precision diagnosis. In: Jensen TS, Turner JA &
Wiesenfeld-Hallin Z (eds.) Proceedings of the 8th world congress on pain, progress on pain
research and management, IASP Press, Seattle, p 507525.
Boos N, Rieder R, Schade V, Spratt KF, Semmer N & Aebi M (1995) 1995 Volvo Award in clinical
sciences. The diagnostic accuracy of magnetic resonance imaging, work perception, and
psychosocial factors in identifying symptomatic disc herniations. Spine 20: 26132625.
Bouter LM, van Tulder MW & Koes BW (1998) Methodologic issues in low back pain research in
primary care. Spine 23: 20142020.
Breivik H, Hesla PE, Molnar I & Lind B (1976) Treatment of chronic low back pain and sciatica:
comparison of caudal epidural injections of bupivacaine and methylprednisolone with
bupivacaine followed by saline. In: Bonfica JJ & Albe-Fessard DG (eds) Advances in pain
research and therapy. Vol. 1. Raven Press, New York, p 927932.
Brewton RG & Mayne R (1994) Heterotypic type II, IX and XI fibrils: comparison of vitreous and
cartilage forms. In: Yurchenko PD, Birk PD & Mecham RP (eds) Extracellular matrix assembly
and structure. Academic Press, San Diego, p 129170.
Brisby H, Byrd G, Olmarker K, Miller VM, Aoki Y & Rydevik B (2000) Nitric oxide as a mediator
of nucleus pulposus-induced effects on spinal nerve roots. J Orthop Res 18: 815820.
Buchner M, Zeifang F, Brocai DR & Schiltenwolf M (2000) Epidural corticosteroid injection in the
conservative management of sciatica. Clin Orthop 375: 149156.
Buckwalter JA (1995) Aging and degeneration of the human intervertebral disc. Spine 20: 1307
1314.
Bush K & Hillier S (1991) A controlled study of caudal epidural injections of triamcinolone plus
procaine for the management of intractable sciatica. Spine 16: 572575.
Byrd G, Olmarker K, Konno S, Larsson K, Takahashi K & Rydevik B (1995) A rapid transport route
between the epidural space and the intraneural capillaries of the nerve roots. Spine 20: 138143.
Byrd G, Otani K, Brisby H, Rydevik B & Olmarker K (2000) Methylprednisolone reduces the early
vascular permeability increase in spinal nerve roots induced by epidural nucleus pulposus
application. J Orthop Res 18: 983987.

76
Carette S, Leclaire R, Marcoux S, Morin F, Blaise GA, St.-Pierre A, Truchon R, Parent F, Levesque
J, Bergeron V, Montminy P & Blanchette C (1997) Epidural corticosteroid injections for sciatica
due to herniated nucleus pulposus. N Engl J Med 336: 16341640.
Carey TS, Garrett J, Jackman A, McLaughlin C, Fryer J & Smucker DR (1995) The outcomes and
costs of care for acute low back pain among patients seen by primary care practitioners,
chiropractors, and orthopedic surgeons. The North Carolina Back Pain Project. N Engl J Med 333:
913917.
Carragee EJ & Kim DH (1997) A prospective analysis of magnetic resonance imaging findings in
patients with sciatica and lumbar disc herniation. Correlation of outcomes with disc fragment and
canal morphology. Spine 22: 16501660.
Cavanaugh JM (1995) Neural mechanisms of lumbar pain. Spine 20: 18041809.
Chang J, Gilman SC & Lewis AJ (1986) Interleukin 1 activates phospholipase A2 in rabbit
chondrocytes: a possible signal for IL 1 action. J Immunol 136: 12831287.
Chao CC, Hu S, Ehrlich L & Peterson PK (1995) Interleukin-1 and tumor necrosis factor-alpha
synergistically mediate neurotoxicity: involvement of nitric oxide and of N-methyl-D-aspartate
receptors. Brain Behav Immun 9: 355365.
Chatani K, Kawakami M, Weinstein JN, Meller ST & Gebhart GF (1995) Characterization of thermal
hyperalgesia, c-fos expression, and alterations in neuropeptides after mechanical irritation of the
dorsal root ganglion. Spine 20: 27789.
Chen C, Cavanaugh JM, Ozaktay AC, Kallakuri S & King AI (1997) Effects of phospholipase A2 on
lumbar nerve root structure and function. Spine 22: 10571064.
Cohen MS, Wall EJ, Brown RA, Rydevik B & Garfin SR (1990) 1990 AcroMed Award in basic
science. Cauda equina anatomy. II: Extrathecal nerve roots and dorsal root ganglia. Spine 15:
12481251.
Cohran, W. G. and Cox, G. M. (1957) Experimental Designs. Wiley, New York.
Conrad DA & Deyo RA (1994) Economic decision analysis in the diagnosis and treatment of low
back pain. A methodologic primer. Spine 19: S21012106.
Cooper RG, Freemont AJ, Hoyland JA, Jenkins JP, West CG, Illingworth KJ & Jayson MI (1995)
Herniated intervertebral disc-associated periradicular fibrosis and vascular abnormalities occur
without inflammatory cell infiltration. Spine 20: 591598.
Cornefjord M, Sato K, Olmarker K, Rydevik B & Nordborg C (1997) A model for chronic nerve root
compression studies. Presentation of a porcine model for controlled, slow-onset compression with
analyses of anatomic aspects, compression onset rate, and morphologic and neurophysiologic
effects. Spine 22: 946957.
Crisi G, Carpeggiani P & Trevisan C (1993) Gadolinium-enhanced nerve roots in lumbar disk
herniation. AJNR Am J Neuroradiol 14: 13791392.
Cuckler JM, Bernini PA, Wiesel SW, Booth RE Jr, Rothman RH & Pickens GT (1985) The use of
epidural steroids in the treatment of lumbar radicular pain. A prospective, randomized, doubleblind study. J Bone Joint Surg [Am] 67: 6366.
Cupps TR & Fauci AS (1982) Corticosteroid-mediated immunoregulation in man. Immunol Rev 65:
133155.
Darnay BG & Aggarwal BB (1997) Early events in TNF signaling: a story of associations and
dissociations. J Leukoc Biol 61: 559566.
Derby R, Kine G, Saal JA, Reynolds J, Goldthwaite N, White AH, Hsu K & Zucherman J (1992)
Response to steroid and duration of radicular pain as predictors of surgical outcome. Spine 17:
S17683.
Deyo RA, Andersson G, Bombardier C, Cherkin DC, Keller RB, Lee CK, Liang MH, Lipscomb B,
Shekelle P, Spratt KF et al. (1994) Outcome measures for studying patients with low back pain.
Spine 19: S20322036.

77
Deyo RA, Battie M, Beurskens AJ, Bombardier C, Croft P, Koes B, Malmivaara A, Roland M, Von
Korff M & Waddell G (1998) Outcome measures for low back pain research. A proposal for
standardized use. Spine 23: 20032013.
Deyo RA, Loeser JD & Bigos SJ (1990) Herniated lumbar intervertebral disk. Ann Intern Med 112:
598603.
Deyo RA, Rainville J & Kent DL (1992) What can the history and physical examination tell us about
low back pain? JAMA 268: 760765.
Dhote R, Tudoret L, Bachmeyer C, Legmann P & Christoforov B (1996) Cyclic sciatica. A
manifestation of compression of the sciatic nerve by endometriosis. A case report. Spine 21:
22772279.
Dilke TF, Burry HC & Grahame R (1973) Extradural corticosteroid injection in management of
lumbar nerve root compression. BMJ 2: 635637.
Doita M, Kanatani T, Harada T & Mizuno K (1996) Immunohistologic study of the ruptured
intervertebral disc of the lumbar spine. Spine 21: 235241.
Dooley JF, McBroom RJ, Taguchi T & Macnab I (1988) Nerve root infiltration in the diagnosis of
radicular pain. Spine 13: 7983.
Dudeney S, O'Farrell D, Bouchier-Hayes D & Byrne J (1998) Extraspinal causes of sciatica. A case
report. Spine 23: 494496.
Elliott FA & Schutta HS (1971) The differential diagnosis of sciatica. Orthop Clin North Am 2: 477
484.
Eyre DR (1979) Biochemistry of the intervertebral disc. Int Rev Connect Tissue Res 8: 227291.
Eyre DR, Benya P, Buckwalter JA, Caterson B, Heinegrd D, Oegema TR, Pearce RH, Pope MH &
Urban JP (1989) Basic science perspectives. In: Frymoyer J & Gordon SL (eds) New perspectives
on low back pain. American Academy of Orthopedic Surgeons, Illinois, p 147207.
Eyre DR & Muir H (1976) Types I and II collagens in intervertebral disc. Interchanging radial
distributions in annulus fibrosus. Biochem J 157: 267270.
Fairbank JC, Couper J, Davies JB & O'Brien JP (1980) The Oswestry low back pain disability
questionnaire. Physiotherapy 66: 271273.
Farfan HF, Cossette JW, Robertson GH, Wells RV & Kraus H (1970) The effects of torsion on the
lumbar intervertebral joints: the role of torsion in the production of disc degeneration. J Bone Joint
Surg [Am] 52: 468497.
Franson RC, Saal JS & Saal JA (1992) Human disc phospholipase A2 is inflammatory. Spine 17:
S12932.
Frymoyer J (1991) Epidemiology of spinal diseases. In: Mayer T, Mooney V & Gatchel RJ (eds)
Contemporary conservative care for painful spinal disorders. Lea and Febiger, Philadelphia, p 10
23.
Frymoyer JW (1988) Back pain and sciatica. N Engl J Med 318: 291300.
Frymoyer JW (1992) Lumbar disk disease: epidemiology. Instr Course Lect 41: 217223.
Greene TL, Hensinger RN & Hunter LY (1985) Back pain and vertebral changes simulating
Scheuermann's disease. J Pediatr Orthop 5: 17.
Grnblad M, Hupli M, Wennerstrand P, Jrvinen E, Lukinmaa A, Kouri JP & Karaharju EO (1993)
Intercorrelation and test-retest reliability of the Pain Disability Index (PDI) and the Oswestry
Disability Questionnaire (ODQ) and their correlation with pain intensity in low back pain patients.
Clin J Pain 9: 189195.
Grnblad M, Virri J, Rnkk S, Kiviranta I, Vanharanta H, Seitsalo S, Rashbaum RF & Guyer RD
(1996) A controlled biochemical and immunohistochemical study of human synovial-type (group
II) phospholipase A2 and inflammatory cells in macroscopically normal, degenerated, and
herniated human lumbar disc tissues. Spine. 21: 25312538.
Grnblad M, Virri J, Seitsalo S, Habtemariam A & Karaharju E (2000) Inflammatory cells, motor
weakness, and straight leg raising in transligamentous disc herniations. Spine 25: 28032807.

78
Grnblad M, Virri J, Tolonen J, Seitsalo S, Kp E, Kankare J, Myllynen P & Karaharju EO (1994)
A controlled immunohistochemical study of inflammatory cells in disc herniation tissue. Spine
19: 27442751.
Gunzburg R, Fraser RD & Fraser GA (1990) Lumbar intervertebral disc prolapse in teenage twins. A
case report and review of the literature. J Bone Joint Surg [Br] 72: 914916.
Guyer RD & Ohnmeiss DD (1995) Lumbar discography. Position statement from the North
American Spine Society Diagnostic and Therapeutic Committee. Spine 20: 20482059.
Habtemariam A, Grnblad M, Virri J, Seitsalo S & Karaharju E (1998) A comparative
immunohistochemical study of inflammatory cells in acute- stage and chronic-stage disc
herniations. Spine 23: 21592165.
Hakelius A (1970) Prognosis in sciatica. A clinical follow-up of surgical and non- surgical treatment.
Acta Orthop Scand 129: 176.
Hakelius A & Hindmarsh J (1972) The comparative reliability of preoperative diagnostic methods in
lumbar disc surgery. Acta Orthop Scand 43: 234238.
Hanai F, Matsui N & Hongo N (1996) Changes in responses of wide dynamic range neurons in the
spinal dorsal horn after dorsal root or dorsal root ganglion compression. Spine 21: 140814.
Hanania M & Kitain E (1998) Perisciatic injection of steroid for the treatment of sciatica due to
piriformis syndrome. Reg Anesth Pain Med 23: 223228.
Haro H, Shinomiya K, Komori H, Okawa A, Saito I, Miyasaka N & Furuya K (1996) Upregulated
expression of chemokines in herniated nucleus pulposus resorption. Spine 21: 16471652.
Haro H, Komori H, Okawa A, Murakami S, Muneta T & Shinomiya K (1997) Sequential dynamics
of monocyte chemotactic protein-1 expression in herniated nucleus pulposus resorption. J Orthop
Res 15: 734741.
Haro H, Crawford HC, Fingleton B, Shinomiya K, Spengler DM & Matrisian LM (2000) Matrix
metalloproteinase-7-dependent release of tumor necrosis factor-alpha in a model of herniated disc
resorption. J Clin Invest 105: 143150.
Hashizume H, Kawakami M, Nishi H & Tamaki T (1997) Histochemical demonstration of nitric
oxide in herniated lumbar discs. A clinical and animal model study. Spine 22: 10801084.
Hashizume H, Rutkowski MD, Weinstein JN & DeLeo JA (2000) Central administration of
methotrexate reduces mechanical allodynia in an animal model of radiculopathy/sciatica. Pain 87:
159169.
Hasue M & Kikuchi S (1997) Nerve root injections. In: Frymoyer J (ed) The adult spine: principles
and practice. Lippincott-Raven Publishers, Philadelphia, p 647653.
Haueisen DC, Smith BS, Myers SR & Pryce ML (1985) The diagnostic accuracy of spinal nerve
injection studies. Their role in the evaluation of recurrent sciatica. Clin Orthop 198: 179183.
Hayashi N, Weinstein JN, Meller ST, Lee HM, Spratt KF & Gebhart GF (1998) The effect of epidural
injection of betamethasone or bupivacaine in a rat model of lumbar radiculopathy. Spine 23: 877
885.
Heikkil JK, Koskenvuo M, Helivaara M, Kurppa K, Riihimki H, Heikkil K, Rita H & Videman
T (1989) Genetic and environmental factors in sciatica. Evidence from a nationwide panel of 9365
adult twin pairs. Ann Med 21: 393398.
Heithoff KB, Gundry CR, Burton CV & Winter RB (1994) Juvenile discogenic disease. Spine 19:
335340.
Helivaara M, Vanharanta H, Korpi J & Troup JD (1986) Herniated lumbar disc syndrome and
vertebral canals. Spine. 11: 433435.
Helivaara M (1987a) Body height, obesity, and risk of herniated lumbar intervertebral disc. Spine
12: 469472.
Helivaara M (1987b) Occupation and risk of herniated lumbar intervertebral disc or sciatica leading
to hospitalization. J Chronic Dis 40: 259264.

79
Helivaara M, Impivaara O, Sievers K, Melkas T, Knekt P, Korpi J & Aromaa A (1987a) Lumbar
disc syndrome in Finland. J Epidemiol Community Health 41: 251258.
Helivaara M, Knekt P & Aromaa A (1987b) Incidence and risk factors of herniated lumbar
intervertebral disc or sciatica leading to hospitalization. J Chronic Dis 40: 251258.
Helivaara M (1989) Risk factors for low back pain and sciatica. Ann Med 21: 257264.
Helivaara M, Sievers K, Impivaara O, Maatela J, Knekt P, Mkel M & Aromaa A (1989)
Descriptive epidemiology and public health aspects of low back pain. Ann Med 21: 327333.
Helivaara M, Mkel M, Knekt P, Impivaara O & Aromaa A (1991) Determinants of sciatica and
low-back pain. Spine 16: 608614.
Herron LD (1989) Selective nerve root block in patient selection for lumbar surgery: surgical results.
J Spinal Disord 2: 7579.
Herzog RJ (1996) The radiologic assessment for a lumbar disc herniation. Spine 21: S1938.
Howe JF, Loeser JD & Calvin WH (1977) Mechanosensitivity of dorsal root ganglia and chronically
injured axons: a physiological basis for the radicular pain of nerve root compression. Pain 3: 25
41.
Hrubec Z & Nashold BS Jr (1975) Epidemiology of lumbar disc lesions in the military in World War
II. Am J Epidemiol 102: 367376.
Hukins DW (1988) Disc structure and function. In: Ghosh P (ed) The biology of the intervertebral
disc. CRC Press, Boca Raton, Fl, p 137.
Hurme M & Alaranta H (1987) Factors predicting the result of surgery for lumbar intervertebral disc
herniation. Spine. 12: 933938.
Hutubessy RC, van Tulder MW, Vondeling H & Bouter LM (1999) Indirect costs of back pain in the
Netherlands: a comparison of the human capital method with the friction cost method. Pain 80:
201207.
Igarashi T, Kikuchi S, Shubayev V & Myers RR (2000) Volvo Award winner in basic science studies:
Exogenous tumor necrosis factor-alpha mimics nucleus pulposus-induced neuropathology.
Molecular, histologic, and behavioral comparisons in rats. Spine 25: 29752980.
Ikeda T, Nakamura T, Kikuchi T, Umeda S, Senda H & Takagi K (1996) Pathomechanism of
spontaneous regression of the herniated lumbar disc: histologic and immunohistochemical study.
J Spinal Disord 9: 136140.
Ilmarinen J, Louhevaara V, Korhonen O, Nygrd CH, Hakola T & Suvanto S (1991) Changes in
maximal cardiorespiratory capacity among aging municipal employees. Scand J Work Environ
Health 17: 99109.
Ilmarinen J, Suurnkki T, Eskelinen L, Huuhtanen P, Jrvinen M, Peltomaa T, Merisalo T, Fahlstrm
P, Jrvinen E, Aalto L & Wger G (1985) Kunnallisten ammattien tyn profiilit elkein
perusteena (Work profiles of communal jobs as the basis of the retirement age). Investigations of
the Institute for Occupational Health 3: 164211.
Ito T, Homma T & Uchiyama S (1999) Sciatica caused by cervical and thoracic spinal cord
compression. Spine 24: 12651267.
Ito T, Yamada M, Ikuta F, Fukuda T, Hoshi SI, Kawaji Y, Uchiyama S, Homma T & Takahashi HE
(1996) Histologic evidence of absorption of sequestration-type herniated disc. Spine 21: 230234.
Jensen MC, Brant-Zawadzki MN, Obuchowski N, Modic MT, Malkasian D & Ross JS (1994)
Magnetic resonance imaging of the lumbar spine in people without back pain. N Engl J Med 331:
6973.
Jnsson B & Strmqvist B (1995) The straight leg raising test and the severity of symptoms in lumbar
disc herniation. A preoperative evaluation. Spine 20: 2730.
Jnsson B & Strmqvist B (1996) Clinical appearance of contained and noncontained lumbar disc
herniation. J Spinal Disord 9: 3238.

80
Junge A, Dvorak J & Ahrens S (1995) Predictors of bad and good outcomes of lumbar disc surgery.
A prospective clinical study with recommendations for screening to avoid bad outcomes. Spine
20: 460468.
Kang, J. D., Stefanovic-Racic, M., McIntyre, L. A., Georgescu, H. I., and Evans, C. H. (1997) Toward
a biochemical understanding of human intervertebral disc degeneration and herniation.
Contributions of nitric oxide, interleukins, prostaglandin E2, and matrix metalloproteinases. Spine
22: 10651073.
Karppinen J, Inkinen RI, Kp E, Lammi MJ, Tammi MI, Holm S & Vanharanta H (1995) Effects
of tiaprofenic acid and indomethacin on proteoglycans in the degenerating porcine intervertebral
disc. Spine 20: 11701177.
Kawaguchi Y, Osada R, Kanamori M, Ishihara H, Ohmori K, Matsui H & Kimura T (1999)
Association between an aggrecan gene polymorphism and lumbar disc degeneration. Spine 24:
24562460.
Kawakami M, Weinstein JN, Chatani K, Spratt KF, Meller ST & Gebhart GF (1994a) Experimental
lumbar radiculopathy. Behavioral and histologic changes in a model of radicular pain after spinal
nerve root irritation with chromic gut ligatures in the rat. Spine 19: 17951802.
Kawakami M, Weinstein JN, Spratt KF, Chatani K, Traub RJ, Meller ST & Gebhart GF (1994b)
Experimental lumbar radiculopathy. Immunohistochemical and quantitative demonstrations of
pain induced by lumbar nerve root irritation of the rat. Spine 19: 17801794.
Kawakami M, Tamaki T, Hayashi N, Hashizume H & Nishi H (1998) Possible mechanism of painful
radiculopathy in lumbar disc herniation. Clin Orthop 351: 241251.
Kawakami M, Matsumoto T, Kuribayashi K & Tamaki T (1999) mRNA expression of interleukins,
phospholipase A2, and nitric oxide synthase in the nerve root and dorsal root ganglion induced by
autologous nucleus pulposus in the rat. J Orthop Res 17: 941946.
Kawakami M, Tamaki T, Hayashi N, Hashizume H, Matsumoto T, Minamide A & Kihira T (2000a)
Mechanical compression of the lumbar nerve root alters pain-related behaviors induced by the
nucleus pulposus in the rat. J Orthop Res 18: 257264.
Kawakami M, Tamaki T, Matsumoto T, Kuribayashi K, Takenaka T & Shinozaki M (2000b) Role of
leukocytes in radicular pain secondary to herniated nucleus pulposus. Clin Orthop 376: 268277.
Kayama S, Konno S, Olmarker K, Yabuki S & Kikuchi S (1996) Incision of the anulus fibrosus
induces nerve root morphologic, vascular, and functional changes. An experimental study. Spine
21: 25392543.
Kayama S, Olmarker K, Larsson K, Sjgren-Jansson E, Lindahl A & Rydevik B (1998) Cultured,
autologous nucleus pulposus cells induce functional changes in spinal nerve roots. Spine 23:
21552158.
Keegan JJ & Garret FD (1948) The segmental distribution of the cutaneous nerves in the limbs of
man. Anat Rec 102: 409437.
Kelsey JL & Hardy RJ (1975) Driving of motor vehicles as a risk factor for acute herniated lumbar
intervertebral disc. Am J Epidemiol 102: 6373.
Kelsey JL & Ostfeld AM (1975) Demographic characteristics of persons with acute herniated lumbar
intervertebral disc. J Chronic Dis 28: 3750.
Kelsey JL, Githens PB, White AA 3rd, Holford TR, Walter SD, O'Connor T, Ostfeld AM, Weil U,
Southwick WO & Calogero JA (1984) An epidemiologic study of lifting and twisting on the job
and risk for acute prolapsed lumbar intervertebral disc. J Orthop Res 2: 6166.
Keskimki I, Seitsalo S, sterman H & Rissanen P (2000) Reoperations after lumbar disc surgery: a
population-based study of regional and interspecialty variations. Spine 25: 15001508.
Kikuchi S & Hasue M (1988) Combined contrast studies in lumbar spine diseases. Myelography
(peridurography) and nerve root infiltration. Spine 13: 13271331.
Kikuchi S, Hasue M, Nishiyama K & Ito T (1984) Anatomic and clinical studies of radicular
symptoms. Spine 9: 2330.

81
Kimura T, Nakata K, Tsumaki N, Miyamoto S, Matsui Y, Ebara S & Ochi T (1996) Progressive
degeneration of articular cartilage and intervertebral discs. An experimental study in transgenic
mice bearing a type IX collagen mutation. Int Orthop 20: 177181.
Klenerman L, Greenwood R, Davenport HT, White DC & Peskett S (1984) Lumbar epidural
injections in the treatment of sciatica. Br J Rheumatol 23: 3538.
Knuttson B (1961) Comparative value of electromyographic, myelographic and clinical-neurological
examinations in diagnosis of lumbar root compression syndrome. Acta Orthop Scand 49: 1135.
Kobayashi S, Yoshizawa H, Hachiya Y, Ukai T & Morita T (1993) Vasogenic edema induced by
compression injury to the spinal nerve root. Distribution of intravenously injected protein tracers
and gadolinium-enhanced magnetic resonance imaging. Spine 18: 14101424.
Koes BW, Scholten RJ, Mens JM & Bouter LM (1995) Efficacy of epidural steroid injections for lowback pain and sciatica: a systematic review of randomized clinical trials. Pain 63: 279288.
Koivukangas P, Ohinmaa A & Koivukangas J (1995) Nottingham Health Profilen (NHP)
suomalainen versio (Finnish version of the Nottingham Health Profile). Reports of the National
Research and Development Center for Welfare and Health, Helsinki, Finland.
Kopec JA & Esdaile JM (1995) Functional disability scales for back pain. Spine 20: 19431949.
Krkk J, Annunen S, Pihlajamaa T, Prockop DJ & Ala-Kokko L (1998) Conformation sensitive gel
electrophoresis for simple and accurate detection of mutations: comparison with denaturing
gradient gel electrophoresis and nucleotide sequencing. Proc Natl Acad Sci U S A 95: 16811685.
Kortelainen P, Puranen J, Koivisto E & Lhde S (1985) Symptoms and signs of sciatica and their
relation to the localization of the lumbar disc herniation. Spine 10: 8892.
Krempen JF & Smith BS (1974) Nerve-root injection: a method for evaluating the etiology of
sciatica. J Bone Joint Surg [Am] 56: 14351444.
Kuslich SD, Ulstrom CL & Michael CJ (1991) The tissue origin of low back pain and sciatica: a
report of pain response to tissue stimulation during operations on the lumbar spine using local
anesthesia. Orthop Clin North Am 22: 181187.
Kp E, Han X, Holm S, Peltonen J, Takala T & Vanharanta H (1995) Collagen synthesis and types
I, III, IV, and VI collagens in an animal model of disc degeneration. Spine 20: 5966.
Kp E, Zhang LQ, Muona P, Holm S, Vanharanta H & Peltonen J (1994) Expression of type I, III,
and VI collagen mRNAs in experimentally injured porcine intervertebral disc. Connect Tissue Res
30: 203214.
Lee CK, Rauschning W & Glenn W (1988) Lateral lumbar spinal canal stenosis: classification,
pathologic anatomy and surgical decompression. Spine 13: 313320.
Lee HM, Weinstein JN, Meller ST, Hayashi N, Spratt KF & Gebhart GF (1998) The role of steroids
and their effects on phospholipase A2. An animal model of radiculopathy. Spine 23: 11911196.
Lindblom K & Rexed B (1948) Spinal nerve injury in dorsolateral protrusions of lumbar disks. J
Neurosurg 5: 413432.
Lings S & Mikkelsen L (1982) Scheuermann's disease with low localization. A problem of underdiagnosis. Scand J Rehabil Med 14: 7779.
Lipson SJ & Muir H (1981a) 1980 Volvo award in basic science. Proteoglycans in experimental
intervertebral disc degeneration. Spine 6: 194210.
Lipson SJ & Muir H (1981b) Experimental intervertebral disc degeneration: morphologic and
proteoglycan changes over time. Arthritis Rheum 24: 1221.
Lowe TG (1999) Scheuermann's disease. Orthop Clin North Am 30: 475487.
Lutz GE, Vad VB & Wisneski RJ (1998) Fluoroscopic transforaminal lumbar epidural steroids: an
outcome study. Arch Phys Med Rehabil 79: 13621366.
Lutze M, Stendel R, Vesper J & Brock M (1997) Periradicular therapy in lumbar radicular
syndromes: methodology and results. Acta Neurochir 139: 719724.
Macnab I (1971) Negative disc exploration. An analysis of the causes of nerve- root involvement in
sixty-eight patients. J Bone Joint Surg [Am] 53: 891903.

82
Magora A (1973) Investigation of the relation between low back pain and occupation. IV. Physical
requirements: bending, rotation, reaching and sudden maximal effort. Scand J Rehabil Med 5:
186190.
Maigne JY, Rime B & Deligne B (1992) Computed tomographic follow-up study of forty-eight cases
of nonoperatively treated lumbar intervertebral disc herniation. Spine 17: 10711074.
Malmivaara A (1997) Evidence-based intervention for musculoskeletal disorders. Scand J Work
Environ Health 23: 161163.
Manninen P, Riihimki H & Helivaara M (1995) Incidence and risk factors of low-back pain in
middle-aged farmers. Occup Med 45: 141146.
Marras WS, Davis KG, Heaney CA, Maronitis AB & Allread WG (2000) The influence of
psychosocial stress, gender, and personality on mechanical loading of the lumbar spine. Spine 25:
30453054.
Marshall LL, Trethewie ER & Curtain CC (1977) Chemical radiculitis. A clinical, physiological and
immunological study. Clin Orthop 129: 6167.
Mathews JA, Mills SB, Jenkins VM, Grimes SM, Morkel MJ, Mathews W, Scott CM & Sittampalam
Y (1987) Back pain and sciatica: controlled trials of manipulation, traction, sclerosant and
epidural injections. Br J Rheumatol 26: 416423.
Matsui Y, Maeda M, Nakagami W & Iwata H (1998) The involvement of matrix metalloproteinases
and inflammation in lumbar disc herniation. Spine 23: 863868.
McCarron RF, Wimpee MW, Hudkins PG & Laros GS (1987) The inflammatory effect of nucleus
pulposus. A possible element in the pathogenesis of low-back pain. Spine 12: 760764.
Meller ST & Gebhart GF (1994) Spinal mediators of hyperalgesia. Drugs 47:1020.
Merriam WF, Burwell RG, Mulholland RC, Pearson JC & Webb JK (1983) A study revealing a tall
pelvis in subjects with low back pain. J Bone Joint Surg [Br] 65: 153156.
Miller JA, Schmatz C & Schultz AB (1988) Lumbar disc degeneration: correlation with age, sex, and
spine level in 600 autopsy specimens. Spine 13: 173178.
Minamide A, Tamaki T, Hashizume H, Yoshida M, Kawakami M & Hayashi N (1998) Effects of
steroid and lipopolysaccharide on spontaneous resorption of herniated intervertebral discs. An
experimental study in the rabbit. Spine 23: 870876.
Mixter WJ & Barr JS (1934) Rupture of the intervertebral disc with involvement of the spinal canal.
N Engl J Med 211: 210215.
Miyamoto H, Saura R, Harada T, Doita M & Mizuno K (2000) The role of cyclooxygenase-2 and
inflammatory cytokines in pain induction of herniated lumbar intervertebral disc. Kobe J Med Sci
46: 1328.
Modic MT, Steinberg PM, Ross JS, Masaryk TJ & Carter JR (1988) Degenerative disk disease:
assessment of changes in vertebral body marrow with MR imaging. Radiology 166: 193199.
Modic MT, Ross JS, Obuchowski NA, Browning KH, Cianflocco AJ & Mazanec DJ (1995) Contrastenhanced MR imaging in acute lumbar radiculopathy: a pilot study of the natural history.
Radiology 195: 429435.
Moneta GB, Videman T, Kaivanto K, Aprill C, Spivey M, Vanharanta H, Sachs BL, Guyer RD,
Hochschuler SH & Raschbaum RF (1994) Reported pain during lumbar discography as a function
of anular ruptures and disc degeneration. A re-analysis of 833 discograms. Spine 19: 19681974.
Muramoto T, Atsuta Y, Iwahara T, Sato M & Takemitsu Y (1997) The action of prostaglandin E2 and
triamcinolone acetonide on the firing activity of lumbar nerve roots. Int Orthop 21: 172175.
Nachemson A (1969) Intradiscal measurements of pH in patients with lumbar rhizopathies. Acta
Orthop Scand 40: 2342.
Naftulin S, Fast A & Thomas M (1993) Diabetic lumbar radiculopathy: sciatica without disc
herniation. Spine 18: 24192422.
Naylor A (1974) Late results of laminectomy for lumbar disc prolapse. A review after ten to twentyfive years. J Bone Joint Surg [Br] 56: 1729.

83
Nelson CL, Janecki CJ, Gildenberg PL & Sava G (1972) Disk protrusions in the young. Clin Orthop
88: 142150.
Nguyen C, Haughton VM, Ho KC, An HS, Myklebust JB, Hasegawa T, Xu R & Harb JM (1995)
Contrast enhancement in spinal nerve roots: an experimental study. AJNR Am J Neuroradiol 16:
265268.
Nitta H, Tajima T, Sugiyama H & Moriyama A (1993) Study on dermatomes by means of selective
lumbar spinal nerve block. Spine 18: 17821786.
Norlen G (1944) On the value of the neurological symptoms in sciatica for the localisation of a lumbar
disc herniation. Acta Chir Scand (Suppl) 95: 196.
Nygaard OP & Mellgren SI (1998) The function of sensory nerve fibers in lumbar radiculopathy. Use
of quantitative sensory testing in the exploration of different populations of nerve fibers and
dermatomes. Spine 23: 348352.
Nykvist F, Hurme M, Alaranta H & Einola S (1989) A prospective 5-year follow-up study of 276
patients hospitalized because of suspected lumbar disc herniation. Int Disabil Stud 11: 6167.
Ohnmeiss DD, Vanharanta H & Guyer RD (1995) The association between pain drawings and
computed tomographic/discographic pain responses. Spine. 20: 729733.
Ohnmeiss DD, Vanharanta H & Ekholm J (1997) Degree of disc disruption and lower extremity pain.
Spine. 22: 16001605.
Ohnmeiss DD, Vanharanta H & Ekholm J (1999a) Relation between pain location and disc
pathology: a study of pain drawings and CT/discography. Clin J Pain 15: 210217.
Ohnmeiss DD, Vanharanta H & Ekholm J (1999b) Relationship of pain drawings to invasive tests
assessing intervertebral disc pathology. Eur Spine J 8: 126131.
Ojala R, Vhl E, Karppinen J, Klemola R, Blanco-Sequeiros R, Vaara T & Tervonen, O (2000)
Nerve root infiltration of the first sacral root with MRI guidance. J Magn Reson Imaging 12: 556
561.
Olmarker K, Rydevik B, Hansson T & Holm S (1990) Compression-induced changes of the
nutritional supply to the porcine cauda equina. J Spinal Disord 3: 2529.
Olmarker K (1991) Spinal nerve root compression. Nutrition and function of the porcine cauda equina
compressed in vivo. Acta Orthop Scand (Suppl) 242: 127.
Olmarker K, Rydevik B & Nordborg C (1993) Autologous nucleus pulposus induces
neurophysiologic and histologic changes in porcine cauda equina nerve roots. Spine 18: 1425
1432.
Olmarker K, Byrd G, Cornefjord M, Nordborg C & Rydevik B (1994) Effects of
methylprednisolone on nucleus pulposus-induced nerve root injury. Spine 19: 18031808.
Olmarker K, Blomquist J, Strmberg J, Nannmark U, Thomsen P & Rydevik B (1995)
Inflammatogenic properties of nucleus pulposus. Spine 20: 665669.
Olmarker K, Nordborg C, Larsson K & Rydevik B (1996) Ultrastructural changes in spinal nerve
roots induced by autologous nucleus pulposus. Spine 21: 411414.
Olmarker K, Brisby H, Yabuki S, Nordborg C & Rydevik B (1997) The effects of normal, frozen, and
hyaluronidase-digested nucleus pulposus on nerve root structure and function. Spine 22: 471475.
Olmarker K & Larsson K (1998) Tumor necrosis factor alpha and nucleus-pulposus-induced nerve
root injury. Spine 23: 25382544.
Olmarker K & Myers RR (1998) Pathogenesis of sciatic pain: role of herniated nucleus pulposus and
deformation of spinal nerve root and dorsal root ganglion. Pain 78: 99105.
Olmarker K & Rydevik B (2001) Selective inhibition of tumor necrosis factor- prevents nucleus
pulposus-induced thrombus formation, intraneural edema, and reduction of nerve conduction
velocity. Possible implications of future pharmacologic treatment strategies of sciatica. Spine 26:
863869.

84
Osti OL, Vernon-Roberts B & Fraser RD (1990) 1990 Volvo Award in experimental studies. Anulus
tears and intervertebral disc degeneration. An experimental study using an animal model. Spine
15: 762767.
Osti OL, Vernon-Roberts B, Moore R & Fraser RD (1992) Annular tears and disc degeneration in the
lumbar spine. A post- mortem study of 135 discs. J Bone Joint Surg [Br] 74: 678682.
Otani K, Arai I, Mao GP, Konno S, Olmarker K & Kikuchi S (1999) Nucleus pulposus-induced nerve
root injury: relationship between blood flow and motor nerve conduction velocity. Neurosurgery
45: 614619.
zaktay AC, Kallakuri S & Cavanaugh JM (1998) Phospholipase A2 sensitivity of the dorsal root
and dorsal root ganglion. Spine 23: 12971306.
Paajanen H, Alanen A, Erkintalo M, Salminen JJ & Katevuo K (1989a) Disc degeneration in
Scheuermann disease. Skeletal Radiol 18: 523526.
Paajanen H, Erkintalo M, Kuusela T, Dahlstrm S & Kormano M (1989b) Magnetic resonance study
of disc degeneration in young low-back pain patients. Spine 14: 982985.
Paassilta P, Pihlajamaa T, Annunen S, Brewton RG, Wood BM, Johnson CC, Liu J, Gong Y, Warman
ML, Prockop DJ, Mayne R & Ala-Kokko L (1999) Complete sequence of the 23-kilobase human
COL9A3 gene. Detection of Gly-X-Y triplet deletions that represent neutral variants. J Biol Chem
274: 2246922475.
Paassilta P, Lohiniva J, Gring HH, Perl M, Rin S, Karppinen J, Hakala M, Palm T, Krger H,
Kaitila I, Vanharanta H, Ott J & Ala-Kokko L (2001) First common genetic risk factor for lumbar
disc disease. JAMA 285: 18431849.
Pihlajamaa T, Perl M, Vuoristo MM, Nokelainen M, Bodo M, Schulthess T, Vuorio E, Timpl R,
Engel J & Ala-Kokko L (1999) Characterization of recombinant human type IX collagen.
Association of alpha chains into homotrimeric and heterotrimeric molecules. J Biol Chem 274:
2246422468.
Porter RW, Hibbert CS & Wicks M (1978) The spinal canal in symptomatic lumbar disc lesions. J
Bone Joint Surg [Br] 60B: 485487.
Powell MC, Wilson M, Szypryt P, Symonds EM & Worthington BS (1986) Prevalence of lumbar disc
degeneration observed by magnetic resonance in symptomless women. Lancet 2: 13661367.
Puranen J & Orava S (1991) The hamstring syndrome a new gluteal sciatica. Ann Chir Gynaecol
80: 212214.
Redford EJ, Hall SM & Smith KJ (1995) Vascular changes and demyelination induced by the
intraneural injection of tumour necrosis factor. Brain 118: 869878.
Reust P, Wendling D, Lagier R, Pageaut G, Reverdin A, Jacquet G, Guidet M & Fallet G. H (1988)
Degenerative spondylolisthesis, synovial cyst of the zygapophyseal joints, and sciatic syndrome:
report of two cases and review of the literature. Arthritis Rheum 31: 288294.
Ridley MG, Kingsley GH, Gibson T & Grahame R (1988) Outpatient lumbar epidural corticosteroid
injection in the management of sciatica. Br J Rheumatol 27: 295299.
Riew KD, Yin Y, Gilula L, Bridwell KH, Lenke LG, Lauryssen C & Goette K (2000) The effect of
nerve-root injections on the need for operative treatment of lumbar radicular pain. A prospective,
randomized, controlled, double-blind study. J Bone Joint Surg [Am] 82-A: 15891593.
Riihimki H (1985) Back pain and heavy physical work: a comparative study of concrete
reinforcement workers and maintenance house painters. Br J Ind Med 42: 226232.
Riihimki H, Wickstrm G, Hnninen K & Luopajrvi T (1989) Predictors of sciatic pain among
concrete reinforcement workers and house painters a five-year follow-up. Scand J Work Environ
Health 15: 415423.
Riihimki H, Viikari-Juntura E, Moneta G, Kuha J, Videman T & Tola S (1994) Incidence of sciatic
pain among men in machine operating, dynamic physical work, and sedentary work. A three-year
follow-up. Spine 19: 138142.

85
Roberts S, Menage J & Urban JP (1989) Biochemical and structural properties of the cartilage endplate and its relation to the intervertebral disc. Spine 14: 166174.
Rothoerl RD, Woertgen C, Holzschuh M, Rueschoff J & Brawanski A (1998) Is there a clinical
correlate to the histologic evidence of inflammation in herniated lumbar disc tissue? Spine 23:
11971200.
Russell LB, Gold MR, Siegel JE, Daniels N & Weinstein MC (1996) The role of cost-effectiveness
analysis in health and medicine. Panel on Cost-Effectiveness in Health and Medicine. JAMA 276:
11721177.
Rydevik B, Brown MD & Lundborg G (1984) Pathoanatomy and pathophysiology of nerve root
compression. Spine 9: 715.
Rydevik BL, Myers RR & Powell HC (1989) Pressure increase in the dorsal root ganglion following
mechanical compression. Closed compartment syndrome in nerve roots. Spine 14: 574576.
Saal JA, Saal JS & Herzog RJ (1990a) The natural history of lumbar intervertebral disc extrusions
treated nonoperatively. Spine 15: 683686.
Saal JS, Franson RC, Dobrow R, Saal JA, White AH & Goldthwaite N (1990b) High levels of
inflammatory phospholipase A2 activity in lumbar disc herniations. Spine 15: 674678.
Saal JS (1995) The role of inflammation in lumbar pain. Spine 20: 18211827.
Salminen JJ, Erkintalo MO, Pentti J, Oksanen A & Kormano MJ (1999) Recurrent low back pain and
early disc degeneration in the young. Spine 24: 13161321.
Schellinger D, Wener L, Ragsdale BD & Patronas NJ (1987) Facet joint disorders and their role in
the production of back pain and sciatica. Radiographics 7: 923944.
Seitz RJ, Heininger K, Schwendemann G, Toyka KV & Wechsler W (1985) The mouse blood-brain
barrier and blood-nerve barrier for IgG: a tracer study by use of the avidin-biotin system. Acta
Neuropathol (Berl.) 68: 1521.
Shackleford IM & Mulholland RC (1994) Can we improve the technique of nerve root infiltration
with the aid of a nerve stimulator? Presented at the Annual Meeting of the International Society
for the Study of the Lumbar Spine, Seattle, USA.
Shaw LM & Olsen BR (1991) FACIT collagens: diverse molecular bridges in extracellular matrices.
Trends Biochem Sci 16: 191194.
Shubayev VI & Myers RR (2000) Upregulation and interaction of TNFalpha and gelatinases A and
B in painful peripheral nerve injury. Brain Res 855: 8389.
Smyth MJ & Wright J (1958) Sciatica and the intervertebral disk. An experimental study. J Bone Joint
Surg 40-A: 14011418.
Snoek W, Weber H & Jorgensen B (1977) Double blind evaluation of extradural methyl prednisolone
for herniated lumbar discs. Acta Orthop Scand 48: 635641.
Spangfort EV (1972) The lumbar disc herniation. A computer-aided analysis of 2,504 operations.
Acta Orthop Scand (Suppl) 142: 195.
Spengler DM, Ouellette EA, Battie M & Zeh J (1990) Elective discectomy for herniation of a lumbar
disc. Additional experience with an objective method. J Bone Joint Surg [Am] 72: 230237.
Stadnik TW, Lee RR, Coen HL, Neirynck EC, Buisseret TS & Osteaux MJ (1998) Annular tears and
disk herniation: prevalence and contrast enhancement on MR images in the absence of low back
pain or sciatica. Radiology 206: 4955.
Stanley D, McLaren MI, Euinton HA & Getty CJ (1990) A prospective study of nerve root infiltration
in the diagnosis of sciatica. A comparison with radiculography, computed tomography, and
operative findings. Spine 15: 540543.
Stefanovic-Racic M, Morales TI, Taskiran D, McIntyre LA & Evans CH (1996) The role of nitric
oxide in proteoglycan turnover by bovine articular cartilage organ cultures. J Immunol 156: 1213
1220.

86
Sugawara O, Atsuta Y, Iwahara T, Muramoto T, Watakabe M & Takemitsu Y (1996) The effects of
mechanical compression and hypoxia on nerve root and dorsal root ganglia. An analysis of ectopic
firing using an in vitro model. Spine 21: 20892094.
Takahashi H, Suguro T, Okazima Y, Motegi M, Okada Y & Kakiuchi T (1996) Inflammatory
cytokines in the herniated disc of the lumbar spine. Spine 21: 218224.
Takahashi K, Miyazaki T, Ohnari H, Takino T & Tomita K (1995) Schmorl's nodes and low-back
pain. Analysis of magnetic resonance imaging findings in symptomatic and asymptomatic
individuals. Eur Spine J 4: 5659.
Taneichi H, Abumi K, Kaneda K & Terae S (1994) Significance of Gd-DTPA-enhanced magnetic
resonance imaging for lumbar disc herniation: the relationship between nerve root enhancement
and clinical manifestations. J Spinal Disord 7: 153160.
Tertti MO, Salminen JJ, Paajanen HE, Terho PH & Kormano MJ (1991) Low-back pain and disk
degeneration in children: a case-control MR imaging study. Radiology 180: 503507.
Tervonen O, Lhde S & Vanharanta H (1991) Ultrasound diagnosis of lumbar disc degeneration.
Comparison with computed tomography/discography. Spine 16: 951954.
Tetlow LC, Adlam DJ & Woolley DE (2001) Matrix metalloproteinase and proinflammatory
cytokine production by chondrocytes of human osteoarthritic cartilage: associations with
degenerative changes. Arthritis Rheum 44: 585594.
Thelander U, Fagerlund M, Friberg S & Larsson S (1992) Straight leg raising test versus radiologic
size, shape, and position of lumbar disc hernias. Spine 17: 395399.
Thelander U, Fagerlund M, Friberg S & Larsson S (1994) Describing the size of lumbar disc
herniations using computed tomography. A comparison of different size index calculations and
their relation to sciatica. Spine 19: 19791984.
Thomas M, Grant N, Marshall J & Stevens J (1983) Surgical treatment of low backache and sciatica.
Lancet 2(8365-66): 14371439.
Toyone T, Takahashi K, Kitahara H, Yamagata M, Murakami M & Moriya H (1993) Visualisation
of symptomatic nerve roots. Prospective study of contrast-enhanced MRI in patients with lumbar
disc herniation. J Bone Joint Surg [Br] 75: 529533.
Uden A & Landin LA (1987) Pain drawing and myelography in sciatic pain. Clin Orthop 216: 124
130.
Vadas P & Pruzanski W (1986) Role of secretory phospholipases A2 in the pathobiology of disease.
Lab Invest 55: 391404.
van Akkerveeken PF (1996) Pain patterns and diagnostic blocks. In: Wiesel SW, Weinstein JN,
Herkowitz H, Dvorak J & Bell G (eds) The lumbar spine. W.B. Saunders Company, Philadelphia,
p 105122.
Vanharanta H, Sachs BL, Spivey MA, Guyer RD, Hochschuler SH, Rashbaum RF, Johnson RG,
Ohnmeiss DD & Mooney V (1987) The relationship of pain provocation to lumbar disc
deterioration as seen by CT/discography. Spine. 12: 295298.
Vanharanta H, Guyer RD, Ohnmeiss DD, Stith WJ, Sachs BL, Aprill C, Spivey M, Rashbaum RF,
Hochschuler SH & Videman T (1988a) Disc deterioration in low-back syndromes. A prospective,
multi-center CT/discography study. Spine. 13: 13491351.
Vanharanta H, Sachs BL, Spivey M, Hochschuler SH, Guyer RD, Rashbaum RF, Ohnmeiss DD &
Mooney V (1988b) A comparison of CT/discography, pain response and radiographic disc height.
Spine. 13: 321324.
Vanharanta H, Sachs BL, Ohnmeiss DD, Aprill C, Spivey M, Guyer RD, Rashbaum RF, Hochschuler
SH, Terry A & Selby D (1989) Pain provocation and disc deterioration by age. A CT/discography
study in a low-back pain population. Spine. 14: 420423.
Varlotta GP, Brown MD, Kelsey JL & Golden AL (1991) Familial predisposition for herniation of a
lumbar disc in patients who are less than twenty-one years old. J Bone Joint Surg [Am] 73: 124
128.

87
Videman T, Nurminen M & Troup JD (1990) 1990 Volvo Award in clinical sciences. Lumbar spinal
pathology in cadaveric material in relation to history of back pain, occupation, and physical
loading. Spine 15: 728740.
Videman T, Leppvuori J, Kaprio J, Battie MC, Gibbons LE, Peltonen L & Koskenvuo M (1998)
Intragenic polymorphisms of the vitamin D receptor gene associated with intervertebral disc
degeneration. Spine 23: 24772485.
Videman T & Battie MC (1999) The influence of occupation on lumbar degeneration. Spine 24:
11641168.
Videman T, Gibbons LE, Battie MC, Maravilla K, Vanninen E, Leppvuori J, Kaprio J & Peltonen
L (2001) The relative roles of intragenic polymorphisms of the vitamin d receptor gene in lumbar
spine degeneration and bone density. Spine 26: E7E12.
Vroomen PC, de Krom MC, Wilmink JT, Kester AD & Knottnerus JA (1999) Lack of effectiveness
of bed rest for sciatica. N Engl J Med 340: 418423.
Vroomen PC, de Krom MC, Slofstra PD & Knottnerus JA (2000) Conservative treatment of sciatica:
a systematic review. J Spinal Disord 13: 463469.
Vucetic N, Mttnen H & Svensson O (1995) Pain and pathology in lumbar disc hernia. Clin Orthop
320: 6572.
Vucetic N, strand P, Guntner P & Svensson O (1999) Diagnosis and prognosis in lumbar disc
herniation. Clin Orthop 361: 116122.
Waddell G, Morris EW, Di Paola MP, Bircher M & Finlayson D (1986) A concept of illness tested
as an improved basis for surgical decisions in low-back disorders. Spine 11: 712719.
Wagner R & Myers RR (1996a) Endoneurial injection of TNF-alpha produces neuropathic pain
behaviors. Neuroreport 7: 28972901.
Wagner R & Myers RR (1996b) Schwann cells produce tumor necrosis factor alpha: expression in
injured and non-injured nerves. Neuroscience 73: 625629.
Wagner R, Janjigian M & Myers RR (1998) Anti-inflammatory interleukin-10 therapy in CCI
neuropathy decreases thermal hyperalgesia, macrophage recruitment, and endoneurial TNF-alpha
expression. Pain 74: 3542.
Watanabe H, Nakata K, Kimata K, Nakanishi I & Yamada Y (1997) Dwarfism and age-associated
spinal degeneration of heterozygote cmd mice defective in aggrecan. Proc Natl Acad Sci U S A.
94: 69436947.
Watts RW & Silagy CA (1995) A meta-analysis on the efficacy of epidural corticosteroids in the
treatment of sciatica. Anaesth Intensive Care 23: 564569.
Weber H (1983) Lumbar disc herniation. A controlled, prospective study with ten years of
observation. Spine 8: 131140.
Weber H, Holme I & Amlie E (1993) The natural course of acute sciatica with nerve root symptoms
in a double-blind placebo-controlled trial evaluating the effect of piroxicam. Spine 18: 1433
1438.
Wehling P, Cleveland SJ, Heininger K, Schulitz KP, Reinecke J & Evans CH (1996)
Neurophysiologic changes in lumbar nerve root inflammation in the rat after treatment with
cytokine inhibitors. Evidence for a role of interleukin-1. Spine 21: 931935.
Weiner BK & Fraser RD (1997) Foraminal injection for lateral lumbar disc herniation. J Bone Joint
Surg [Br] 79: 804807.
Weinstein SM, Herring SA & Derby R (1995) Contemporary concepts in spine care. Epidural steroid
injections. Spine 20: 18421846.
Weir BK (1979) Prospective study of 100 lumbosacral discectomies. J Neurosurg 50: 283289.
Weishaupt D, Zanetti M, Hodler J & Boos N (1998) MR imaging of the lumbar spine: prevalence of
intervertebral disk extrusion and sequestration, nerve root compression, end plate abnormalities,
and osteoarthritis of the facet joints in asymptomatic volunteers. Radiology 209: 661666.

88
White AH (1983) Injection techniques for the diagnosis and treatment of low back pain. Orthop Clin
North Am 14: 553567.
Wiesel SW, Tsourmas N, Feffer HL, Citrin CM & Patronas N (1984) A study of computer-assisted
tomography. I. The incidence of positive CAT scans in an asymptomatic group of patients. Spine
9: 549551.
Wilppula E & Jussila P (1977) Spinal nerve block. A diagnostic test in sciatica. Acta Orthop Scand
48: 458460.
Wrocklage C, Wassmann H & Paulus W (2000) COL9A2 allelotypes in intervertebral disc disease.
Biochem Biophys Res Commun 279: 398400.
Wu JJ & Eyre DR (1989) Covalent interactions of type IX collagen in cartilage. Connect Tissue Res
20: 241246.
Yabuki S & Kikuchi S (1995) Nerve root infiltration and sympathetic block. An experimental study
of intraradicular blood flow. Spine 20: 901906.
Yabuki S, Kikuchi S, Olmarker K & Myers RR (1998a) Acute effects of nucleus pulposus on blood
flow and endoneurial fluid pressure in rat dorsal root ganglia. Spine 23: 25172523.
Yabuki S, Kawaguchi Y, Nordborg C, Kikuchi S, Rydevik B & Olmarker K (1998b) Effects of
lidocaine on nucleus pulposus-induced nerve root injury. A neurophysiologic and histologic study
of the pig cauda equina. Spine 23: 23832389.
Yabuki S, Igarashi T & Kikuchi S (2000) Application of nucleus pulposus to the nerve root
simultaneously reduces blood flow in dorsal root ganglion and corresponding hindpaw in the rat.
Spine 25: 14711476.
Yabuki S, Onda A, Kikuchi S & Myers R (2001) Prevention of compartment syndrome in dorsal root
ganglia caused by exposure to nucleus pulposus. Spine 26: 870875.
Yamashita K, Hiroshima K & Kurata A (1994) Gadolinium-DTPA enhanced magnetic resonance
imaging of a sequestered lumbar intervertebral disc and its correlation with pathologic findings.
Spine 19: 479482.
Yasuma T, Arai K & Yamauchi Y (1993) The histology of lumbar intervertebral disc herniation. The
significance of small blood vessels in the extruded tissue. Spine 18: 17611765.
Yoshizawa H, Kobayashi S & Morita T (1995) Chronic nerve root compression. Pathophysiologic
mechanism of nerve root dysfunction. Spine 20: 397407.
Yrjm M, Tervonen O, Kurunlahti M & Vanharanta H (1997) Bony vibration stimulation test
combined with magnetic resonance imaging. Can discography be replaced? Spine. 22: 808813.
Yrjm M, Tervonen O & Vanharanta H (1996) Ultrasonic imaging of lumbar discs combined with
vibration pain provocation compared with discography in the diagnosis of internal anular fissures
of the lumbar spine. Spine 21: 571575.
Yrjm M & Vanharanta H (1994) Bony vibration stimulation: a new, non-invasive method for
examining intradiscal pain. Eur Spine J 3: 233235.
Yu SW, Haughton VM, Ho PS, Sether LA, Wagner M & Ho KC (1988a) Progressive and regressive
changes in the nucleus pulposus. Part II. The adult. Radiology 169: 9397.
Yu SW, Sether LA, Ho PS, Wagner M & Haughton VM (1988b) Tears of the anulus fibrosus:
correlation between MR and pathologic findings in cadavers. AJNR Am J Neuroradiol 9: 367
370.
Yu SW, Haughton VM, Sether LA & Wagner M (1989) Comparison of MR and diskography in
detecting radial tears of the anulus: a postmortem study. AJNR Am J Neuroradiol 10: 10771081.
Zamani MH and MacEwen GD (1982) Herniation of the lumbar disc in children and adolescents. J
Pediatr Orthop 2: 528533.
Zitting P, Rantakallio P & Vanharanta H (1998) Cumulative incidence of lumbar disc diseases
leading to hospitalization up to the age of 28 years. Spine 23: 23372343.