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

JAROKARPPINEN

Department of Physical Medicine andRehabilitation, University of Oulu

OULU 2001

JARO KARPPINEN

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

Academic Dissertation to be presented with the assent ofthe Faculty of Medicine, University of Oulu, for publicdiscussion in the Auditorium 5 of the University Hospitalof Oulu, on September 28th, 2001, at 12 noon.

OULUN YLIOP ISTO, OULU 2001

Copyright © 2001University of Oulu, 2001

Manuscript received 24 August 2001Manuscript accepted 30 August 2001

Communicated byDocent Ilkka KivirantaProfessor Kjell Olmarker

ISBN 951-42-6480-0 (URL: http://herkules.oulu.fi/isbn9514264800/)

ALSO AVAILABLE IN PRINTED FORMATISBN 951-42-6479-7ISSN 0355-3221 (URL: http://herkules.oulu.fi/issn03553221/)

OULU UNIVERSITY PRESSOULU 2001

Karppinen, Jaro, Sciatica. Studies of symptoms, genetic factors, and treatment withperiradicular infiltration Department of Physical Medicine and Rehabilitation, University of Oulu, P.O.Box 5000, FIN-90014 University of Oulu, Finland 2001Oulu, Finland(Manuscript received 24 August 2001)

Abstract

The nature of symptoms and signs of sciatica, genetic factors, and efficacy of periradicular infiltrationwere 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) wereevaluated. ENMG and 1.5-T MRI were performed on every patient. Presence of the Trp2 and Trp3alleles of collagen IX was determined from blood samples. After informed consent, patients wererandomized for periradicular infiltration with either methylprednisolone–bupivacaine, or saline. Thefinal follow-up assessment was 1 year after the intervention. Economic analysis was based on datagathered from the patients, medical records and the National Insurance Register.

At baseline, symptoms of sciatica did not correlate with the type of displacement of thesymptomatic 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 L4–5 level. A significantgenotype-phenotype association was found for the Trp3 allele: 15 of 34 (44%) patients with the Trp3allele were positive for thoracolumbar Scheuermann’s disease in MRI compared to 19% for sciaticpatients without the allele (p = 0.003).

Periradicular infiltration with methylprednisolone–bupivacaine produced a significant treatmenteffect compared to saline at 2 weeks for leg pain, straight leg raising, lumbar flexion and patientsatisfaction. At 6 months, saline was superior to steroid in back and leg pain. By 1 year, 18 patientsin 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 mostpronounced for contained herniations and symptomatic lesions situated at the L4–5 (or L3–4) disclevel. Patients with a contained herniation were less likely to undergo back surgery when receivingthe 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 findingsare 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 treatmentintervention results, periradicular infiltration with a combination of steroid and anaesthetic may berecommended for sciatica as it offers at least short-term pain relief. Furthermore, in the case ofcontained 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 depart-ment, Professor Heikki Vanharanta, who introduced my to the topic of periradicular infilt-ration, and taught me all I know about intervertebral discs. Throughout these years he hassupported me unfailingly and guided me on the path to fullfilling my dream.

My other official advisor was Docent Antti Malmivaara, without whom this thesiswould not have materialized; he steered me safely through all kinds of hazards and taughtme 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 wri-ting and thinking. In addition to being an outstanding expert, and not merely in collagenresearch, she is also a delightful person and true friend. I hope our research efforts toget-her will continue.

The radiologic expertise of Docent Osmo Tervonen proved a crucial factor in the cur-rent studies, and he taught me all I know about the interpretation of MRI scans. He is avisionary, 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 IlkkaKiviranta and Professor Kjell Olmarker. Their constructive criticism improved the qua-lity of the thesis considerably.

Sincere thanks are due to all my coauthors: Mauno Kurunlahti, M.D., Eero Kyllönen,M.D., Ph.D., Jaana Lohiniva, M.C., Docent Pentti Nieminen, Docent Arto Ohinmaa, Pet-teri Paassilta, M.D., Tuomo Pienimäki, M.D., Ph.D., Docent Eija Pääkkö, Susanna Räinä(former Annunen), M.D., Pirjo Syrjälä, M.D. and Pekka Vasari, M.Sc. Without them, thisthesis 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 Käsmä, Mrs. Raija Jalopaasi and Mrs.Marjatta Riihimäki) and radiology for their valuable help during the trial.

I wish to thank Professor Esa Läärä 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 myson Mikael, this thesis could even have been attempted. Their patience and supportthroughout these long years has been crucial. Because I spent far less at home than Iwanted, Kirsi ran the household as I pursued my scientific activities. The care of ourdogs, Angela and Miška (may their souls rest in peace) and our newcomer Zinï, has beenin Kirsi’s capable hands. Thank you Kirsi!

Financial support was gratefully received from the Yrjö Jahnsson Foundation, the Fin-nish Office for Health Technology Assessment, and the Finnish Work Environment Fund.

Oulu, August 2001 Jaro Karppinen

Abbreviations

AF anulus fibrosusAUC area-under-the-curveCI confidence intervalCGRP calcitonin gene related peptideCT computed tomographyCSGE conformation sensitive gel electrophoresisDRG dorsal root ganglionEMG needle electromyographyENMG electroneuromyographyFIM Finnish marksGd-DTPA Gadolinium-diethylenetriamine pentaacetic acidHNP herniated nucleus pulposusIL interleukinINOS inducible nitric oxide synthaseMRI magnetic resonance imagingNSAID nonsteroidal anti-inflammatory drugNHP Nottingham Health ProfileNO nitric oxideNP nucleus pulposusPCR polymerase chain reactionPG proteoglycanPLA2 phospholipase A2RCT randomized controlled trialSLR straight leg raisingSP substance PTE echo timeTLS thoracolumbar Scheuermann’s diseaseTNFα tumor necrosis factor αTR repetition timeTrp2 allele sequence variation in the COL9A2 gene changing a codon for glutamine

to one for tryptophan in the α2 chain of collagen IX

Trp3 allele sequence variation in the COL9A3 gene changing a codon for arginineto one for tryptophan in the α3 chain of collagen IX

VAS visual analog scaleVIP vasoactive intestinal peptide

List of original publications

This thesis is based on the following articles referred to in the text by their Romannumerals:I Karppinen J, Malmivaara A, Tervonen O, Pääkkö E, Kurunlahti M, Syrjälä P,

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

II Karppinen J, Pääkkö E, Räinä S, Tervonen O, Kurunlahti M, Nieminen P,Malmivaara A, Ala-Kokko L & Vanharanta H. Magnetic Resonance Imagingfindings in relation to the COL9A2 tryptophan allele among sciatic patients. SpineIn Press.

III Karppinen J, Pääkkö E, Paassilta P, Lohiniva J, Kurunlahti M, Tervonen O,Nieminen P, Malmivaara A, Vanharanta H & Ala-Kokko L. Importance of MRI inphenotypic evaluation of lumbar disc disease. Association between thoracolumbarScheuermann’s disease and COL9A3 tryptophan allele. Submitted for publication.

IV Karppinen J, Malmivaara A, Kurunlahti M, Kyllönen E, Pienimäki T, Nieminen P,Ohinmaa A, Tervonen O & Vanharanta H (2001) Periradicular infiltration forsciatica. A randomized controlled trial. Spine 26:1059-1067

V Karppinen J, Ohinmaa A, Malmivaara A, Kurunlahti M, Kyllönen E, Pienimäki T,Nieminen P, Tervonen O & Vanharanta H. Cost-effectiveness of periradicularinfiltration for sciatica. Subgroup analysis of a randomized controlled trial. Spine InPress.

Contents

Abstract Acknowledgements Abbreviations List of original publications 1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 152 Review of the literature . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17

2.1 Pathogenesis of sciatic pain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 172.1.1 Intervertebral disc herniation (HNP) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17

2.1.1.1 Intervertebral disc . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 172.1.1.2 Mechanisms of disc herniation . . . . . . . . . . . . . . . . . . . . . . . . . . . 182.1.1.3 Nerve root compromise by the HNP . . . . . . . . . . . . . . . . . . . . . . . 19

2.1.2 Other causes of sciatica . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 212.2 Pathophysiological mechanisms of sciatica . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21

2.2.1 Compression of nerve roots . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 212.2.1.1 Chronic compression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 222.2.1.2 Compression of the dorsal root ganglia (DRG) . . . . . . . . . . . . . . . 22

2.2.2 Inflammation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 232.2.2.1 Inflammatory mechanism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 232.2.2.2 Inflammatory mediators . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24

2.2.3 Combination of compression and inflammation . . . . . . . . . . . . . . . . . . . . 262.2.4 Pain sensitization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 272.2.5 Effect of methylprednisolone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28

2.3 Etiognosis of sciatica . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 282.3.1 Constitutional factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 282.3.2 Environmental and behavioural factors . . . . . . . . . . . . . . . . . . . . . . . . . . . 292.3.3 Genetic factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30

2.4 Diagnosis of sciatica . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 322.4.1 Medical history . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 322.4.2 Physical signs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 322.4.3 Imaging and other diagnostic tests . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 332.4.4 Associations of symptoms and clinical signs with MRI findings . . . . . . . 34

2.5 Treatment of sciatica . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 352.5.1 Natural history . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35

2.5.2 Conservative treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 352.5.2.1 Epidural steroids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 362.5.2.2 Periradicular infiltration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37

2.5.3 Surgical treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 373 Aims of the study . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 394 Subjects and methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40

4.1 Study population . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 404.2 Evaluation of patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40

4.2.1 Demographics and clinical symptoms (I–V) . . . . . . . . . . . . . . . . . . . . . . . 404.2.2 Genetic analysis (II and III) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 414.2.3 Diagnostic evaluation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41

4.2.3.1 Clinical examination (I–V) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 414.2.3.2 Magnetic Resonance Imaging (MRI) (I–V) . . . . . . . . . . . . . . . . . . 424.2.3.3 Electroneuromyography (ENMG) (I, IV and V) . . . . . . . . . . . . . . 43

4.3 Patient information and randomization (IV and V) . . . . . . . . . . . . . . . . . . . . . . . 434.4 Periradicular infiltration (IV and V) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 434.5 Other interventions (IV and V) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 444.6 Follow-ups and outcome assessment (IV and V) . . . . . . . . . . . . . . . . . . . . . . . . 454.7 Economic analysis (IV and V) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 454.8 Statistical analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45

4.8.1 Calculation of sample size (I–V) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 454.8.2 Reliability of MRI findings (I–V) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 464.8.3 Associations of MRI findings, clinical tests and symptoms (I) . . . . . . . . . 464.8.4 Evaluation of patients with the Trp2 and Trp3 alleles (II and III) . . . . . . . 464.8.5 Estimation of treatment efficacy and cost-effectiveness (IV and V) . . . . . 474.8.6 Subgroup analysis (V) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48

5 Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 495.1 Baseline characteristics of the patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 495.2 Correlations of symptoms and signs to MRI findings (I) . . . . . . . . . . . . . . . . . . 515.3 Evaluation of patients with the Trp2 and Trp3 alleles (II and III) . . . . . . . . . . . 52

5.3.1 Demographic and clinical characteristics . . . . . . . . . . . . . . . . . . . . . . . . . . 525.3.2 MRI findings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 535.3.3 Thoracolumbar Scheuermann’s disease (TLS) . . . . . . . . . . . . . . . . . . . . . 53

5.4 Clinical efficacy of periradicular infiltration.Intention-to-treat analysis (IV) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55

5.5 Clinical efficacy of periradicular infiltration. Subgroup analysis (V) . . . . . . . . . 605.5.1 Contained herniations vs. extrusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 605.5.2 Disc level . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 61

5.6 Cost-effectiveness of the treatments in subgroups (V) . . . . . . . . . . . . . . . . . . . . 615.6.1 Contained herniations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 615.6.2 Extrusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 625.6.3 Disc level . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64

6 Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 656.1 Study population . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 656.2 Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 666.3 MRI findings versus symptoms and signs of sciatica (I) . . . . . . . . . . . . . . . . . . 67

6.4 Phenotype of patients with the Trp2 allele (II) . . . . . . . . . . . . . . . . . . . . . . . . . . 676.5 Phenotype of patients with the Trp3 allele (III) . . . . . . . . . . . . . . . . . . . . . . . . . 686.6 Intention-to-treat analysis of periradicular infiltration (IV) . . . . . . . . . . . . . . . . 706.7 Subgroup analysis of periradicular infiltration (V) . . . . . . . . . . . . . . . . . . . . . . . 71

7 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 738 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 74

1 Introduction

Sciatic pain is classified as radicular pain – pain radiating from the back into thedermatome of the affected nerve root along the femoral or sciatic nerve trunk, or asnonradicular pain – pain radiating in the leg in a nondermatomal pattern (vanAkkerveeken 1996). True radiculopathy is defined as radicular pain in the presence of aneurological deficit (Bogduk 1997a).

Various surveys have found the prevalence of sciatic pain in the adult population to bebetween 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(Heliövaara et al. 1987a). A diagnosis of lumbar disc syndrome was made for 5.1% of themen 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 of19 (Zitting et al. 1998). In Finland, the prevalence of age-adjusted work disability insciatica has been reported to be over 14 % (Heliövaara et al. 1989). In 1999,compensation was paid for almost 600 000 days of sick leave because of some ICD-10M51-diagnosis (e.g. radiculopathy M51.1, and disc displacement M51.2, but not low backpain M54.5). According to the National Insurance Register, the reimbursement cost ofthese 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 commonin asymptomatics (Boden et al. 1990, Jensen et al. 1994), and that disc ruptures without aherniation can induce similar sciatic symptoms to HNP (Ohnmeiss et al. 1997, Ohnmeisset al. 1999). The concept of inflammation underlying sciatica was presented (McCarron etal. 1987, Olmarker et al. 1993, Olmarker et al. 1995, Saal 1995). Furthermore, the geneticbackground 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. Patientswere thoroughly examined clinically and by MRI in order to describe the determinants ofsciatic symptoms and signs, and the phenotypes of the different Trp alleles of collagen IX.

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Patients were randomized to receive periradicular infiltration with either a combination ofsteroid 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 operationsperformed with local anaesthesia. In these studies, sciatic pain could be produced only bypressure 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 isHNP (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 centralgelatinous nucleus pulposus (NP), and thin vertebral endplates. Collagens andproteoglycans (PG) are the primary structural components of the intervertebral discmacromolecular 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 glycosaminoglycanside-chains (chondroitin and keratan sulphates) covalently bound to a protein core. Thenegatively charged sulphate and carboxyl groups attract cations (Na+, H+). Indeed, inchildren and young adults, water accounts for over 80% of the weight of the NP.Hyaluronic acid, long, nonsulphated glycosaminoglycan, binds multiple aggrecanmolecules stabilized by a link protein, to form large PG aggregates (Eyre 1979). PGs

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account for 50 % of the dry weight of the NP from a child, whereas collagens account forabout 20 % (Buckwalter 1995). Collagen II is the major collagen of human NP (~80 %),but collagen VI (~15 %), collagen IX (1–2%), collagen XI (3%) and traces of collagen IIIcan also be found (Hukins 1988, Eyre et al. 1989, Buckwalter 1995).

The AF consists of 10–20 concentric lamellae of collagen fibres. The lamellae of theouter 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 (upto 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 (1–2%) andtraces of type III collagen (Eyre et al. 1989, Buckwalter 1995).

The end-plates consist of hyaline cartilage, which is approximately 1 mm thick. Incontrast to articular cartilage, there are no collagenous connections directly anchoring theend-plates to the bone of the underlying vertebral bodies. The collagen fibers of the innerAF are attached to the end-plates. The cells of the cartilaginous end-plate arechondrocytic cells. The end-plate has a lower PG and water content, and a higher collagencontent than do adjacent regions of the disc (Roberts et al. 1989). Its function is to serveas a semipermeable membrane to facilitate diffusion of solutes from the vertebra to thedisc (Eyre 1979).

Human intervertebral discs undergo age-related degenerative changes, potential causesof which include declining nutrition, loss of viable cells, cell senescence, post-translational modification of matrix proteins, accumulation of degraded matrix proteins,and fatigue failure of the matrix (Buckwalter 1995). The onset of disc degeneration is notpossible to observe in humans, but the process has been studied thoroughly in animalmodels. After incision of rabbit AF, acute herniation of the NP was produced, followed byprogressive dehydration of the NP with a concomitant decrease in total uronic acidcontent (constituent of PGs) (Lipson & Muir 1981a, Lipson & Muir 1981b). Similarresults (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 afterthe injury; instead of producing collagen II, the chondrocytes begin to produce collagensI, III, IV and VI (Kääpä et al. 1994, Kääpä et al. 1995).

2.1.1.2 Mechanisms of disc herniation

Mechanisms of disc injuries have been studied in animal and cadaver models. After theinjury, progressive water and PG loss in the NP occurs (Karppinen et al 1995). In post-mortem 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 notseen in MRI. Transverse, or rim lesions are suggested to be due to trauma rather thanbiochemical degradation, and they develop independently of nuclear degeneration (Osti etal. 1992). High-intensity zone (HIZ) lesions, which seem to associate with typical pain indiscography, represent a combination of radial and circumferential tears (Aprill &Bogduk 1992).

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Tears of the anulus are suggested to play an important role in the degeneration of theintervertebral joint complex (Osti et al. 1990). Radial ruptures are especially interestingas they precede disc degeneration (Yu et al. 1988a, Osti et al. 1992). Radial tearsextending from the NP into the middle layers of the AF are associated with subjectivepain 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 thecomponent of lateral bending where the AF was stretched the most (Adams & Hutton1982). The fissure through which the nuclear pulp was extruded usually occurred at theboundary between the AF and the end-plate. Large central nuclear extrusions ruptured theposterior longitudinal ligament, whereas smaller extrusions either formed a bulge behindit or were deflected sideways and appeared on one or both posterior lateral margins of thedisc (Adams & Hutton 1982). In the same study it was shown that the susceptibility of adisc to prolapse depends on age, degree of disc degeneration and spinal level. Slightlydegenerated lower lumbar discs of people aged between 40 and 50 seemed particularlyvulnerable (Adams & Hutton 1982). The same authors showed that even young discs canprolapse slowly over days or months by fatigue compressive loading of a flexed disc(Adams & Hutton 1985). Disc deterioration occurred gradually. Distortion of theposterior lamellae is first observed, then breaking through the lamellae, and thereaftergradual nuclear extrusion through posteriolateral anular fissures and disruption of anularlamellae (Adams & Hutton 1985). This gradual disc prolapse mechanism probablyaccounts 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 toirritation by the HNP are nerve roots. At each lumbar level, a pair of dorsal and a pair ofventral 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 (Figure1A). 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 (Aδ and Aβfibers) ranges between 1.5 and 16 µm, while the unmyelinated nociceptor axons (Cfibres) range between 0.4 and 1.6 µm (Olmarker 1991, Bogduk 1997a). The soma ofventral roots lie in the ventral horn of the spinal cord, whereas the soma of the afferentdorsal roots lie in the dorsal root ganglia (DRG). A DRG typically lies at the distal end ofthe dorsal root inside the apex of the dural sleeve, directly inferior to the pedicle and closeto the nerve root axilla (Cohen et al. 1990).

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

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 thespinal cord, whereas the cell bodies of the sensory axons of the dorsal root are located in thedorsal 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 continuationof the pia mater covering the spinal cord. The spinal cord and nerve roots are floating freely inthe cerebrospinal fluid (CSF) in the subarachnoid space. D=dura. B) Schematic drawing ofvascular supply to the spinal cord and nerve roots. The nervous system branch of the segmentalartery (SA) joins the nerve root and forms a ganglionic plexus (GP) in the DRG and caudalnerve 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).

DRG

VR

DR

SN

RS

D

CSF

SA

GP

NRA

A

B

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2.1.2 Other causes of sciatica

Other causes of sciatica can be divided into intraspinal or extraspinal. Intraspinal causesinclude spondylosis and osteoarthritis with encroachment upon the intervertebralforamina (Schellinger et al. 1987). Lateral lumbar spinal canal stenosis due toosteoarthritis can be divided into entrance zone, mid zone and exit zone stenosis (Lee etal. 1988). The most common cause of entrance zone stenosis is hypertrophicosteoarthritis of the facet joint, particularly involving the superior articular process,whereas exit zone stenosis is caused typically by a subluxed facet joint or by anosteophytic ridge along the superior margin of the disc. However, mid zone stenosis isclinically the most important entity, because the DRG occupies a large part of the midzone. Two common causes are osteophyte formation under the pars interarticularis wherethe ligamentum flavum is attached, and fibrocartilagenous or bursal tissue hypertrophic ata spondylolytic defect (Lee et al. 1988). Spondylolisthesis is occasionally responsible forsciatica, and symptoms are usually bilateral (Kikuchi & Hasue 1988). Zygoapophysealjoint cyst, on the other hand, produces unilateral symptoms (Reust et al. 1988). Otherintraspinal processes causing sciatica include tumors, abscesses and tuberculosis (Elliott& Schutta 1971).

Extraspinal causes can be differentiated into diseases of the lumbosacral plexus andlesions of the sciatic nerve or its branches. Lesions of the lumbosacral plexus usuallyproduce symptoms of more than one segment, and often the pelvic condition responsiblefor lumbosacral pain overshadows sciatica. In disease of the sciatic nerve, pain is notusually a prominent symptom (Elliott & Schutta 1971). Diseases of the lumbosacralplexus 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 causedby compression of the nerve as in hamstring (Puranen & Orava 1991) and piriformissyndromes (Hanania & Kitain 1998), or by vascular compromise as in diabetes (Naftulinet al. 1993). A rare cause of sciatica is cervical and thoracic spinal cord compression (Itoet al. 1999).

Physicians have to recognize nondermatomal pain which is synonymous with referredpain from the mesenchymal structures (bones, joints, ligaments and bursae) of thelumbosacral spine, the pelvis and the lower extremity. Referred pain is deep, dull, boringand aching. It follows the distribution of the myotomes and sclerotomes (Elliott & Schutta1971, 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 thecause of sciatica, although HNP can be found in 20% to 36%, depending on the age, ofasymptomatic subjects (Wiesel et al. 1984, Boden et al. 1990, Jensen et al. 1994).

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Similarly, internal disc ruptures (without HNP) may also induce disabling radicular pain,indicating the existence of an alternative mechanism to neural compression (Ohnmeiss etal. 1997, Ohnmeiss et al. 1999).

The effect of compression on the nerve roots has been studied extensively in animalmodels. Rapid onset (0.05–0.1 s) compression of porcine nerve roots induced intraneuraloedema after 2 minutes compression at 50 mmHg, whereas following slow onset (15–20 s) compression, oedema occurred after 2 hours (Olmarker 1991). Significant reduction(20–30 %) of nutrition was already observed at 10 mmHg compression, probably due toimpairment of cerebrospinal fluid flow (Olmarker 1991). Intraneural oedema mayincrease the endoneural fluid pressure and lead to impairment of intraneural blood flow asin the closed compartment syndrome (Rydevik et al. 1989). In dogs, compression induceda marked extravasation of protein tracers; electron microscopy showed the tight junctionsof the intraneural capillaries opened and vesicular transport increased, indicatingdisruption of the blood-nerve barrier (Kobayashi et al. 1993). In MRI, this was reflectedas 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 briefdischarge of maximally 20 impulses was observed (Howe et al. 1977). Chronic injury,however, greatly increased their mechanical sensitivity. When chronic compression ofcanine nerve roots was studied with a silastic tube model, impairment of the blood-nervebarrier (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 rootdysfunction due to chronic compression is intraradicular oedema induced by increasedlocal vascular permeability (Yoshizawa et al. 1995). Similar nerve root enhancement andaxonal degeneration, along with marked inflammatory cell infiltration, were also found inbaboons (Nguyen et al. 1995). Destruction of large myelinated fibers was observed after1 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 morecommon 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 tocompression, gentle pressure producing prolonged repetitive firing in single afferentfibers (Howe et al. 1977). This was confirmed by measuring the responses in dorsal hornwide 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 spontaneousfiring in an in vitro model (Sugawara et al. 1996). The relevance of DRGs in the

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pathophysiology of sciatica is supported by observations that the DRG is the most likelysite 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 nerveroots (Olmarker et al. 1993). The functional changes include focal degeneration ofmyelinated fibers and focal Schwann cell damage in nondegenerated axons. The damageto the Schwann cells resulted in a disintegration of Schmidt-Lanterman incisures(Olmarker et al. 1996). These incisures connect the cytoplasm of the Schwann cellssituated outside the myelin sheath to the part on its inner side, the external parts of theSchwann 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, butsimilar functional nerve root damage was also observed in pigs after experimental discherniation (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, manysubstances, including hydrogen ions and glycoproteins, has been suspected to causechemical radiculitis (Nachemson 1969, Marshall et al. 1977). However, NP is alsochemotactic, attracting leukocytes, and it may also induce macromolecular leakage andspontaneous firing of axons in vitro (Olmarker et al. 1995). In chronic compressionstudies, inflammatory cell infiltrates, mainly macrophages, have been observed(Yoshizawa et al. 1995, Nguyen et al. 1995). Furthermore, in a rat model of mechanicalhyperalgesia induced by application of NP to nerve roots, depletion of leukocytesinhibited the generation of hyperalgesia (Kawakami et al. 2000b). This indicated thatleukotactic properties of the HNP are important in the production of pain-relatedbehaviour. The cells first appearing in and around the herniated NP on nerve root werepolymorphonuclear leukocytes, whereas macrophages, originating from monocytes, didnot predominate until after a few days and then remained in the affected region until theinflammation subsided (Kawakami et al. 2000b).

The observed decrease in nerve conduction velocity may be due to impaired ionexchange following changes in Schmidt-Lanterman incisures (Olmarker et al. 1996) or toischaemia (Kayama et al. 1996). The latter mechanism is supported by the finding thatautologous NP increased endoneural pressure and reduced blood flow (assessed with alaser Doppler flow probe) by 10 % to 20 % in the DRG (Yabuki et al. 1998a). Irritation ofa nerve root thus caused a “compartment syndrome” in the DRG. Interestingly, blood flow

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in the ipsilateral hind paw was reduced, too (Yabuki et al. 2000). Also after experimentalherniation, blood flow in canine nerve root was reduced, correlating with the decrease innerve conduction velocity (Otani et al. 1999). The decrease in blood flow was maximal at1 week, recovering within 1 month. In the DRG, however, there was a statisticallysignificant decrease in blood flow only at 1 week, and no reduction/recovery pattern wasobserved (Otani et al. 1999).

2.2.2.2 Inflammatory mediators

The neurotoxicity of the NP seems to be associated with disc cells, as freezing preventedthe neuronal damage (Olmarker et al. 1997, Kayama et al. 1998). In the following, thepossible inflammatory candidates in the NP are discussed.

Phospholipase A2. Phospholipase A2 (PLA2) is the rate-limiting enzyme in thesynthesis of proinflammatory lipid mediators (prostaglandins, leukotrienes, lipoxenies,and platelet-activating factor). The enzyme liberates arachidonic acid from the membranephospholipids, and is secreted extracellularly by activated phagocytes in response tocytokines (Vadas & Pruzanski 1986). Additionally, it is released from rabbit chondrocytesby IL-1 (Chang et al. 1986). PLA2 is found in extraordinarily high concentrations inherniated 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 plasmamembranes 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(Özaktay et al. 1998). This resembled the observed neuroexitatory effect of NP (multiunitdischarge lasting for several minutes) (Cavanaugh 1995). Furthermore, when PLA2 wasinjected epidurally, motor weakness, demyelinisation, and increased sensitivity of dorsalroots 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 inherniated tissue samples (Grönblad et al. 1996), because surgery is usually undertakenseveral weeks after the onset of symptoms. In fact, phospholipase A2 activity was foundto be maximal 1 week after chromic gut ligature, whereas thermal hyperalgesia wasmaximal 3 weeks after surgery (Lee et al. 1998). In a rat model, NP-induced mechanicalhyperalgesia was abolished by mepacrine, a selective inhibitor of phospholipase A2(Kawakami et al. 1998). Interestingly, anulus or a combination of anulus and NP inducedmechanical hyperalgesia only after addition of a selective inhibitor of inducible nitricoxide synthase (iNOS), indicating a role for nitric oxide (NO) in reducing mechanicalhyperalgesia in this model (Kawakami et al. 1998).

Tumor necrosis factor (TNF-α). TNF-α is a cytokine produced mainly by activatedmacrophages and T cells in response to inflammation, and by mast cells and Schwanncells in response to peripheral nerve injury (Wagner & Myers 1996b, Bemelmans et al.1996). It activates the transcription factors NF-κB and AP-1 by binding to its p55 TNFreceptor (TNFRI), thereby inducing the production of proinflammatory and

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immunomodulatory genes (Darnay & Aggarwal 1997). Endoneurial TNF-α causesdemyelinisation, axonal degeneration, and hyperalgesic pain states (Wagner & Myers1996a), while anti-inflammatory IL-10 treatment in chronic constriction injury toperipheral nerves decreases thermal hyperalgesia, macrophage recruitment andendoneurial TNF-α expression (Wagner et al. 1998). However, TNF-α also has animportant role in the resorption of disc herniation (Haro et al. 2000). Macrophages secretematrilysin-enzyme (MMP-7), which liberates soluble TNF-α from macrophage cellmembranes. Soluble TNF-α induced disc chondrocytes to secrete stromelysin-1 enzyme(MMP-3), which was required for the release of a macrophage chemoattractant andsubsequent 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-α expression. It seems that the first TNF-α peak, 6 hours after the peripheral nerve injury, is due to the local expression of thecytotoxic transmembrane 26 kDa TNF-α protein released by the resident Schwann cell,mast cells and macrophages. This peak in TNF-α expression corresponds to an increasein activity of gelatinase B (MMP-9), which is already greatly upregulated 3 hours afterthe injury. The second peak occurs 5 days after the injury, and may represent TNF-αprotein released by haematogenously recruited macrophages. The second peakcorresponds to an increase in soluble 17 kDa TNF-α and gelatinase A (MMP-2)upregulation (Shubayev & Myers 2000). When degenerated and normal human articularcartilage were compared, TNF-α (and IL-1β) was expressed only in the superficial zoneof degenerated cartilage. However, the phenotype of chondrocytes varied widely even indegenerated cartilage, 5 to 40 % of cells expressing these cytokines (Tetlow et al. 2001).

Recently it was found immunohistochemically that TNF-α was expressed in the NP(Olmarker & Larsson 1998); in fact, 17 kDa cytokine was expressed at a concentration ofapproximately 0.5 ng per disc (Igarashi et al. 2000). Consistent with the results of Haroand co-workers (Haro et al. 2000), TNF-α (and other cytokines) was produced inprotrusion type herniations by chondrocytes, but in extrusions by histiocytes, fibroblasts,and endothelial cells constituting granulation tissue (Takahashi et al. 1996).

Exogenous TNF-α produced neuropathological and behavioural changes (Walleriandegeneration of nerve fibers, macrophage recruitment to phagocytoze the debris, splittingof the myelin sheath) that mimicked those of the NP (Igarashi et al. 2000). Later, in achronic peripheral nerve injury model, remyelinisation and reactive changes inendothelial cells (collagen deposition in response to fibroblast activation) have beenobserved after intraneural injection of TNF-α (Redford et al. 1995). In herniated disctissues similar changes, such as endothelial proliferation, vascular activation and collagenproliferation have been observed (Cooper et al. 1995). Treatment with doxycycline, anonspecific TNF-α antagonist, blocked the NP-induced reduction of nerve conductionvelocity (Olmarker & Larsson 1998). More recently, both soluble TNF-α receptor(Embrel™) and TNF-α antibodies (Remicade™) reversed NP-induced nerve conductionblock (Olmarker & Rydevik 2001). Furthermore, these antagonists also specificallyblocked the NP-induced oedema and thrombus formation, indicating that these vascularchanges were TNF-α mediated. In another study, topical pentoxifylline, an inhibitor of

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TNF-α synthesis, prevented the NP-induced compartment syndrome in the DRG (Yabukiet al. 2001). In conclusion, it seems that TNF-α exerts a crucial role in NP-induced nerveroot damage.

Other inflammatory mediators. IL-1 plays an important role in experimental allergicradiculitis induced in rats, since IL-1 receptor antagonist ameliorated the symptoms(Wehling et al. 1996). In fact, IL-1 and IFNγ act synergistically with TNF-α and are moreor less neurotoxic (Chao et al. 1995). In vitro, herniated discs spontaneously producenitric oxide, matrix metalloproteinases, IL-6 and PgE2 (Kang et al. 1997). Even controldiscs synthetized these substances when the tissue samples were exposed to IL-1β (butnot without). In herniated discs, IL-1β further increased the production of NO, IL-6 andPgE2 (Kang et al. 1997).

In a canine model, PgE2 produced ectopic firing of nerve roots, which was suppressedwith steroid (Muramoto et al. 1997). PgE2 production in vitro could also be blocked withinducible 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) producedthermal hyperalgesia in a rat model (Kawakami et al. 1998). Thermal hyperalgesia wasabated with epidural saline and abolished with a specific inhibitor of iNOS. In pigs, aspecific inhibitor of iNOS, aminoguanidine, prevented the formation of NP-inducedoedema and a negative effect on the nerve conduction velocity (Brisby et al. 2000), but inthe rat model NO reduced mechanical hyperalgesia (Kawakami et al. 1998). NO seemsthus to have a dual action on the nerve roots, both negative and positive, similar toarticular 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 thesetwo were compared in rats, thermal hyperalgesia was induced only by the combination ofcompression and NP (Kawakami et al. 2000a). Even though silk ligature did not effectthermal withdrawal latency, histologically there were fewer large and more small-diameter 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 NPapplied 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 significantreduction in mechanical threshold at days 2, 4, 16 and 18, and significant thermalhyperalgesia from day 2 until day 14 post-operatively in the combination protocolanimals. Histologically, a significant cellular injury by 21 days post-operatively wasnoticeable. Oedema and fibrotic reactions were observed in the subperitoneal/root sheatharea and in the endoneural space. There was also perivascular oedema and indications ofreactive endothelial cells, axonal demyelination, myelin splitting, and Schwann cellhypertrophy (Olmarker & Myers 1998). On the basis of these studies, the probable

27

scenario is that the ruptured intervertebral disc with leaking nucleus sensitizes the nerveroot(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 herniateddisc tissue reproduces sciatic pain (Smyth & Wright 1958, Kuslich et al. 1991). In theseanimal models, autologous NP has mainly been used. However, in articular cartilage,TNF-α expression was confined only to the degenerated samples, and even indegenerated cartilage 5–40 % of cells expressed the cytokine (Tetlow et al. 2001).Nondegenerated animal disc tissue may, thus, not be fully comparable with degeneratedtissue. This explains the discrepancy between these animal results and the clinicalsituation where prolonged sciatica is encountered without disc herniation.

2.2.4 Pain sensitization

Peripheral nerve endings become sensitized by chemical mediators that are releasedduring tissue damage and inflammation. These include neurogenic mediators, such assubstance P, and non-neurogenic mediators, such as bradykinin, histamine andprostaglandins (Cavanaugh 1995). In addition to local increase in the excitability of Cfibers, spinal mechanisms are important in the production and maintenance ofhyperalgesia. Thermal hyperalgesia requires the activation of N-methyl-D-aspartate(NMDA) receptors and is primarily mediated by production of nitric oxide, whereasmechanical hyperalgesia requires α-amino-3-hydroxy-5-methylisoxazole-5-propionate(AMPA) and metabotropic glutamate receptor coactivation, and is primarily mediated bycyclooxygenase products and PLA2 activation (Meller & Gebhart 1994).

In rats, compression of nerve roots by loose chromic gut ligatures induced prolongedthermal hyperalgesia (related to neuropathic pain), and initial transient motor dysfunctionand mechanical hypoalgesia (Kawakami et al. 1994a). Pain-related behaviour correlatedwith increased dorsal horn c-fos and dorsal ganglion VIP amounts. Similarly, DRGirritation generated thermal hyperalgesia, which was accompanied by increased c-fosexpression and spontaneous pain-related behaviour (Chatani et al. 1995).

Epidural betamethasone, but not bupivacaine, inhibited thermal hyperalgesia generatedby ligating rat nerve roots with chromic gut ligatures (Hayashi et al. 1998). However, inthis 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-relatedbehaviour, which indicates that rather than mechanical compression, a chemical irritantreleased from chromic gut is responsible for thermal hyperalgesia (Kawakami et al.1994b). Interestingly, in the rat model PLA2 was involved in mechanical hyperalgesiainduced 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 themechanical allodynia for the first 7 days. Simultaneously, spinal cord IL-1β secretion wasincreased, indicating a neuroimmune component in lumbar radiculopathy (Hashizume etal. 2000). Similarly, one week after relocation of autologous NP on rat L4 and L5 nerve

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roots, nerve root and DRG IL-1β expression were increased. In the same study, IL-6expression 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 theNP-induced vascular permeability and functional impairment (decrease of nerveconduction velocity) (Olmarker et al. 1994). Histologically, no differences between theNP and NP + methylprednisolone groups were observed. The nerve loss was, however,focal (Olmarker et al. 1994). Methylprednisolone also inhibited the NP-induced increaseof vascular permeability (Byröd et al. 2000).

In the rat model, PLA2 activity was found to be maximal 1 week after chromic gutligature, 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 aftersurgery) 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, althoughlongitudinal cohort studies potentially yield more relevant information. In the followingchapters, determinants of lumbar disc disease (herniated disc or typical sciatica) arereviewed in three parts: constitutional factors such as body height, age, gender andobesity; environmental and behavioural factors such as occupation, smoking, leisure timeactivities and psychological factors; and finally genetic factors, knowledge of which isincreasing constantly.

2.3.1 Constitutional factors

Sciatica and risk of undergoing surgery is highest during the fourth and fifth decades oflife (Kelsey & Ostfeld 1975, Frymoyer 1988). This age-related vulnerability is alsosupported by findings from cadaver studies (Adams & Hutton 1982), and it may berelated to greater prevalence of disc ruptures. The reduced incidence of disc herniation inold 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 forsciatica (Spangfort 1972, Naylor 1974, Thomas et al. 1983). On the other hand, in onestudy 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

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5.1% for men and 3.7% for women aged 30 years or over (Heliövaara et al. 1987a). Thediagnosis was based on medical history, symptoms and physical examination. In a recentlongitudinal Finnish cohort study, the incidence of disc disease (HNP or sciatica) at theage 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 riskfactor for HNP in both sexes (Heliövaara 1987a). The relative risk increased on averageby 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(Heliövaara 1987a).

Obesity measured as body mass index has been found to be a significant predictor ofdisc disease only in men (Heliövaara 1987a). Herniations are often found inasymptomatic subjects (Boden et al. 1990, Jensen et al. 1994), but narrowing of thelumbar canal may predispose to symtomatic disc lesions and sciatica as the space islimited (Porter et al. 1978, Heliövaara 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 areknown to increase the risk of sciatica (Heliövaara 1989, Riihimäki et al. 1989). Motorvehicle driving is also positively associated with HNP and sciatica (Kelsey & Hardy1975, Kelsey et al. 1984, Heliövaara 1987b). The incidence of sciatica during a 3-yearfollow-up period was 22% for machine operators, 24% for carpenters and 14% for officeworkers (Riihimäki et al. 1994). However, lifetime loading is more relevant than currentconditions (Videman & Battie 1999). Moreover, many occupations are also associatedwith various lifestyle factors that can act as confounding factors in attempts to determineoccupational effects (Ilmarinen et al. 1991). When lumbar disc degeneration amongFinnish twins was studied, heavier lifetime occupational and leisure physical loading wasassociated with greater disc degeneration at the upper lumbar levels, whereas sedentarywork was associated with lesser degeneration (Battie et al. 1995).

Accident-related trauma has also been suspected of causing structural damage andaccelerating degenerative changes (Videman et al. 1990). The risk of sciatic pain hasindeed been reported to be increased among workers who had earlier had back accidents(Riihimäki 1985, Riihimäki et al. 1989, Heliövaara et al. 1991).

Self-assessed stenuousness of work was a significant risk factor for sciatica in women(Heliövaara 1987b). In a Finnish follow-up study, distress symptoms predicted hospitaladmissions for HNP or sciatica among women who reported no severe back trouble atentry (Heliövaara et al. 1987b, Heliövaara et al. 1991). The findings are in agreementwith a recent experimental study where the influence of psychosocial stress, gender and

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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 ofdifferences in muscle coactivation. Women's anterior-posterior shear forces increased inresponse to stress, whereas men's decreased. Certain personality traits (e.g. introverts andthinkers) were associated with increased spine loading compared with those with anopposing personality trait, and explained loading differences between subjects (Marras etal. 2000).

The effect of smoking on the incidence of sciatica is controversial. In a Finnish follow-up study, smokers and ex-smokers had a similar increased risk of sciatica (Manninen etal. 1995), whereas in other studies smoking was of borderline or no significance(Heliövaara et al. 1987b, Riihimäki et al. 1994).

2.3.3 Genetic factors

Findings of a study with Finnish identical twin pairs indicated that environmental factorsaccount for more than 80 % of the aetiology of sciatica, whereas genetic factors weremore significant in individuals under 40 years (Heikkilä et al. 1989). In the same studypopulation, 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 familialaggregation improved the model so that 77 % of the variability was explained (Battie etal. 1995). At the lower levels, the model explained only 43 % of the variability, but herealso familial aggregation, including both genetic influences and early childhoodenvironment, was the most important determinant. In concordance with the twin studies,several authors have reported the association of a positive family history of low backpain, 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 adolescentpatients with disc herniation were compared with matched controls, 32% of patients hadfirst-degree relatives with a history of severe back pain, sciatica or herniated disccompared with 7% in the control group (Varlotta et al. 1991). It was estimated that therisk of developing a herniated lumbar disc before the age of 21 years was four to fivetimes greater in adolescents with a positive family history.

The search for candidate genes is ongoing. Recently, two intragenic polymorphisms ofthe vitamin D receptor gene revealed an association with disc degeneration and anulartears (Videman et al. 1998, Videman et al. 2001). However, the role of vitamin D receptorgene polymorphism in disc disease is somewhat unclear because the receptor is not foundin the discs. Aggrecan, on the other hand, is a major constituent of the disc. The codingregion of the aggrecan gene contains a highly conserved repeat region. A total of 13alleles differing by the number of nucleotide repeats have so far been observed. As theresult 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 ashorter 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

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respiratory failure (Watanabe et al. 1997). The phenotype of heterozygotes included slightdwarfism and a delayed onset spinal disorder. Within 19 months of age, the miceexhibited spastic gait due to misalignment of cervical spine. Histological examinationrevealed a high incidence of disc herniations and disc degeneration (Watanabe et al.1997).

Collagen IX is a heterotrimeric protein consisting of three genetically distinct αchains, α1(IX), α2(IX) and α3(IX), encoded by the COL9A1, COL9A2 and COL9A3genes (Shaw & Olsen 1991, Brewton & Mayne 1994, Pihlajamaa et al. 1999, Paassilta etal. 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 betweencollagen fibril structure and other matrix molecules (Figure 2). Its role in intervertebraldisc disease is supported by the findings of transgenic mice expressing mutant α1(IX)chain (Kimura et al. 1996). These mice developed accelerated intervertebral discdegeneration with partial disruption of endplates and fissures in the anulus. A sequencevariation in the COL9A2 gene that changes a codon for glutamine to one for tryptophanin the α2 chain of collagen IX (Trp2 allele) has been found to associate with dominantlyinherited disc disease characterized by sciatica in about 4 % of Finnish patients (Annunenet al. 1999). This allele was not detected in the controls. Recently, a similar sequencevariation changing a codon for arginine to one for tryptophan was found in the COL9A3gene coding for the α3 chain of collagen IX (Trp3 allele) (Paassilta et al. 2001). The Trp3allele was observed in 24.4% of the sciatic patients, but in only 9.3% of the controls. Theallele was found to increase the risk of lumbar disc disease almost threefold, representingthe first common genetic risk factor for the disease (Paassilta et al. 2001). Sincetryptophan is not normally found in collagen IX it is possible that, as the mosthydrophobic amino acid, it may render intervertebral discs fragile by disturbing thecollagen triple helix or interfering with the molecular interactions (Annunen et al. 1999,Paassilta et al. 2001).

Fig. 2. A schematic presentation of collagen IX. It is covalently cross-linked to the surface of col-lagen II fibril, but a portion of the molecule projects from the fibril surface. Collagen IX is aheterotrimeric protein consisting of three genetically distinct α chains, α1(IX), α2(IX) andα3(IX). Helical domains are interrupted with globular domains (circles). The glycosaminogly-can (GAG) chain is attached to an α3-chain. The defect in α2(IX) leads to a change of codon forglutamine to that for tryptophan, which may interrupt the covalent binding of collagen IX withcollagen II.

Type IX collagen Type II collagen fibrilGAG

Crosslinks between type IX and type II collagen

Globular domain

Helical domain

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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 withnumbness or tingling (paresthesia) and is aggravated by increased intradiscal pressure orspecific 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 progressespain is felt distally along the dermatome. The extent of radiation of pain appears todepend on the severity of the pathologic process affecting the nerve roots (Smyth &Wright 1958). In clinical practice, the physician mostly encounters sciatica caused byirritation of lumbosacral nerve roots L4, L5 or S1. The upper roots (L1-L3) are involvedin less than 5% of surgical patients (Andersson & Deyo 1996). Patients with central orlateral lumbar spinal stenosis present typically with leg pain during or after walking(neurogenic claudication). Pain is often bilateral and in contrast to arterial ischemicclaudication, neurogenic claudication is more likely to occur on standing alone withoutambulation (Deyo et al. 1992).

Pain may be distributed along the whole segment, or confined to certain circumscribedareas. Thus, disease of the L4 nerve root can cause localized pain just below the kneeanteriorly and down the shin. L5 nerve root lesion may present with pain in the large toeor 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 footand also in the middle of the calf (Norlen 1944, Agency for Health Care Policy andResearch (AHCPR) 1994). There is, however, considerable overlapping between thedermatomes (Nitta et al. 1993). A medical history of current sciatica per se has a highsensitivity for lumbar nerve root compression (AHCPR 1994). The level of discherniation can be correctly predicted in over 90% of the cases by the pain location aloneor 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 theneurological status of the lower limbs. The straight leg raising test stretches the L5 andS1 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). Roottension tests are sensitive but unspecific as to the location and cause of nerve rootirritation. SLR is sensitive, but unspecific, whereas crossed SLR is very specific, but itssensitivity is low (Hakelius & Hindmarsh 1972, Spangfort 1972). L4 root lesions may beaccompanied by reduction of the knee jerk whereas impaired ankle reflex is fairly

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pathognomic for the S1 root (Norlen 1944, Knuttson 1961, Hakelius & Hindmarsh 1972,Spangfort 1972). Reflex testing is less useful in recurrent sciatica, and the lowerextremity 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 defectsare almost always confined to the periphery of the dermatome. Thus, in L4 root disordersdiminished sensation may be present over the medial part of the lower leg, in L5 rootlesions over the first three or four toes on the dorsum of the foot, and in S1 root diseasealong 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 (Blower1981, Kortelainen et al. 1985). When small nerve fibers were studied using tests forthermal thresholds and the large myelinated fibers by vibrametry, it was found that theadjacent nerve roots are also involved in the pathophysiology of sciatica in patients withlumbar disc herniation (Nygaard & Mellgren 1998).

Clinical examination is recommended to include: 1) testing of dorsiflexion strength ofthe ankle and the big toe, with weakness suggesting mainly L5 dysfunction; 2) testing ofankle reflexes to evaluate S1 root dysfunction; 3) testing of light touch sensation in themedial (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 twopercentage points (Bogduk 1997b); most of the relevant information can be obtained bylistening to the patient (Vucetic et al. 1999). The accuracy of neurological tests can,however, be improved by combining the tests (parallel testing) (Andersson & Deyo1996).

2.4.3 Imaging and other diagnostic tests

The anatomic level of imaging study findings must correspond to the side and the level oflesion detected via the history, physical examination or other methods. CT (with orwithout myelography) and MRI should be used only when there exist sciatica andclinically specific detectable nerve root compromise, or history of neurogenicclaudication with symptoms severe enough to consider surgical intervention, or clinicalfindings or other tests suggesting other serious conditions affecting the spine (Agency forHealth Care Policy and Research (AHCPR) 1994). Physicians treating sciatic patientsshould, however, remember that abnormal findings are common among asymptomaticsubjects 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 importantdifferences between CT, CT-myelography and MRI in terms of their true positive and truenegative rates for diagnosing lumbar disc herniation, although all these tests are betterthan plain myelography (AHCPR 1994). MRI is nowadays regarded as the best imagingmode (Herzog 1996), but in the diagnosis of internal disc ruptures pain provocation isneeded. Therefore, a combination of CT and discography is recommended (Vanharanta etal. 1987, Vanharanta et al. 1988a, Vanharanta et al. 1988b, Vanharanta et al. 1989,

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Moneta et al. 1994). However, discography is an invasive method with possiblecomplications (Guyer & Ohnmeiss 1995), but it can be replaced with the bony vibrationtest (Yrjämä & Vanharanta 1994). This test, combined with MRI (Yrjämä et al. 1997) ordiagnostic ultrasound (Yrjämä et al. 1996), was a sensitive method compared todiscography, although the specificity was lower in both studies. Transabdominalultrasound alone also proved a sensitive screening test for intradiscal abnormalities(Tervonen et al. 1991), but the method depends on the experience of the radiologistperforming 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 (muscleabnormalities). EMG is used to assess acute and chronic nerve root dysfunction,myelopathy, and myopathy. H-reflex and F-wave response are tests measuring sensoryconduction through nerve roots, used mostly to assess S1 radiculopathies and proximalneuropathies, respectively. The results of EMG are, however, unreliable until sciatic painhas 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 withinformation from imaging and clinical findings (Spengler et al. 1990).

Pain drawing is independent of language, and correlates with spinal pathology inmyelography (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 painthan patients with nondiscogenic pain (Ohnmeiss et al. 1999b). Pain drawing can also beused in the level diagnosis of lumbar disc pathology (Vuceticn et al. 1995, Ohnmeiss etal. 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 ofextensive study. On the basis of clinical experiments, it is known that only irritated nerveroots produce pain when compressed (Smyth & Wright 1958, Kuslich et al. 1991). On theother hand, abnormalities are common in asymptomatics (Boden et al. 1990, Jensen et al.1994). Certain determinants are known to predispose to sciatica and HNP (Heliövaara etal. 1991). The asymptomatic populations in the afore mentioned studies might have beenbiased with respect to these determinants. However, when symptomatic patients werecompared with risk factor-matched controls, disc herniations were common in bothgroups (Boos et al. 1995). Symptomatic patients could be differentiated only on the basisof neural compromise. Nerve compression and disc extrusion also seem to predict distalleg pain reliably (Beattie et al. 2000).

An association has been observed between the severity of sciatica and the size oflumbar 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 (Jönsson &

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Strömqvist 1996). Furthermore, extrusions are uncommon in asymptomatics (Jensen et al.1994, Weishaupt et al. 1998). The similarity of symptoms in patients with or without discherniation has been observed (Modic et al. 1995). Although the number of patients in thestudy 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 thesymptoms and signs of sciatica (Grönblad et al. 2000, Rothoerl et al. 1998). Theassociation of nerve root enhancement with sciatic symptoms is far from clear (Toyone etal. 1993, Crisi et al. 1993, Taneichi et al. 1994), whereas SLR restriction seems tocorrelate with disability (Thelander et al. 1992, Jönsson & Strömqvist 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 fromsciatica 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 onethird had undergone surgery. In another study, only 11.4% of conservatively treatedsciatic patients reported that the predominant pain had completely disappeared at the 1-year 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 herniationswill 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 extraspinalfactors, being closely linked in industrialized countries to the legal framework of socialinsurance (Waddell et al. 1986). Female sex, longer duration of symptoms, litigation orcompensation pending, poor psychosocial circumstances and comorbidities have beenshown 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 handicappedby the limited number of randomized controlled trials (RCT). A recent systematic reviewfound only 19 RCTs, of which 8 met the three major requirements (comparability ofgroups, observer blinding, and intention-to-treat analysis) (Vroomen et al. 2000). In the1980s, the treatment of sciatica consisted of 2 weeks bed rest, and thereafter gradualmobilization combined with anti-inflammatory drugs (NSAIDs) (Bell & Rothman 1984).

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

2.5.2.1 Epidural steroids

Epidural injection of medication allows a concentrated amount of the treatment agents tobe deposited and retained, exposing the nerve roots to the medication for a prolongedperiod of time. When a combination of epidural steroid and anaesthetic was comparedwith local anaesthetic at a tender spot over the sacrum, epidural steroid was superior at 3months, but not at the 1, 6, or 12-month follow-up assessments (Mathews et al. 1987). Acombination of epidural steroid and anaesthetic was found to give better short-term (3–4weeks) leg pain relief than epidural saline (two injections 2 weeks apart) (Bush & Hillier1991), than epidural anaesthetic (bupivacaine) (Breivik et al. 1976), and than interspinousinjections (Dilke et al. 1973, Ridley et al.1988). No long-term effect of this combinationhas 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 epiduralinjections of methylprednisolone acetate were compared with saline among patients withsciatica due to HNP (Carette et al. 1997). In the steroid group, significant improvementswere found in finger-to-floor distance and sensory deficits at 3 weeks, and leg pain at 6weeks. At three months, there were no significant differences between the groups and thecumulative probability of back surgery was similar (around 25 %). As a conclusion theauthors 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 theneed for surgery (Carette et al. 1997). Two meta-analyses of epidural corticosteroids havebeen conducted. One found no, or at most a short-term effect of epidural steroids in LBPand sciatica (Koes et al. 1995), whereas the other found epidural steroid effective inradicular pain in both the short- and long-term (Watts & Silagy 1995). Epiduralcorticosteroid injections can be recommended as additional therapy, especially in theacute phase of the conservative management of sciatica (Buchner et al. 2000, Vroomen etal. 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 isconsidered (Krempen & Smith 1974, Wilppula & Jussila 1977, Herron 1989, Stanley et

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al. 1990). In the procedure, the pharmaceutical agents are injected between the nerve rootand the epiradicular sheath, depicting the nerve root in tubular fashion (Hasue & Kikuchi1997), which permits precise application of steroids into the vicinity of the irritated nerveroot 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 symptomaticroot, sensitivity of 100%, and positive predictive value of 93% to 95% have beenpresented for periradicular infiltration (Haueisen et al. 1985, Dooley et al. 1988, vanAkkerveeken 1996, Hasue & Kikuchi 1997). Indications for periradicular infiltrationinclude radicular pain and/or intermittent claudication without neurologic findings,atypical leg pain, multiple nerve root signs, radicular pain and/or intermittent claudicationassociated with other types of pain, multilevel abnormalities on imaging studies,discrepancy between imaging studies and clinical findings, nerve root and/or spineanomalies, failed back syndrome, and intra- and extraforaminal lesions (Hasue & Kikuchi1997). The mechanism of periradicular infiltration may be blocking of afferent impulsesfrom 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 degenerativespondylolisthesis had more therapeutic benefit than those with disc herniation andspondylolytic spondylolisthesis (Kikuchi et al. 1984, Hasue & Kikuchi 1997). Recentuncontrolled studies confirm these observations of a therapeutic effect (Weiner & Fraser1997, Lutz et al. 1998). In HNP induced radiculopathy, there was a 75 % long-termrecovery after on average of 1.8 transforaminal injections per patient of betamethasoneacetate combined with xylocaine. The outcome was better, with symptom duration of lessthan 36 weeks (Lutz et al. 1998). Nerve root injection is also effective in sciatica due tolateral disc herniations, which are difficult to treat by other therapeutic means (Weiner &Fraser 1997). For postoperative radicular pain, however, the technique seems not to havetherapeutic effect, and CT-guided injection seems to be superior to fluoroscope-assistedfor both its visualization and a longer-lasting effect (Lutze et al. 1997). An MRI-guidedprocedure 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 tothat of conservatively treated patients (Nykvist et al. 1989, Atlas et al. 1996), but for mildsymptoms the benefits of surgical and conservative treatments are similar (Atlas et al.1996). Only one RCT compared standard discectomy with conservative therapy (Weber1983). At the 1-year follow-up there were significantly more patients with good or fairresults in the surgery group (90% vs. 61% in non-surgery group), but at the 4- and 10-year follow-ups the results were similar in both groups. During the first year, 26% of thenonsurgery 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(Heliövaara et al. 1987, Deyo et al. 1990, Frymoyer 1992), but even higher figures havebeen obtained (Balague et al. 1999). According to the Mini-Finland survey, 32 % of

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sciatic patients had been in hospital and 21% operated on for a low-back condition(Heliövaara et al. 1989). In 1995, the overall rate of lumbar disc surgery in Finland wasnearly 78 per 100 000 (Keskimäki et al. 2000). The clinician should consider referral to aspecialist for disc herniation surgery when all of the following conditions are met: 1)sciatica is both severe and disabling, 2) symptoms of sciatica persist withoutimprovement or with progression, and 3) there is clinical evidence of nerve rootcompromise (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 interventionprognostic 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 unilateralsymptoms to below the knee that had lasted 3 to 28 weeks. Leg pain had to be at leastcomparable with that of back pain. A positive dural tension sign (limited straight legraising) was not a prerequisite for entry. The exclusion criteria were an earlier backoperation, an application for early retirement, clinical depression anticoagulationtreatment, unstable diabetes, epidural injection during the preceding three months,pregnancy, allergy to any ingredients of the treatment agents, and rare causes of sciaticasuch as synovial cysts and non-degenerative spondylolisthesis. The patients had beenreferred by general practitioners in the catchment area of Oulu University Hospital(population 360 000). The study protocol was approved by the ethics committee of theOulu 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 patientswith the Trp2 allele excluded).

4.2 Evaluation of patients

4.2.1 Demographics and clinical symptoms (I–V)

The self-administered questionnaire items included education, estimation of physicalworkload, mental job stress, days on sick leave (only sick leaves related to the currentsciatic episode), smoking, medical history (including back pain and sciatica) and historyof current episode. Job status of those patients currently employed was characterized by a3-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

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disability with the Oswestry Low Back Disability Questionnaire (Fairbank et al. 1980,Grönblad et al. 1993). The patients also estimated their quality-of-life on the NottinghamHealth 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 analysedfor sequence variations in the human COL9A1, COL9A2 and COL9A3 genes (Annunenet al. 1999, Paassilta et al. 1999, Pihlajamaa et al. 1999, Paassilta et al. 2001). Theanalysis consisted of PCR amplification of all exons and exon boundaries of the genes.The PCR products were subjected to CSGE analysis (Körkkö et al. 1998). Sequencevariations observed in CSGE analysis as heteroduplexes were identified by automatedsequencing (ABI PRISM™ 377 Sequencer and dRhod Dye Terminator Cycle SequencingKit, 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 (I–V)

The clinical examination took place within the week prior to MRI. The straight legraising test of the ipsilateral (SLR) and contralateral legs (crossed SLR) was performed inthe standard way, and the position where back or leg pain prevented further elevation wasrecorded with a goniometer to the nearest 5°. Lumbar flexion was measured by themodified Schober procedure (the difference between a 15-cm distance marked on theback 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 dermatomaldistribution of pain radiation was evaluated as normal: For L4 an area centred on themedial aspect of the lower leg; For L5 an area from the medial aspect of the foot acrossthe dorsum of the foot and onto the lateral aspect of the lower leg; For S1 a band from theposterior sacrum along the entire posterior length of the lower limb and to the lateralaspect of the foot (Keegan & Garret 1948, Bogduk 1997a). Big toe extension weaknesswas 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 andResearch (AHCPR) 1994, Andersson & Deyo 1996).

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4.2.3.2 Magnetic Resonance Imaging (MRI) (I–V)

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 4000msec and echo time (TE) of 95 msec (T2-weighted) and axial images with a TR/TE of640/14 msec (T1-weighted) before and immediately after intravenous injection ofgadolinium-diethylenetriamine pentaacetic acid (0.1 mmol/kg Gd-DTPA, Magnevist,Schering, Berlin, Germany). Frequency-selected fat saturation was used for thepostcontrast axial images. The technical specifications included a slice thickness of 4 mmwith interslice gaps of 1.0 and 0.5 mm, a field of view of 30 and 20 cm for sagittal andaxial images, respectively, and a matrix of 192 by 256/ two excitations (NEX). Allimages were read by two experienced MRI -radiologists blinded to the clinical status ofthe patients. In the case of any discrepancies between the radiologists, a consensus wasreached before the final grading.

Disc displacement was graded as normal (grade 1); bulge (grade 2: a symmetricalextension of the peripheral annulus beyond the margins of the vertebral endplates);contained herniation (grade 3: a focal extrusion of disc material through the annulus butnot through the posterior longitudinal ligament (PLL)); noncontained herniation (grade 4:an extrusion of disc material through the PLL); and sequester (grade 5: a disc fragmentnot in contact with the parent disc). Postcontrast enhancement of the nerve roots wasregarded as positive if there was clear intraneural or perineural enhancement (comparedto the contralateral asymptomatic root) distinct from the rim enhancement around the discherniation. The extent of neural compromise was graded as none, minor (dislocation ofthe nerve root by disc herniation), or major (compression of the nerve root by discherniation 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); andgrade 3 (hypointense nucleus with disc space narrowing) (Stadnik et al. 1998). The end-plates and adjacent bone marrow were evaluated by Modic’s criteria (Modic et al. 1988).Schmorl’s nodes were evaluated from the sagittal scans (Takahashi et al. 1995).Intervertebral disc tears were evaluated from the posterior anulus fibrosus according Yu’scriteria (1989). A radial tear extended as a hyperintense line from the nucleus to the outerpart of anulus fibrosus on T2-sequences, and with Gd-DTPA no enhancement wasobserved. Radial tears were evaluated only from nonherniated discs. A transverse tear waslocated in the outer part of anulus near either end-plate (Stadnik et al. 1998). High-intensity zone (HIZ) lesions were bright spots in the dorsal annulus on T2-weightedsagittal scans (Aprill & Bogduk 1992). The presence of thoracolumbar Scheuermann’sdisease (TLS) was evaluated from the T2-weighted sagittal scans: disc space narrowing,disc dehydration, end-plate irregularities, wedging of anterior vertebral body margins, andSchmorl’s nodes in the thoracolumbar region. Either end-plate irregularities or Schmorl’snodes and two of the other criteria at three or more disc levels from T10-11 to L3-4 had tobe present for thoracolumbar Scheuermann (Heithoff et al. 1994).

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

ENMG was performed on every patient. H-reflexes of the tibialis posterior nerve and F-responses of the peroneus profundus nerve were measured on both sides. Musclescorresponding to root levels LIII-SI (vastus lateralis, tensor fasciae latae, semitendinosus,tibialis anterior, flexor hallucis longus, medial gastrocnemius, short head of bicepsfemori, and gluteus maximus) in the affected leg and paravertebral muscles down tomultifidus were examined. The criteria for myelin damage were asymmetry of F-responseof the peroneus profundus nerve and abnormality of H-reflex of the tibialis posteriornerve, in L5 and S1 nerve root irritation, respectively.

The symptomatic disc of each patient was evaluated in terms of clinical and ENMGfindings. If no abnormalities were thereby detected, the symptomatic disc was evaluatedsolely on the basis of pain distribution (van Akkerveeken 1996). In addition, theneurophysiologist evaluated on the basis of pain drawing and ENMG if the sciatic painexperienced by each patient was radicular or nonradicular. Radicular pain is here definedas 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 preliminaryinformation about the infiltration procedure and the trial. Patients were informed of thetrial option both orally and with a written description of its content and purpose. Wherewritten consent was obtained, patients underwent the investigations and completed thequestionnaires. The randomization process took place immediately before theintervention, and was based on a published list of random permutations (Cohran & Cox1957) with a block size of 16. A person uninvolved in the study placed the assignments insealed 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 theDepartment of Radiology, where an authorized nurse filled a tape-covered syringe withthe 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.) usingconventional technique (Derby et al. 1992) under repeated fluoroscopic screening (C-arm) with a 22- to 25-G spinal needle. For the L4 and L5 roots the needle was advancedobliquely toward the base of the corresponding pedicle. For the S1 root the needle wasaimed 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 identifiedthe 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 volumeof the injection was 2 ml for L4 and L5 blocks and 3 ml for S1 based on anatomicdifferences.

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) S1neurogram.

4.5 Other interventions (IV and V)

Every patient was given back school instructions by the physiotherapist at the 2-weekfollow-up assessment. In cases of persisting sciatic pain, the patients received painmedication and traditional physiotherapy. In the case of severe sciatic pain from discherniation and pronounced disability, the patient was referred to a neurosurgeon fordiscectomy evaluation. Each additional treatment and its cost to the patient weredocumented 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 apaper questionnaire, which was filed separately from the other data. At the follow-upchecks (2 weeks, 1 month, 3 months, 6 months, and 1 year after the intervention) thesame questionnaires as those at the baseline were completed (NHP was not recorded at 2weeks). Usually, the same physician performed the patient’s clinical examinations werethroughout the follow up assessments. The managing physician decided possible futureinterventions and documented the clinical status on separate forms filed with the rest ofthe patient data.

At the 2-week follow-up assessment, the attending physicians were asked to judgewhich of the two interventions had been used. Their determination was correct in 59% ofthe 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 andhelp at home, was based on the responses to the 4-week, 3-month, 6-month and 1-yearfollow-up questionnaires. The cost of the infiltration procedure itself ($200) was notincluded in the saline group. The charge of MRI ($550) was included in the costs for bothgroups. Data on days of sick leave and costs of medication were obtained from theNational Insurance Register. Because of the controversy over human capital and frictioncost analysis, the monetary value of sick leaves was not assessed (Hutubessy et al. 1999).All additional treatments and visits to physiotherapists, osteopaths and physicians wereestimated from the data entered on the questionnaires and from medical records. For thecosts of physician and physiotherapist visits, the charges of the University Hospital wereused ($55 for a physician visit and $38 for a physiotherapist visit). Data on backoperations were gathered from the questionnaires and from medical records. The cost of adiscectomy at the University Hospital ($3215) includes three inpatient postoperativedays, with additional days costing $205. Home help was defined as help from thepatient’s spouse, children, relatives or friends. The monetary value of 1 hour of homehelp was taken as the hourly wage of a munipical home helper ($9). Dollar costs werecalculated at the 1998 exchange rate ($1=5.096 Finnish marks).

4.8 Statistical analysis

4.8.1 Calculation of sample size (I–V)

Preliminary calculations showed a need for 68 patients in both (steroid and saline)treatment groups (α=0.90, two-sided β=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%. Afteradjusting for a 20 % loss to follow-up evaluation, 80 persons were enrolled for bothgroups.

4.8.2 Reliability of MRI findings (I–V)

Kappa statistics were used to establish interobserver (reader 1 vs. reader 2) andintraobserver (reader 1 vs. reread of reader 1) reliabilities of the various MRI findings(Altman 1991). Interobserver and intraobserver kappa values for the various MRIfindings showed mostly moderate to substantial agreement (I, table 1). The interobserverkappa 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 Spearmancorrelation analysis. The significances were tested with the Pearson chi-square andFisher’s exact test (2x2 tables) for nominal and ordinal variables or with Student’s t-testand Kruskal-Wallis ANOVA (depending on the skewness of the variable in question) forquantitative 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 roottransfomation 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 wereanalyzed by the presence of the Trp2 allele and the significancies were tested with thechi-square or Fisher’s exact test (2x2 tables) for nominal and ordinal variables, and theStudent’s t-test or Kruskal-Wallis test for quantitative variables. Three controls of similarage and occupation, and from the same gender were selected for each of the patients withthe Trp2 allele. MRI findings of the patients with the Trp2 allele and their controls, andfamily members with and without the Trp2 allele were investigated by contingency tablesand chi-square or Fisher’s exact test.

47

The presence of TLS was analyzed by presence of the Trp3 allele, and the statisticalsignificance evaluated with Fisher’s exact test. Logistic regression analysis wasperformed to clarify the determinants of TLS; these included the Trp3 allele, gender, age,duration of symptoms, occupational load, sciatic and back pain history, smoking, bodymass index and height.

Demographic variables, symptoms and clinical signs of the patients with sciatica wereanalyzed by presence of the Trp3 allele, and the significances were tested with thePearson chi-square or Fisher’s exact test (2x2 tables) for nominal and ordinal variablesand the Student’s t-test or Kruskal-Wallis test for quantitative variables.

In the evaluation of intervertebral disc degeneration, end-plate degeneration, dorsaltransverse tears, high-intensity zone lesions, and Schmorl’s nodes by Trp3 allele presence,for each of the Trp3 allele positive patients, a control matched for age, gender andoccupation was selected from the patients without the allele. Matched pair analysis waswarranted 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 yearsfor 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 mixedjob vs. physical job). For the statistical analyses, end-plates were graded as normal ordegenerated. The statistical significance of the differences in the MRI findings betweenpatients with the Trp3 allele and their matched controls was investigated by the marginalhomogeneity test (extension of the McNemar test) for intervertebral disc degenerationand by the McNemar test for the other MRI findings. P-values less than 0.05 wereconsidered 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 inscores for the different outcomes between adjacent follow-up assessments and baselinewere calculated with 95% confidence intervals. Treatment effects were determined byreducing the adjusted scores of the saline group from those of the methylprednisolonegroup. Additionally, the percentage of painless patients (=responders, ≥75% decrease ofleg pain from the baseline scores) for both methylprednisolone-bupivacaine and salinegroups were evaluated at every follow-up assessment. Operated patients were alwaysregarded as nonresponders. The statistical significance of difference was evaluated withFisher’s exact test. Repeated measures analysis of variance was used for the estimation ofwithin-groups changes over time. Between-groups treatment difference over time(efficacy) was analyzed with the AUC-method (Altman 1991). The AUC-scores wereadjusted, in addition to symptomatic disc level and days of sick leave before theintervention, with the baseline value of the respective outcome (except for medical costs)and duration of symptoms. The AUC-scores of selected outcomes were calculatedseparately from baseline to 3 months, and from 3 months to 1 year. The AUC-scores fordifferent 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 12months 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 Student’s t-test.

4.8.6 Subgroup analysis (V)

The efficacy and cost-effectiveness were evaluated with respect to the duration ofsymptoms, age, the symptomatic disc level, and the MRI classification. For MRIclassification, noncontained herniations and sequesters were combined as extrusions. Ageof patients did not have any significant effect on the treatment differences. Duration ofsymptoms modified the total costs at 6 months so that the patients with shorter symptomduration (≤ 2 months) before the intervention had greater monetary savings with thesteroid injection. Therefore the AUC-scores for medical costs have been adjusted also forsymptom duration. The rate of operations in different subgroups was evaluated byKaplan-Meier curves and log-rank tests (Altman 1991). P-values less than 0.05 wereconsidered statistically significant. For the statistical analysis, SPSS version 8.0 (SPSSCorp., 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 1997to May 1998. Of the 171 eligible patients, 8 refused to take participate. None specifiedthe 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 studypopulation (160 patients), 97 were men and 63 women. The mean age of the patients was43.7 years (range 19–78 years), and the mean duration of symptoms 2.5 months. Theirclinical signs and symptoms are presented in Table 1.

Five patients had L4, 89 had L5, and 66 had S1 radiculopathy. MRI identified a discherniation corresponding to the symptoms in 131 (82 %) patients, as well as nerve rootenhancement in 3 patients with a non-herniated symptomatic disc. The degree of discdisplacement 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 toreceive periradicular infiltration either with methylprednisolone-bupivacaine or saline.*

Characteristic Methylprednisolone-bupivacaine

(n = 80)

Saline

(n = 80)

Total

(n = 160)Age (year) 43.8±13 43.7±13 43.7±13Male gender (%) 64 58 61High school graduates (%) 15 16 16Work-related features

Employed (%) 73 78 75Retired (%) 11 11 11Others (unemployed, students) 16 11 14

Duration of sciatica (months) 2.4±1.5 2.6±1.5 2.5±1.5First or second episode of sciatica (%) 59 47 53Level affected on MRI (%)

L3-L4 3 5 4L4-L5 61 40 51L5-S1 36 55 45

MRI-classification of the symptomatic disc (%)Bulge or normal 22 14 18Contained herniation 30 32 31Extrusion 48 54 51

Leg pain intensity (100-mm VAS) 71 ± 18 75 ± 19 73 ± 18Back pain intensity (100-mm VAS) 53 ± 25 60 ± 25 56 ± 25Oswestry score (%) 43 ± 16 44 ± 15 43 ± 15Nottingham Health Profile§

Dimension of energy 21 ± 28 17 ± 25 19 ± 27Dimension of emotional reactions 11 ± 15 10 ± 13 10 ± 14Dimension of sleep 28 ± 32 31 ± 31 29 ± 31Dimension of pain 66 ± 26 72 ± 25 69 ± 26Dimension of mobility 33 ± 19 34 ± 17 34 ± 18Dimension of social isolation 4 ± 9 2 ± 8 3 ± 8

Mean duration of sick leave (days) 14 ± 18 22 ± 26 18 ± 23Physical measures

Straight leg raising test (°) 58 ± 18 60 ± 19 59 ± 19Lumbar flexion (cm)¶ 4.8±1.5 4.9±1.5 4.8±1.5

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 health-related 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 notassociated 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 MRIclassification (Figure 4). The results were similar when patients with non-radicular painradiation into the leg were excluded; only associations with SLR and neural enhancementwere weaker. The associations of root level, nerve root enhancement by Gd-DTPA, anddegree of neural compromise were also analyzed with the symptoms of sciatica. Therewere 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 thesymptoms (Spearman coefficients 0.19–0.27). The correlations for lumbar flexion weresimilar, but weaker. Analyzed by stepwise regression analysis with SLR restriction as theoutcome, MRI classification of non-herniations versus herniations explained 20.4% of thevariance in SLR restriction. MRI classification did not explain any of the variance in theOswestry index, or back pain.

Fig. 4. Boxplots comparing low-back specific disability measured by Oswestry Index (upperscale) and straight leg raising (SLR, lower scale, shaded boxes) with MRI classification. Notethat disability is not associated with the degree of disc displacement, whereas SLR is. Theboxplots 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 sciaticpatients (prevalences 4 % and 22 %, respectively). Two of the Trp3 positive patients werehomozygous 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 alleledid not differ from the other 153 sciatic patients, except that they had significantly moreoften sedentary job (p < 0.05; Table 2). Patients with the Trp3 allele had generally highereducation (chi-square p < 0.05), but otherwise they did not differ from the patientswithout 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. 2.4months, 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. Means±SD shown unless otherwisestated.

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

Characteristic Trp2 allele +(n=6)

Trp3 allele +(n=34)

Negatives(n=119)

Age (years) 45 ± 13 43 ± 13 44±13

Symptom duration (months) 2.9 ± 1.7 3.0 ± 1.8 (p<0.05) 2.4±1.3

Height (cm) 175 ± 6 172 ± 8 171±9

Female (%) 0 41 41

Primary school or less (%) 17 21 (p<0.05) 41

Sedentary job (%)† 80 (p<0.05) 35 38

Sciatica >6 mo/last year (%) 17 15 8

Recurrent sciatica (%)‡ 0 18 18

Back pain (100-mm VAS) 40 ± 29 57 ± 23 57±26

Leg pain (100-mm VAS) 73 ± 8 72 ± 17 73±19

Disability Index (Oswestry%) 33 ± 12 39 ± 14 45±15

Lumbar flexion (cm) 5.9 ± 1.1 (p<0.05) 5.0 ± 1.9 4.8±1.4

Straight leg raising test (°) 70 ± 15 60 ± 20 58±18

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

53

significantly from the other sciatic patients. Likewise, patients with the Trp3 allele did notdiffer from the other sciatic patients on the basis of clinical symptoms and findings (Table2). Both two patients homozygous for the allele were male (39 and 50 years of age). Theclinical symptoms and findings of the homozygous did not differ significantly from thoseheterozygous for the allele.

5.3.2 MRI findings

With respect to the Trp2 allele, no significant differences were detected in intervertebraldisc degeneration, end-plate degeneration, Schmorl’s nodes, dorsal transverse tears andHIZ lesions at any lumbar level. Three of the patients (3 of 6) with the Trp2 allele hadradial rupture in nonherniated disc at the L4-5 level, but not at other levels. The controlshad no radial ruptures in nonherniated discs (0 of 18). The difference at the L4-5 level didnot, however, reach statistical significance (p = 0.055). Two of the three patients with aradial tear in nonherniated disc had also oedema in the symptomatic nerve root. Familymembers with the Trp2 allele were slightly (but not significantly) older than memberswithout the Trp allele. They had significantly more intervertebral disc and end-platedegeneration 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 memberswith the Trp2 allele (3 of 11) had a radial tear in a nonherniated disc, and none of thefamily members without the Trp2 allele (0 of 11). Two of the family members with aradial tear at the L4-5 level, were symptomatic at the time of the investigation. The thirdfamily 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 nodifferences in end-plate degeneration, dorsal transverse tears, or HIZ-lesions. Patientswith the Trp3 allele had, however, significantly more disc degeneration at the L4-5 levelcompared to the matched controls (P = 0.007). Disc degeneration at the other levels wassimilar in both groups. The number of Schmorl’s nodes tended to be higher at the L1-2level in the Trp3 allele positive patients (5 of 34 vs. 0 of 34; P = 0.06).

5.3.3 Thoracolumbar Scheuermann’s disease (TLS)

Fifteen of 34 (44%) patients with the Trp3 allele were positive for TLS compared to 23 of119 (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 thisdifference was not statistically significant. Other determinants significantly associatedwith 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 thepresence of TLS contained three significant determinants: male sex (OR 4.7; 95% CI,1.8–12.2; p<0.001), the Trp3 allele (OR 4.7; 95% CI, 1.8–12.1; p=0.001) and physical job(OR 7.1; 95% CI, 2.1–23.6; 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 theheterozygous patients (Figure 5).

Table 3. Significant determinants of thoracolumbar Scheuermann’s disease in MRIanalyzed by stepwise logistic regression analysis. Odds ratios (OR) with 95% ConfidenceIntervals (CI) and p-values presented.

Characteristic OR (95% CI) P-values to remove

Gender

Female (reference) 1.0

Male 4.7 (1.8–12.2) <0.001

Trp3 allele

Negative (reference) 1.0

positive 4.7 (1.8–12.1) 0.001

Occupational load

Sedentary job (reference) 1.0

Mixed job 2.7 (1.0–7.5)

Physical job 7.1 (2.1–23.6) 0.04

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

55

Fig. 5. Magnetic resonance imaging scans of a 50-year old storeman with right-sided sciatica for1.5 months. He is homozygous for the Trp3 allele. Left, T1-weighted sagittal scan, right, T2-weighted sagittal scan. Schmorl’s nodes at the L1-2, L2-3, L3-4 and L4-5 levels. Grade 3 discdegeneration at the L1-2, L2-3 and L4-5 levels. Contained herniation at the L4-5 level. He hasthoracolumbar Scheuermann’s disease with multiple Schmorl’s nodes and disc degeneration inthe 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 receivedmethylprednisolone-bupivacaine injection. The affected level on MRI was more often theL4-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 salinegroup (p = 0.03), although number of patients on sick leave was similar between thegroups. These differences were considered clinically important confounders, and thescores of the treatment effects were adjusted accordingly. For the days on sick leave, a

56

categorical staging was used: 0 days, 1–30 days and over 30 days. For disc level, the L3-L4 discs were combined with the L4-L5 discs.

In each treatment group, follow-up information was obtained at 2 weeks for 79patients, 4 weeks for 80 patients and 3 months for 79 patients. At the 6-month and 1-yearfollow-up assessments, information was obtained for 99% of the patients (n=158). Twodrop-outs occurred in the steroid group: One patient moved away and the other lived inthe remote countryside. A retroperitoneal hematoma developed in one patient onanticoagulant therapy as a complication of the injection (steroid group). The extra costs ofthe complication were not included in the economic analysis, and no furthercomplications were encountered.

Information on the immediate effects of the intervention on leg and back pain wasobtained for 78 patients in the saline group and 79 patients in the methylprednisolone-bupivacaine 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 inleg pain was significantly better in the steroid group (11.9; 95% CI, 2.0–21.8; 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 significantimprovement from baseline was observed in every outcome parameter except lumbarflexion (within-group data not shown). There was a significant between-group treatmenteffect 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 % inthe steroid group (Figure 6A, p < 0.01). Patient satisfaction also was significantly greaterin the steroid group (12.1; 95% CI, 1.2–23; p = 0.03). At the 4-week follow-up, there wasno significant between-group treatment differences in favor of either treatment. At the 3-month follow-up assessment, a significant treatment effect in favor of the saline treatmentfor back pain was observed, whereas at 6 months, the treatment effects for both leg painand 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 onaverage by 65% in both groups. No differences between the two treatments in the AUC-scores of evaluated outcomes were found.

Table 4. Betw

een-groups treatment differences follow

ing periradicular infiltration with steroid or saline in the w

hole study population(total), and in subgroups of contained herniations, extrusions and disc levels L

3–4–5. Positive treatment difference values indicate that the

steroid treatment w

as superior to saline.§

Characteristic

MR

I-classification †D

isc levelTotal

Contained herniations

ExtrusionsL3–4/L4–5

Difference (95%

CI)

pD

ifference (95% C

I)p

Difference (95%

CI)

pD

ifference (95% C

I)p

Two w

eeks

Leg pain (100-mm

VAS)

24 (8 to 41)0.006

11 (–5 to 26)N

S 25 (10 to 40)

0.002 13 (2 to 23)

0.02

Disability (O

swestry %

) 8 (–0.3 to 16)

NS

8 (–0.4 to 16)N

S 10 (2 to 17)

0.009 5 (–0.3 to 10)

NS

Straight leg raising (º) 7 (–1 to 16)

NS

6 (–3 to 15)N

S 9 (0.3 to 18)

0.043 6 (1 to 12)

0.03

Four weeks

Leg pain (100-mm

VAS)

19 (3 to 36)0.023

6 (–10 to 22)N

S 20 (5 to 35)

0.008 2 (–9 to 13)

NS

Disability (O

swestry %

) 3 (–5 to 10)

NS

9 (–0.4 to 18)N

S 9 (1 to 17)

0.027 2 (–4 to 7)

NS

NH

P pain 13 (–9 to 35)

NS

6 (–10 to 21)N

S 13 (–3 to 29)

NS

–1 (–12 to 11)N

S

NH

P emotional reactions

5 (–6 to 16)N

S 5 (–5 to 14)

NS

7 (–2 to 16)N

S 2 (–4 to 8)

NS

Straight leg raising (º) 9 (–2 to 19)

NS

5 (–5 to 14)N

S 8 (4 to 22)

0.006 5 (–1 to 11)

NS

Three months

Leg pain (100-mm

VAS)

1 (–20 to 23)N

S–3 (–19 to 12)

NS

3 (–14 to 19)N

S–1 (–12 to 11)

NS

Disability (O

swestry %

)–2 (–13 to 9)

NS

3 (–8 to 14)N

S 3 (–7 to 13)

NS

–1 (–9 to 6)N

S

NH

P pain–5 (–27 to 17)

NS

0 (–18 to 17)N

S 0 (–19 to 19)

NS

–5 (–18 to 7)N

S

NH

P emotional reactions

13 (4 to 23)0.008

–2 (–9 to 5)N

S 5 (–0.6 to 14)

NS

3 (–2 to 8)N

S

Straight leg raising (º) –2 (–12 to 10)

NS

3 (–8 to 13)N

S 6 (–4 to 15)

NS

2 (–5 to 9)N

S

Six months

Leg pain (100-mm

VAS)

–23 (–40 to –5)0.014

–17 (–32 to –1)0.033

–8 (–23 to 6)N

S–16 (–27 to –6)

0.003

Disability (O

swestry %

)–14 (–24 to –3)

0.01–1 (–11 to 9)

NS

–2 (–10 to 7)N

S–6 (–12 to 1)

NS

NH

P pain–22 (–43 to –0.3)

0.047–8 (–25 to 9)

NS

–7 (–23 to 9)N

S–12 (–24 to 0.03)

NS

57

Table 4. Continued.

MR

I-classification †D

isc levelTotal

Contained herniations

ExtrusionsL3–4/L4–5

DifferLence (95%

CI)

pD

ifference (95% C

I)p

Difference (95%

CI)

pD

ifference (95% C

I)p

NH

P emotional reactions

–3 (–13 to 7)N

S 3 (–5 to 10)

NS

3 (–4 to 10)N

S–2 (–7 to 3)

NS

Straight leg raising (º)–9 (–21 to 3)

NS

–1 (–11 to 8)N

S 1 (–9 to 10)

NS

–2 (–9 to 5)N

S

One year

Leg pain (100-mm

VAS)

0 (–16 to 16)N

S–8 (–22 to 7)

NS

7 (–7 to 20)N

S–5 (–16 to 5)

NS

Disability (O

swestry %

)–1 (–12 to 9)

NS

4 (–6 to 13)N

S 4 (–4 to 13)

NS

0 (–7 to 6)N

S

NH

P pain 0 (–22 to 22)

NS

–5 (–21 to 11)N

S–1 (–17 to 15)

NS

–4 (–16 to 8)N

S

NH

P emotional reactions

–3 (–13 to 7)N

S 3 (–5 to 10)

NS

2 (–4 to 8)N

S–2 (–7 to 4)

NS

Straight leg raising (º) 4 (–7 to 16)

NS

–1 (–10 to 8)N

S 7 (–2 to 16)

NS

5 (–2 to 11)N

S

§ Num

bers of patients at the 2-week, 4-w

eek, 3-month, 6-m

onth and 1-year follow-ups w

ere 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 com

bined L3–4 & L4–5 levels.

†The betw

een-group mean values of present the difference betw

een the adjusted change from baseline in the m

ethylprednisolone–bupivacaine and saline groups (95% C

I andp-values are also presented). The values are adjusted to the level of the sym

ptomatic disc and days on sick leave before the intervention.

VAS = visual analog scale, M

RI = m

agnetic resonance imaging, C

I = confidence interval, NH

P = Nottingham

Health Profile, N

S = not significant.

58

59

Fig. 6. Leg pain (mm on VAS, standard deviations indicated with vertical bars) at baseline andat each follow-up assessment after the nerve root infiltration with either methylprednisolone–bupivacaine ( • ) or saline (— • —). The upper box presents the number of patients at eachfollow-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 respectivefollow-up <0.05, **p<0.01.

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252525262626242424242324

522612420

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(mm

)

Follow-up time (weeks)

60

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 thetreatments in the AUC-scores of evaluated outcomes or number of painless patients wereobserved.

5.5.1 Contained herniations vs. extrusions

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

0

10

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30

40

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*

Extrusions

SteroidSaline

424243434343383837383838

522612420

Leg

pain

(mm

)

Follow-up time (weeks)

61

5.5.2 Disc level

For symptomatic lesions situated at the L3-4-5 levels, the steroid treatment was superiorto 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 ofpainless patients at 4 weeks favored significantly the steroid option (P<0.05 for both).The treatment difference in NHP emotional reactions almost reached statisticalsignificance in favor of the steroid group. At the L5-S1 level, between-group treatmentdifference 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 weresimilar.

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

After adjustment for baseline differences and duration of symptoms, the total costs duringthe 1 year follow-up period did not differ between the two treatment groups. At the 4-week follow-up assessment, therapy visits (physiotherapists and osteopaths; P<0.05) anddrug cost (P = 0.005) were significantly less in the methylprednisolone group. From the4-week follow-up onward, no significant cost differences between the treatmentsemerged at any time point. At 1 year, the mean cumulative cost per patient was $2195(95% CI 1729–2661) in the steroid group and $2180 (95% CI 1694–2666) in the salinegroup. No differences in cost-effectiveness between the treatments were observed. After1 month only, one patient in the saline group underwent surgery, and by 1 year 18 patientsin 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 leaveswere observed. Cost-effectiveness of the treatments was likewise similar: to obtain onepainless 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 forhomecare ($200 per patient; 95% CI, $46 to $355, P = 0.013) at 4 weeks and for totalcosts at 6 months ($1795; 95% CI, $1069 to $2521, P < 0.001). Medical costs at eachfollow-up are presented in Figure 7A. By 1 year, 42 % of patients were operated in thesaline group vs. 20 % in the steroid group (p = 0.1). When the rate of operations wasevaluated by Kaplan-Meier curves and log-rank tests, p-value of 0.1 was obtained (Figure8). Because of the different operation rate, days on sick leave by 6 months (7.4 days permonth per patient; 95% CI, 2.3–12.5 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. TheAUC-scores of medical costs from 3 to 12 months were also in favor of the steroidtreatment (p < 0.001) in accordance with the other data.

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No significant short-term differences were observed in cost-effectiveness, but by 12months 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*.

5.6.2 Extrusions

For extrusions, cost of therapy visits at 4 weeks was significantly less with the steroidinjection ($182; 95% CI, $79 to $285, P = 0.001). Medical costs at each follow-upassessment are presented in Figure 7B. By 1 year, 13 % underwent surgery in the salinegroup vs. 32 % in the steroid group (chi-square value 3.9, df 1, p = 0.05). By Kaplan-Meier analysis, p-value was 0.1 (Figure 8). Because of the higher operation rate in thesteroid group, the area-under-the-curve scores of medical costs from 3 to 12 months weresignificantly (P = 0.004) in favor of saline, whereas for cumulative costs at 12 monts onlya trend (P = 0.08) in favor of saline existed. No significant differences in sick leaves wereobserved.

No significant short-term differences were observed in cost-effectiveness, but by 12months the steroid treatment was more expensive: $4445 more per one painless patient(P<0.01; Table 5).

Timepoint Bulges Contained herniations Extrusions

Steroid Saline p Steroid Saline p Steroid Saline p

Three months 2640 2116 NS 5850 6360 NS 4081 2230 NS

Twelvemonths

3740 3629 NS 4432 17098 0.0073 7165 2484 0.0058

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

63

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

500

1000

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**

Contained herniations

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ical

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ts ($

)

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42424343433838373838

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ical

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ts (%

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64

Fig. 8. Kaplan-Meier curves for the number of operated patients versus time of operation inweeks 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 withrespect to need for homecare at the L3–4–5 level ($120; 95% CI, $31 to $209, P = 0.01).No significant differences with respect to cumulative medical costs, rate of operations orwork absenteism or cost-effectiveness were observed between the treatments.

0 10 20 30 40 500

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ted

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nts

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6 Discussion

6.1 Study population

In order to obtain a homogenous study population and avoid chronicity, the inclusioncriteria included dermatomal unilateral pain below the knee (dermatomes LIV to SI) withsymptom duration from 3 to 28 weeks. Depressed patients and those applying for earlyretirement were excluded, because it was anticipitated that their treatment responsescould be confounded. Patients who had undergone back surgery were excluded for thesame reason. The physicians working in the University Hospital catchment area werethoroughly informed about the trial and most of the patients were referred directly fromprimary care, which means that the findings of these studies can be generalized to anunoperated sciatic population with a limited symptom duration. The final studypopulation was in fact similar to other sciatic populations with respect to age and gender(Jönsson & Strömqvist 1993, Carette et al. 1997). Selection bias was probablyinsignificant because consecutive eligible patients were enrolled, and of the eligiblepatients only 8 refused to take part in the study. The recruitment of 160 patients wasbased on power calculations with an assumption of 15 % clinical effect and 10 % drop-out rate. Only two patients were lost during the follow-up period, which means that thetreatment effects could be calculated reliably. However, even this study population wasnot large enough to reliably characterize the phenotype of the Trp2 allele. The studypopulation was, however, comparatively homogenous. Most of the patients hadexperienced a disc herniation, and the mean disability and leg pain scores indicated asevere 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 discdisplacement and clinical signs and symptoms would not have been obtained.

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6.2 Methods

In this study, sciatic patients were characterized using validated questionnaires (VAS,Oswestry, NHP), clinical examination, ENMG and MRI. Clinical examinations andENMG at baseline were performed by experienced physicians. The patient’s clinicalexaminations during the follow-up period were usually performed by one and the samephysician, who was familiar with the study protocol. Sequence variations in the humanCOL9A1, COL9A2 and COL9A3 genes were analysed with advanced methods in anexperienced laboratory (Körkkö et al. 1998).

The MRI scans were obtained with a high-resolution 1.5-T imaging system and readby two experienced radiologists blinded to the patients’ clinical status. The intertester andintratester reliabilities were moderate to substantial. The most common disagreement inthe degree of disc displacement was for contained herniation versus noncontainedherniation, but in study I the scores in these subgroups were similar (whereas theydiffered significantly in study V) . The major weakness in our MRI protocol was the lackof proton density-weighted sagittal images, which visualize well the disruption of theposterior longitudinal ligament. However, contrast-enhancement compensated somewhatfor this shortcoming. The periradicular infiltrations were performed by an experiencedradiologist using a conventional technique (Derby et al. 1992). Only one complicationwas encountered during the trial.

Randomization (studies IV and V) was done with random number tables, and resultedin only minor imbalances in baseline characteristics between the treatment groups.Adjustments were made for these imbalances in the multivariate analyses. One importantcomponent 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 patientreceived the treatment immediately after randomization, and no further interventions wereundertaken. In addition, cointerventions, including booster injections, were avoided tooptimize the treatment standardization. The study was conducted in a double-blindmanner. Patients were not asked to guess the treatment they received, but the responses ofthe 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 treatmentof the patients after the injection. In conclusion, the current RCT fulfilled all three majorrequirements (comparability of groups, observer blinding, and intention-to-treat analysis)requested of an intervention prognostic study (Vroomen et al. 2000). Subgroup analysisof intention-to-treat studies is controversial. It has been stated that it is essential toidentify homogenous groups of low back pain patients, and that the efficacy ofinterventions in these subgroups should be studied in randomized controlled trials (Bouteret al 1998). However, subdividing sciatic patients into homogenous strata has thedisadvantage of poorer generalizability of results to heterogenous populations (Bloch1987).

One problem in comparing studies on sciatica and low back pain is the diversity ofoutcome measures. There is an urgent need to standardize outcome measures and includehealth-related quality-of-life (HRQOL) measures in economic assessment studies (Deyoet 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) isbasically a ratio, where changes in health due to an intervention are captured in thedenominator 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-effectivenessestimate 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 interms of the severity of their symptoms, in contrast to results of some earlier studies(Thelander et al. 1994, Jönssön & Strömqvist 1996). This suggests that pain mechanismsother than the extent of disc herniation in MRI generate the subjective symptoms, andaccords with the results of Modic et al. (1995), who showed that patients with or withoutdisc herniation had similar disability. The lack of association between imaging andclinical findings was also observed in the study of Balague and co-workers (1999). Ourresult is further supported by the high prevalence of false-positive MRI findings amongasymptomatic subjects (Boden et al. 1990, Jensen et al. 1994).

In a study population including symptomatics and asymptomatics, herniations were ascommon in both groups (Boos et al. 1995). The best predictor of symptoms was theextent of neural compromise. In the present study, neural compromise was not associatedwith the symptoms, but most of the patients had major neural compromise. Straight legraising restriction was a good measure of nerve root entrapment, but it could notdifferentiate the subclasses of disc herniations. The association of SLR restriction anddisability has also been observed by others (Thelander et al. 1992, Jönsson & Strömqvist1995).

These findings are similar to those of a study in which patients with painful discdisruption but without deformation of the outer anular wall had similar leg pain topatients 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 bepresent, even when MRI findings are minor; and vice versa, prominent MRI findings maynot 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 mutationthat is strongly associated with intervertebral disc disease (Annunen et al. 1999). Patientswith the Trp2 allele were significantly more flexible than patients without the allele,which may be related to altered interactions between collagen IX and other matrixmolecules. 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 theTrp2 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 theintervertebral joint complex (Osti et al. 1990). Anular tears can be classified intoconcentric, transverse and radial tears, of which MRI can demonstrate the transverse andradial tears (Yu et al. 1988b). HIZ-lesions, on the other hand, represent a combination ofradial and circumferential tears (Aprill & Bogduk 1992). Radial ruptures are interestingas they precede disc degeneration (Yu et al. 1988a, Osti et al. 1992), and are associatedwith subjective pain in discography (Moneta et al. 1994). Radial tears are also known tocause sciatic pain (Ohnmeiss et al. 1997). In the current study, patients with the Trp2allele were mostly in sedentary jobs and relatively young, yet three of them, and none ofthe other patients, had a radial tear in a nonherniated disc in MRI. Moreover, two of themhad 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 thosewithout it, had a radial tear. The occurrence of radial ruptures at the most mobile lumbardisc, i.e. the L4-5 level, may relate to mechanical factors. In accordance, intervertebraldisc 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 Trp2allele. Indeed, histological analysis of post-mortem lumbar spines has indicated thattransverse 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 tointervertebral disc degeneration, but the patients (and their controls) had mostly sedentarywork. A hard physical job, and, particulararly frequent lifting and postural stress, increasethe risk of sciatica (Heliövaara 1989, Riihimäki et al. 1989), whereas a sedentary job maydecrease the risk of both sciatica (Riihimäki et al. 1994) and intervertebral discdegeneration (Battie et al. 1995). Interestingly, family members with the Trp2 allele hadsignificantly more disc degeneration at the L5-S1 level than those without the amino acidsubstitution. They were, however, slightly older and there might also exist somedifference 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 bydiscography with a larger patient population. Recently, a German population of patientsoperated for an intervertebral disc herniation was screened for the presence of the Trp2allele (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 radiologicphenotype was not characterized. The role of collagen IX in intervertebral disc disease issupported by the findings in transgenic mice expressing mutant α1(IX) chain: there wasaccelerated intervertebral disc degeneration with partial disruption of end-plates andfissures 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 insciatic 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 andclinical characteristics were similar in patients with or without the allele. These and ourprevious findings emphasise the importance of collagen IX for end-plate andintervertebral disc integrity (Annunen et al. 1999, Paassilta et al. 2001).

Scheuermann’s disease already presents typically as rigid kyphosis of the thoracic orthoracolumbar spine in adolescence (Lowe 1999). The association of the Trp3 allele withTLS 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 underestimatedthrough being missed or attributed to poor posture (Lowe 1999). A Danish study amongpatients with low back pain found considerably higher prevalences of both high(=thoracic; 28%) and low (=thoracolumbar; 26%) Scheuermann’s disease (Lings &Mikkelsen 1982).

TLS may also associate with lower lumbar discogenic disease. In one study 9 % of1419 patients with TLS also had lower lumbar disc disease, and since 81 % were under 40years and 9 % younger than 21 years, the authors proposed the term “juvenile discogenicdisease” (Heithoff et al. 1994). The association of the two diseases and the early onsetalso led them to suggest that an intrinsic defect of the disc and/or end-plate, principally inproteoglycan or collagen, could be responsible for the structural weakness (Heithoff et al.1994). The co-occurrence of Scheuermann-type changes with discogenic disease is alsosupported by findings from a Finnish long-term follow-up study. Children andadolescents with intervertebral disc degeneration and Scheuermann’s disease had anincreased risk of recurrent low back pain at this age, and also a long-term risk of recurrentpain 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 moreoften in sciatic patients with the Trp3 allele (44 %) than without it (19 %) emphasises theimportance of genetic factors. Further support comes from reports suggesting that TLS isinherited autosomally dominantly with incomplete penetrance and variable expression(Lowe 1999). In addition, histologic findings suggest that abnormal collagen matrix maybe an aetiologic factor in the disease (Aufdermaur 1981). The importance of intactcollagen IX for the development of TLS is also highlighted by the present finding thatboth individuals who were homozygous for the allele had the disease. Moreover, thefinding that collagen IX defect is associated with TLS accords with the the presence ofthe 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, maypredispose to recurrent low back pain problems. The role of other risk factors is supportedby findings that TLS is associated with repetitive trauma, and tends to occur primarily inadolescent boys engaged in heavy physical activity (Lowe 1999).

Patients with the Trp3 allele had significantly more disc degeneration on T2-weightedscans at the L4-5 level than those without the allele. Intervertebral disc degeneration hasmultifactorial aetiology (Battie et al. 1995). Among identical twins disc degeneration maybe explained primarily by genetic influences and unidentified factors, which may includecomplex, unpredictable interactions (Battie et al. 1995). Involvement of genetic factors inintervertebral 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 steroidwith that of saline for unilateral discogenic sciatica. The findings of the study indicatethat both treatments had already induced clinical improvements at the 2-week follow-up.Periradicular infiltration with a combination of methylprednisolone and bupivacaine wassuperior to saline injection for leg pain, straight leg raising and lumbar flexion (inaddition to patient satisfaction) according to findings at 2 weeks, but not at later follow-up assessments. The saline injection was more effective for back pain at the 3- and 6-month follow up assessments, and for leg pain as shown at 6 months. The economicanalysis showed that the methylprednisolone treatment had produced savings in costs oftherapy visits and medications at 4 weeks, but other uses of resources and their respectivecosts and mean duration of sick leave were more or less equal in the two groupsthroughout the follow-up period. The total number of operations did not differsignificantly between the treatment groups. The 21 % overall rate of operations wassimilar 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 forsciatica (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 & Silagy1995, Vroomen et al. 2000). Basically, epidural steroids could be effective in sciaticabecause a rapid direct transport from the epidural space to the axons of the spinal nervesin pigs was observed following application of Evans-blue-labelled albumin (Byröd et al1995). It has been found, however, that even in experienced hands up to 25 % of epiduralneedle placements may be incorrect (White 1983), and additionally, there is a possibilitythat epidural corticosteroids might be effective in a subgroup that is overlooked becauseof heterogeneity in the study populations, follow-up times and intervention methods(Weinstein et al. 1995).

Periradicular injections have been recommended, but unfortunately only twouncontrolled prospective series have been published (Weiner & Fraser 1997, Lutz et al.1998). Both studies suggest that such injections might have a beneficial effect ondiscogenic sciatic pain. Recently, multiple periradicular infiltrations with eitherbupivacaine or a combination of bupivacaine and betamethasone were compared (Riew etal. 2000). The combination of steroid and anaesthetic significantly reduced the need foroperative treatment during the follow-up period (13 to 28 months). Eight patients of 28 inthe steroid surgery underwent surgery compared to 18 of 27 in the bupivacaine group.

Periradicular injection of a corticosteroid anaesthetic combination was found to haveonly a short-term, but clinically meaningful, effect compared with saline injection. Thiswas a single-injection study, and repeated injections could possibly produce a more

71

sustainable effect. Decisive clinical improvement had already occurred in both treatmentgroups at 2 weeks. Interestingly, in a rat model, thermal hyperalgesia was abated withepidural 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 NO-mediated cascade. However, the data as such does not allow any inference that salineinjection 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 treatmentwas most pronounced for contained herniations and symptomatic lesions situated at theL4–5 (or L3–4) disc level. Patients with a contained herniation were less likely toundergo back surgery when receiving the steroid treatment and they also had significantlyfewer days on sick leave from 3 to 6 months. Counter-effectiveness of the steroidtreatment was most pronounced for extrusions, where the steroid injection generatedsignificantly higher medical costs and a greater likelihood of surgery. The authors are notaware of any other studies where the response to epidural or periradicular epiduralsteroids was analyzed according to the type of disc displacement.

Outcome measures in low back research can be divided into disease-specific andgeneric functional status, or quality-of-life questionnaires (Deyo et al. 1994). The short-term efficacy of the methylprednisolone–bupivacaine injection compared to saline at theL4-5 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 efficacywas seen in leg pain and one dimension of the generic questionnaire (NHP). TheOswestry and Million scales have often been employed as outcomes in longitudinal ”pre-post” studies (Kopec & Esdaile 1995), yet the Oswestry disability questionnaire may beless sensitive than the Roland-Morris questionnaire (Bouter et al. 1998). Another possibleexplanation for the lesser disease-specific effect in the case of contained herniations is thesmaller patient number in this subgroup. This could also explain why we found nodifference between the treatments in the case of bulges, although an uncontrolled studysuggested that foraminal steroids could be effective in this subgroup (Shackleford &Mulholland 1994).

Periradicular infiltration with steroid seemed to prevent surgery in containedherniations, 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-1α, IL-1β, IL-6 and TNFα) and PgE2 from harvested disc herniation tissues in vitro (Takahashiet al. 1996). Local anaesthetic might also exert some beneficial effect, as in the porcinemodel lidocaine appeared to have an anti-inflammatory effect (Yabuki et al. 1998b). Inthis study, 42 % of patients with contained herniation underwent surgery after the salineinjection, contrasted with 20% after the steroid injection. The operated patients werealmost entirely painless after surgery, which may explain the between-group differencesin favour of saline at 6 months. For contained herniations repeated steroid injections

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could be recommended, maybe 2 to 4 weeks after the index injection, as the steroidtreatment does not increase the rate of disc operations and is effective in diminishing legpain.

Macrophages are found in abundance in disc herniations, and are thought to play a rolein 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(Grönblad et al 1994, Haro et al 1996, Matsui et al. 1998, Arai et al. 2000). Whenextrusions were compared with non-extruded herniations, they exhibited more vascularity(Yasuma et al 1993, Haro et al. 1996, Ikeda et al. 1996) and monocyte chemotacticprotein-1 positive cells (Haro et al. 1996). Mononuclear cells infiltrate along the marginsof extruded discs, expressing inflammatory mediators. In co-cultures with endothelialcells, disc cells from extrusions enhanced the proliferation of endothelial cells andfibroblasts significantly more than disc cells from protrusions (Doita et al. 1996). It isspeculated that the extrusion of herniated nucleus pulposus causes damage to the anulusfibrosus and epidural vessels, inducing fibroblasts and endothelial cells to producechemokines, which may recruit macrophages in the initiation of the resorption process ofdisc herniation (Haro et al. 1996). The vascularized granulation tissue can be detectedwith 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, andhistologically 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 ofmacrophages. In fact, in a rabbit model high-dose steroid suppressed the replacement ofgrafted intervertebral disc tissue, in accordance with our results (Minamide et al. 1998).Our subgroup analysis revealed that the steroid injection seemed more harmful forextrusions, which accords with the observation that macrophages are more abundant inextruded disc fragments. While inhibiting the secretion of cytokines (including TNF-α)(Takahashi et al. 1996), steroids may interfere with the resorption of HNP, in which TNF-α plays an important role (Haro et al. 2000). This was clearly seen in our study: steroidand saline were both effective in relieving leg pain, but at approximately 3 monthspatients in the steroid group were more likely to be operated compared to those in thesaline group.

The steroid intervention already produced some monetary savings for containedherniations by 4 weeks, but by 1 year it had saved $1969 per treated patient. The disparityof operation rates in these two subgroups explains the significant differences in medicalcosts, as well as the decrease in days on sick leave at 6 months among the containedherniation cases treated with steroid. The cost-effectiveness analysis indicates that forcontained 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 beeneven greater with dry-needling as placebo. For extrusions, on the other hand, the cost-effectiveness analysis suggests that a better alternative to saline than steroid needs to besought, one possibility being a TNF-α antagonist (Olmarker & Larsson 1998). We did notinclude indirect costs in our economic analysis, because return to work is less responsiveto clinical treatment than symptoms or daily functioning, although it is of utmost socialand personal importance (Deyo et al. 1998). Moreover, the monetary assessment of workabsenteism is controversial (Hutubessy et al. 1999).

7 Conclusions

The findings of this thesis indicate that MRI is unable to distinguish sciatic patients interms of the severity of their symptoms. Symptoms and signs of sciatica should receivethe major emphasis when assessing the severity of the disorder and in subsequent clinicaldecision making.

In this sciatic patient population it was impossible to differentiate the genotypes (Trp2and Trp3 alleles) on the basis of symptoms or clinical signs, whereas MRI has greaterpotential in this respect. A radial tear in a nonherniated disc may indicate the presence ofthe Trp2 allele, and the findings of TLS may indicate the presence of the Trp3 allele. TheTrp2 allele is a rare gene defect, but the Trp3 allele is more common. In fact, in this studyalmost every fourth patient with sciatica had the Trp3 allele. These associations areimportant for physicians treating back pain patients with or without sciatica, as MRIfindings may provide some estimates of the phenotype, and thus about the heredity of thelumbar disc disease to the offspring of the patients.

The present double-blind, controlled trial indicated that periradicular infiltration with acombination of methylprednisolone and bupivacaine offers only short-term clinical andeconomic 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 thesymptomatic level, in terms of both leg pain and medical costs, and possibly also in theneed for operative treatment. In addition, if the lesion is located at the L3–4 or L4–5 level,steroid treatment is more likely to achieve good results in terms of disease-specificoutcomes, but not in medical costs. In the case of extrusions steroid seems to be counter-effective. However, subgroup analyses carry a high risk of bias and the promising resultsin our subgroup analyses call for a verification study, which might be achievable usingoral 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 VolvoAward in Basic Science. Spine 7: 184–191.

Adams MA & Hutton WC (1985) Gradual disc prolapse. Spine 10: 524–531.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: 475–480.Albeck MJ (1996) A critical assessment of clinical diagnosis of disc herniation in patients with

monoradicular sciatica. Acta Neurochir 138: 40–44.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: S10–18.Andersson GB, Svensson HO, & Oden A (1983) The intensity of work recovery in low back pain.

Spine 8: 880–884.Annunen S, Paassilta P, Lohiniva J, Perälä M, Pihlajamaa T, Karppinen J, Tervonen O, Kröger H,

Lähde S, Vanharanta H, Ryhänen L, Göring HH, Ott J, Prockop DJ & Ala-Kokko L (1999) Anallele of COL9A2 associated with intervertebral disc disease. Science 285: 409–412.

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 anddenaturation of the extracellular matrix with growth, maturation, ageing, and degeneration. J ClinInvest 98: 996–1003.

Aprill C & Bogduk N (1992) High-intensity zone: a diagnostic sign of painful lumbar disc onmagnetic resonance imaging. Br J Radiol 65: 361–369.

Arai Y, Yasuma T, Shitoto K, Yamauchi Y & Suzuki F (2000) Immunohistological study ofintervertebral disc herniation of lumbar spine. J Orthop Sci 5: 229–231.

Arantes RM, Lourenssen S, Machado CR & Blennerhassett MG (2000) Early damage of sympatheticneurons after co-culture with macrophages: a model of neuronal injury in vitro . Neuroreport 11:177–181.

Atlas SJ, Deyo RA, Keller RB, Chapin AM, Patrick DL, Long JM & Singer DE (1996) The MainLumbar Spine Study, Part II. 1-year outcomes of surgical and nonsurgical management of sciatica.Spine 21: 1777–1786.

Aufdermaur M (1981) Juvenile kyphosis (Scheuermann's disease): radiography, histology, andpathogenesis. Clin Orthop 154: 166–174.

75

Balague F, Nordin M, Sheikhzadeh A, Echegoyen AC, Brisby H, Hoogewoud HM, Fredman P &Skovron ML (1999) Recovery of severe sciatica. Spine 24: 2516–2524.

Battie MC, Videman T, Gibbons LE, Fisher LD, Manninen H & Gill K (1995) 1995 Volvo Award inclinical sciences. Determinants of lumbar disc degeneration. A study relating lifetime exposuresand magnetic resonance imaging findings in identical twins. Spine 20: 2601–2612.

Beattie PF, Meyers SP, Stratford P, Millard RW & Hollenberg GM (2000) Associations betweenpatient report of symptoms and anatomic impairment visible on lumbar magnetic resonanceimaging. Spine 25: 819–828.

Bell GR & Rothman RH (1984) The conservative treatment of sciatica. Spine 9: 54–56.Bemelmans MH, van Tits LJ & Buurman WA (1996) Tumor necrosis factor: function, release and

clearance. Crit Rev Immunol 16: 1–11.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 andrecommendations: analysis of 32 cases. Spine 24: 1611–1616.

Bloch R (1987) Methodology in clinical back pain trials. Spine 12: 430–432.Blower PW (1981) Neurologic patterns in unilateral sciatica. A prospective study of 100 new cases.

Spine 6: 175–179.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 JointSurg [Am] 72: 403–408.

Bogduk N (1997a) Clinical anatomy of the lumbar spine and sacrum. New York: ChurchillLivingstone.

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 painresearch and management, IASP Press, Seattle, p 507–525.

Boos N, Rieder R, Schade V, Spratt KF, Semmer N & Aebi M (1995) 1995 Volvo Award in clinicalsciences. The diagnostic accuracy of magnetic resonance imaging, work perception, andpsychosocial factors in identifying symptomatic disc herniations. Spine 20: 2613–2625.

Bouter LM, van Tulder MW & Koes BW (1998) Methodologic issues in low back pain research inprimary care. Spine 23: 2014–2020.

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 withbupivacaine followed by saline. In: Bonfica JJ & Albe-Fessard DG (eds) Advances in painresearch and therapy. Vol. 1. Raven Press, New York, p 927–932.

Brewton RG & Mayne R (1994) Heterotypic type II, IX and XI fibrils: comparison of vitreous andcartilage forms. In: Yurchenko PD, Birk PD & Mecham RP (eds) Extracellular matrix assemblyand structure. Academic Press, San Diego, p 129–170.

Brisby H, Byröd G, Olmarker K, Miller VM, Aoki Y & Rydevik B (2000) Nitric oxide as a mediatorof nucleus pulposus-induced effects on spinal nerve roots. J Orthop Res 18: 815–820.

Buchner M, Zeifang F, Brocai DR & Schiltenwolf M (2000) Epidural corticosteroid injection in theconservative management of sciatica. Clin Orthop 375: 149–156.

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 plusprocaine for the management of intractable sciatica. Spine 16: 572–575.

Byröd G, Olmarker K, Konno S, Larsson K, Takahashi K & Rydevik B (1995) A rapid transport routebetween the epidural space and the intraneural capillaries of the nerve roots. Spine 20: 138–143.

Byröd G, Otani K, Brisby H, Rydevik B & Olmarker K (2000) Methylprednisolone reduces the earlyvascular permeability increase in spinal nerve roots induced by epidural nucleus pulposusapplication. J Orthop Res 18: 983–987.

76

Carette S, Leclaire R, Marcoux S, Morin F, Blaise GA, St.-Pierre A, Truchon R, Parent F, LevesqueJ, Bergeron V, Montminy P & Blanchette C (1997) Epidural corticosteroid injections for sciaticadue to herniated nucleus pulposus. N Engl J Med 336: 1634–1640.

Carey TS, Garrett J, Jackman A, McLaughlin C, Fryer J & Smucker DR (1995) The outcomes andcosts 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 333:913–917.

Carragee EJ & Kim DH (1997) A prospective analysis of magnetic resonance imaging findings inpatients with sciatica and lumbar disc herniation. Correlation of outcomes with disc fragment andcanal morphology. Spine 22: 1650–1660.

Cavanaugh JM (1995) Neural mechanisms of lumbar pain. Spine 20: 1804–1809.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: 1283–1287.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-aspartatereceptors. Brain Behav Immun 9: 355–365.

Chatani K, Kawakami M, Weinstein JN, Meller ST & Gebhart GF (1995) Characterization of thermalhyperalgesia, c-fos expression, and alterations in neuropeptides after mechanical irritation of thedorsal root ganglion. Spine 20: 277–89.

Chen C, Cavanaugh JM, Ozaktay AC, Kallakuri S & King AI (1997) Effects of phospholipase A2 onlumbar nerve root structure and function. Spine 22: 1057–1064.

Cohen MS, Wall EJ, Brown RA, Rydevik B & Garfin SR (1990) 1990 AcroMed Award in basicscience. Cauda equina anatomy. II: Extrathecal nerve roots and dorsal root ganglia. Spine 15:1248–1251.

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: S2101–2106.Cooper RG, Freemont AJ, Hoyland JA, Jenkins JP, West CG, Illingworth KJ & Jayson MI (1995)

Herniated intervertebral disc-associated periradicular fibrosis and vascular abnormalities occurwithout inflammatory cell infiltration. Spine 20: 591–598.

Cornefjord M, Sato K, Olmarker K, Rydevik B & Nordborg C (1997) A model for chronic nerve rootcompression studies. Presentation of a porcine model for controlled, slow-onset compression withanalyses of anatomic aspects, compression onset rate, and morphologic and neurophysiologiceffects. Spine 22: 946–957.

Crisi G, Carpeggiani P & Trevisan C (1993) Gadolinium-enhanced nerve roots in lumbar diskherniation. AJNR Am J Neuroradiol 14: 1379–1392.

Cuckler JM, Bernini PA, Wiesel SW, Booth RE Jr, Rothman RH & Pickens GT (1985) The use ofepidural steroids in the treatment of lumbar radicular pain. A prospective, randomized, double-blind study. J Bone Joint Surg [Am] 67: 63–66.

Cupps TR & Fauci AS (1982) Corticosteroid-mediated immunoregulation in man. Immunol Rev 65:133–155.

Darnay BG & Aggarwal BB (1997) Early events in TNF signaling: a story of associations anddissociations. J Leukoc Biol 61: 559–566.

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:S176–83.

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: S2032–2036.

77

Deyo RA, Battie M, Beurskens AJ, Bombardier C, Croft P, Koes B, Malmivaara A, Roland M, VonKorff M & Waddell G (1998) Outcome measures for low back pain research. A proposal forstandardized use. Spine 23: 2003–2013.

Deyo RA, Loeser JD & Bigos SJ (1990) Herniated lumbar intervertebral disk. Ann Intern Med 112:598–603.

Deyo RA, Rainville J & Kent DL (1992) What can the history and physical examination tell us aboutlow back pain? JAMA 268: 760–765.

Dhote R, Tudoret L, Bachmeyer C, Legmann P & Christoforov B (1996) Cyclic sciatica. Amanifestation of compression of the sciatic nerve by endometriosis. A case report. Spine 21:2277–2279.

Dilke TF, Burry HC & Grahame R (1973) Extradural corticosteroid injection in management oflumbar nerve root compression. BMJ 2: 635–637.

Doita M, Kanatani T, Harada T & Mizuno K (1996) Immunohistologic study of the rupturedintervertebral disc of the lumbar spine. Spine 21: 235–241.

Dooley JF, McBroom RJ, Taguchi T & Macnab I (1988) Nerve root infiltration in the diagnosis ofradicular pain. Spine 13: 79–83.

Dudeney S, O'Farrell D, Bouchier-Hayes D & Byrne J (1998) Extraspinal causes of sciatica. A casereport. Spine 23: 494–496.

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: 227–291.Eyre DR, Benya P, Buckwalter JA, Caterson B, Heinegård D, Oegema TR, Pearce RH, Pope MH &

Urban JP (1989) Basic science perspectives. In: Frymoyer J & Gordon SL (eds) New perspectiveson low back pain. American Academy of Orthopedic Surgeons, Illinois, p 147–207.

Eyre DR & Muir H (1976) Types I and II collagens in intervertebral disc. Interchanging radialdistributions in annulus fibrosus. Biochem J 157: 267–270.

Fairbank JC, Couper J, Davies JB & O'Brien JP (1980) The Oswestry low back pain disabilityquestionnaire. Physiotherapy 66: 271–273.

Farfan HF, Cossette JW, Robertson GH, Wells RV & Kraus H (1970) The effects of torsion on thelumbar intervertebral joints: the role of torsion in the production of disc degeneration. J Bone JointSurg [Am] 52: 468–497.

Franson RC, Saal JS & Saal JA (1992) Human disc phospholipase A2 is inflammatory. Spine 17:S129–32.

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: 291–300.Frymoyer JW (1992) Lumbar disk disease: epidemiology. Instr Course Lect 41: 217–223.Greene TL, Hensinger RN & Hunter LY (1985) Back pain and vertebral changes simulating

Scheuermann's disease. J Pediatr Orthop 5: 1–7.Grönblad M, Hupli M, Wennerstrand P, Järvinen E, Lukinmaa A, Kouri JP & Karaharju EO (1993)

Intercorrelation and test-retest reliability of the Pain Disability Index (PDI) and the OswestryDisability Questionnaire (ODQ) and their correlation with pain intensity in low back pain patients.Clin J Pain 9: 189–195.

Grönblad M, Virri J, Rönkkö S, Kiviranta I, Vanharanta H, Seitsalo S, Rashbaum RF & Guyer RD(1996) A controlled biochemical and immunohistochemical study of human synovial-type (groupII) phospholipase A2 and inflammatory cells in macroscopically normal, degenerated, andherniated human lumbar disc tissues. Spine. 21: 2531–2538.

Grönblad M, Virri J, Seitsalo S, Habtemariam A & Karaharju E (2000) Inflammatory cells, motorweakness, and straight leg raising in transligamentous disc herniations. Spine 25: 2803–2807.

78

Grönblad M, Virri J, Tolonen J, Seitsalo S, Kääpä E, Kankare J, Myllynen P & Karaharju EO (1994)A controlled immunohistochemical study of inflammatory cells in disc herniation tissue. Spine19: 2744–2751.

Gunzburg R, Fraser RD & Fraser GA (1990) Lumbar intervertebral disc prolapse in teenage twins. Acase report and review of the literature. J Bone Joint Surg [Br] 72: 914–916.

Guyer RD & Ohnmeiss DD (1995) Lumbar discography. Position statement from the NorthAmerican Spine Society Diagnostic and Therapeutic Committee. Spine 20: 2048–2059.

Habtemariam A, Grönblad M, Virri J, Seitsalo S & Karaharju E (1998) A comparativeimmunohistochemical study of inflammatory cells in acute- stage and chronic-stage discherniations. Spine 23: 2159–2165.

Hakelius A (1970) Prognosis in sciatica. A clinical follow-up of surgical and non- surgical treatment.Acta Orthop Scand 129: 1–76.

Hakelius A & Hindmarsh J (1972) The comparative reliability of preoperative diagnostic methods inlumbar disc surgery. Acta Orthop Scand 43: 234–238.

Hanai F, Matsui N & Hongo N (1996) Changes in responses of wide dynamic range neurons in thespinal dorsal horn after dorsal root or dorsal root ganglion compression. Spine 21: 1408–14.

Hanania M & Kitain E (1998) Perisciatic injection of steroid for the treatment of sciatica due topiriformis syndrome. Reg Anesth Pain Med 23: 223–228.

Haro H, Shinomiya K, Komori H, Okawa A, Saito I, Miyasaka N & Furuya K (1996) Upregulatedexpression of chemokines in herniated nucleus pulposus resorption. Spine 21: 1647–1652.

Haro H, Komori H, Okawa A, Murakami S, Muneta T & Shinomiya K (1997) Sequential dynamicsof monocyte chemotactic protein-1 expression in herniated nucleus pulposus resorption. J OrthopRes 15: 734–741.

Haro H, Crawford HC, Fingleton B, Shinomiya K, Spengler DM & Matrisian LM (2000) Matrixmetalloproteinase-7-dependent release of tumor necrosis factor-alpha in a model of herniated discresorption. J Clin Invest 105: 143–150.

Hashizume H, Kawakami M, Nishi H & Tamaki T (1997) Histochemical demonstration of nitricoxide in herniated lumbar discs. A clinical and animal model study. Spine 22: 1080–1084.

Hashizume H, Rutkowski MD, Weinstein JN & DeLeo JA (2000) Central administration ofmethotrexate reduces mechanical allodynia in an animal model of radiculopathy/sciatica. Pain 87:159–169.

Hasue M & Kikuchi S (1997) Nerve root injections. In: Frymoyer J (ed) The adult spine: principlesand practice. Lippincott-Raven Publishers, Philadelphia, p 647–653.

Haueisen DC, Smith BS, Myers SR & Pryce ML (1985) The diagnostic accuracy of spinal nerveinjection studies. Their role in the evaluation of recurrent sciatica. Clin Orthop 198: 179–183.

Hayashi N, Weinstein JN, Meller ST, Lee HM, Spratt KF & Gebhart GF (1998) The effect of epiduralinjection of betamethasone or bupivacaine in a rat model of lumbar radiculopathy. Spine 23: 877–885.

Heikkilä JK, Koskenvuo M, Heliövaara M, Kurppa K, Riihimäki H, Heikkilä K, Rita H & VidemanT (1989) Genetic and environmental factors in sciatica. Evidence from a nationwide panel of 9365adult twin pairs. Ann Med 21: 393–398.

Heithoff KB, Gundry CR, Burton CV & Winter RB (1994) Juvenile discogenic disease. Spine 19:335–340.

Heliövaara M, Vanharanta H, Korpi J & Troup JD (1986) Herniated lumbar disc syndrome andvertebral canals. Spine. 11: 433–435.

Heliövaara M (1987a) Body height, obesity, and risk of herniated lumbar intervertebral disc. Spine12: 469–472.

Heliövaara M (1987b) Occupation and risk of herniated lumbar intervertebral disc or sciatica leadingto hospitalization. J Chronic Dis 40: 259–264.

79

Heliövaara M, Impivaara O, Sievers K, Melkas T, Knekt P, Korpi J & Aromaa A (1987a) Lumbardisc syndrome in Finland. J Epidemiol Community Health 41: 251–258.

Heliövaara M, Knekt P & Aromaa A (1987b) Incidence and risk factors of herniated lumbarintervertebral disc or sciatica leading to hospitalization. J Chronic Dis 40: 251–258.

Heliövaara M (1989) Risk factors for low back pain and sciatica. Ann Med 21: 257–264.Heliövaara M, Sievers K, Impivaara O, Maatela J, Knekt P, Mäkelä M & Aromaa A (1989)

Descriptive epidemiology and public health aspects of low back pain. Ann Med 21: 327–333.Heliövaara M, Mäkelä M, Knekt P, Impivaara O & Aromaa A (1991) Determinants of sciatica and

low-back pain. Spine 16: 608–614.Herron LD (1989) Selective nerve root block in patient selection for lumbar surgery: surgical results.

J Spinal Disord 2: 75–79.Herzog RJ (1996) The radiologic assessment for a lumbar disc herniation. Spine 21: S19–38.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 WarII. Am J Epidemiol 102: 367–376.

Hukins DW (1988) Disc structure and function. In: Ghosh P (ed) The biology of the intervertebraldisc. CRC Press, Boca Raton, Fl, p 1–37.

Hurme M & Alaranta H (1987) Factors predicting the result of surgery for lumbar intervertebral discherniation. Spine. 12: 933–938.

Hutubessy RC, van Tulder MW, Vondeling H & Bouter LM (1999) Indirect costs of back pain in theNetherlands: a comparison of the human capital method with the friction cost method. Pain 80:201–207.

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: 2975–2980.

Ikeda T, Nakamura T, Kikuchi T, Umeda S, Senda H & Takagi K (1996) Pathomechanism ofspontaneous regression of the herniated lumbar disc: histologic and immunohistochemical study.J Spinal Disord 9: 136–140.

Ilmarinen J, Louhevaara V, Korhonen O, Nygård CH, Hakola T & Suvanto S (1991) Changes inmaximal cardiorespiratory capacity among aging municipal employees. Scand J Work EnvironHealth 17: 99–109.

Ilmarinen J, Suurnäkki T, Eskelinen L, Huuhtanen P, Järvinen M, Peltomaa T, Merisalo T, FahlströmP, Järvinen E, Aalto L & Wäger G (1985) Kunnallisten ammattien työn profiilit eläkeiänperusteena (Work profiles of communal jobs as the basis of the retirement age). Investigations ofthe Institute for Occupational Health 3: 164–211.

Ito T, Homma T & Uchiyama S (1999) Sciatica caused by cervical and thoracic spinal cordcompression. Spine 24: 1265–1267.

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: 230–234.

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 331:69–73.

Jönsson B & Strömqvist B (1995) The straight leg raising test and the severity of symptoms in lumbardisc herniation. A preoperative evaluation. Spine 20: 27–30.

Jönsson B & Strömqvist B (1996) Clinical appearance of contained and noncontained lumbar discherniation. J Spinal Disord 9: 32–38.

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. Spine20: 460–468.

Kang, J. D., Stefanovic-Racic, M., McIntyre, L. A., Georgescu, H. I., and Evans, C. H. (1997) Towarda biochemical understanding of human intervertebral disc degeneration and herniation.Contributions of nitric oxide, interleukins, prostaglandin E2, and matrix metalloproteinases. Spine22: 1065–1073.

Karppinen J, Inkinen RI, Kääpä E, Lammi MJ, Tammi MI, Holm S & Vanharanta H (1995) Effectsof tiaprofenic acid and indomethacin on proteoglycans in the degenerating porcine intervertebraldisc. Spine 20: 1170–1177.

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 24:2456–2460.

Kawakami M, Weinstein JN, Chatani K, Spratt KF, Meller ST & Gebhart GF (1994a) Experimentallumbar radiculopathy. Behavioral and histologic changes in a model of radicular pain after spinalnerve root irritation with chromic gut ligatures in the rat. Spine 19: 1795–1802.

Kawakami M, Weinstein JN, Spratt KF, Chatani K, Traub RJ, Meller ST & Gebhart GF (1994b)Experimental lumbar radiculopathy. Immunohistochemical and quantitative demonstrations ofpain induced by lumbar nerve root irritation of the rat. Spine 19: 1780–1794.

Kawakami M, Tamaki T, Hayashi N, Hashizume H & Nishi H (1998) Possible mechanism of painfulradiculopathy in lumbar disc herniation. Clin Orthop 351: 241–251.

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 byautologous nucleus pulposus in the rat. J Orthop Res 17: 941–946.

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 thenucleus pulposus in the rat. J Orthop Res 18: 257–264.

Kawakami M, Tamaki T, Matsumoto T, Kuribayashi K, Takenaka T & Shinozaki M (2000b) Role ofleukocytes in radicular pain secondary to herniated nucleus pulposus. Clin Orthop 376: 268–277.

Kayama S, Konno S, Olmarker K, Yabuki S & Kikuchi S (1996) Incision of the anulus fibrosusinduces nerve root morphologic, vascular, and functional changes. An experimental study. Spine21: 2539–2543.

Kayama S, Olmarker K, Larsson K, Sjögren-Jansson E, Lindahl A & Rydevik B (1998) Cultured,autologous nucleus pulposus cells induce functional changes in spinal nerve roots. Spine 23:2155–2158.

Keegan JJ & Garret FD (1948) The segmental distribution of the cutaneous nerves in the limbs ofman. Anat Rec 102: 409–437.

Kelsey JL & Hardy RJ (1975) Driving of motor vehicles as a risk factor for acute herniated lumbarintervertebral disc. Am J Epidemiol 102: 63–73.

Kelsey JL & Ostfeld AM (1975) Demographic characteristics of persons with acute herniated lumbarintervertebral disc. J Chronic Dis 28: 37–50.

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 joband risk for acute prolapsed lumbar intervertebral disc. J Orthop Res 2: 61–66.

Keskimäki I, Seitsalo S, Österman H & Rissanen P (2000) Reoperations after lumbar disc surgery: apopulation-based study of regional and interspecialty variations. Spine 25: 1500–1508.

Kikuchi S & Hasue M (1988) Combined contrast studies in lumbar spine diseases. Myelography(peridurography) and nerve root infiltration. Spine 13: 1327–1331.

Kikuchi S, Hasue M, Nishiyama K & Ito T (1984) Anatomic and clinical studies of radicularsymptoms. Spine 9: 23–30.

81

Kimura T, Nakata K, Tsumaki N, Miyamoto S, Matsui Y, Ebara S & Ochi T (1996) Progressivedegeneration of articular cartilage and intervertebral discs. An experimental study in transgenicmice bearing a type IX collagen mutation. Int Orthop 20: 177–181.

Klenerman L, Greenwood R, Davenport HT, White DC & Peskett S (1984) Lumbar epiduralinjections in the treatment of sciatica. Br J Rheumatol 23: 35–38.

Knuttson B (1961) Comparative value of electromyographic, myelographic and clinical-neurologicalexaminations in diagnosis of lumbar root compression syndrome. Acta Orthop Scand 49: 1–135.

Kobayashi S, Yoshizawa H, Hachiya Y, Ukai T & Morita T (1993) Vasogenic edema induced bycompression injury to the spinal nerve root. Distribution of intravenously injected protein tracersand gadolinium-enhanced magnetic resonance imaging. Spine 18: 1410–1424.

Koes BW, Scholten RJ, Mens JM & Bouter LM (1995) Efficacy of epidural steroid injections for low-back pain and sciatica: a systematic review of randomized clinical trials. Pain 63: 279–288.

Koivukangas P, Ohinmaa A & Koivukangas J (1995) Nottingham Health Profilen (NHP)suomalainen versio (Finnish version of the Nottingham Health Profile). Reports of the NationalResearch and Development Center for Welfare and Health, Helsinki, Finland.

Kopec JA & Esdaile JM (1995) Functional disability scales for back pain. Spine 20: 1943–1949.Körkkö J, Annunen S, Pihlajamaa T, Prockop DJ & Ala-Kokko L (1998) Conformation sensitive gel

electrophoresis for simple and accurate detection of mutations: comparison with denaturinggradient gel electrophoresis and nucleotide sequencing. Proc Natl Acad Sci U S A 95: 1681–1685.

Kortelainen P, Puranen J, Koivisto E & Lähde S (1985) Symptoms and signs of sciatica and theirrelation to the localization of the lumbar disc herniation. Spine 10: 88–92.

Krempen JF & Smith BS (1974) Nerve-root injection: a method for evaluating the etiology ofsciatica. J Bone Joint Surg [Am] 56: 1435–1444.

Kuslich SD, Ulstrom CL & Michael CJ (1991) The tissue origin of low back pain and sciatica: areport of pain response to tissue stimulation during operations on the lumbar spine using localanesthesia. Orthop Clin North Am 22: 181–187.

Kääpä E, Han X, Holm S, Peltonen J, Takala T & Vanharanta H (1995) Collagen synthesis and typesI, III, IV, and VI collagens in an animal model of disc degeneration. Spine 20: 59–66.

Kääpä 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 Res30: 203–214.

Lee CK, Rauschning W & Glenn W (1988) Lateral lumbar spinal canal stenosis: classification,pathologic anatomy and surgical decompression. Spine 13: 313–320.

Lee HM, Weinstein JN, Meller ST, Hayashi N, Spratt KF & Gebhart GF (1998) The role of steroidsand their effects on phospholipase A2. An animal model of radiculopathy. Spine 23: 1191–1196.

Lindblom K & Rexed B (1948) Spinal nerve injury in dorsolateral protrusions of lumbar disks. JNeurosurg 5: 413–432.

Lings S & Mikkelsen L (1982) Scheuermann's disease with low localization. A problem of under-diagnosis. Scand J Rehabil Med 14: 77–79.

Lipson SJ & Muir H (1981a) 1980 Volvo award in basic science. Proteoglycans in experimentalintervertebral disc degeneration. Spine 6: 194–210.

Lipson SJ & Muir H (1981b) Experimental intervertebral disc degeneration: morphologic andproteoglycan changes over time. Arthritis Rheum 24: 12–21.

Lowe TG (1999) Scheuermann's disease. Orthop Clin North Am 30: 475–487.Lutz GE, Vad VB & Wisneski RJ (1998) Fluoroscopic transforaminal lumbar epidural steroids: an

outcome study. Arch Phys Med Rehabil 79: 1362–1366.Lutze M, Stendel R, Vesper J & Brock M (1997) Periradicular therapy in lumbar radicular

syndromes: methodology and results. Acta Neurochir 139: 719–724.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: 891–903.

82

Magora A (1973) Investigation of the relation between low back pain and occupation. IV. Physicalrequirements: bending, rotation, reaching and sudden maximal effort. Scand J Rehabil Med 5:186–190.

Maigne JY, Rime B & Deligne B (1992) Computed tomographic follow-up study of forty-eight casesof nonoperatively treated lumbar intervertebral disc herniation. Spine 17: 1071–1074.

Malmivaara A (1997) Evidence-based intervention for musculoskeletal disorders. Scand J WorkEnviron Health 23: 161–163.

Manninen P, Riihimäki H & Heliövaara M (1995) Incidence and risk factors of low-back pain inmiddle-aged farmers. Occup Med 45: 141–146.

Marras WS, Davis KG, Heaney CA, Maronitis AB & Allread WG (2000) The influence ofpsychosocial stress, gender, and personality on mechanical loading of the lumbar spine. Spine 25:3045–3054.

Marshall LL, Trethewie ER & Curtain CC (1977) Chemical radiculitis. A clinical, physiological andimmunological study. Clin Orthop 129: 61–67.

Mathews JA, Mills SB, Jenkins VM, Grimes SM, Morkel MJ, Mathews W, Scott CM & SittampalamY (1987) Back pain and sciatica: controlled trials of manipulation, traction, sclerosant andepidural injections. Br J Rheumatol 26: 416–423.

Matsui Y, Maeda M, Nakagami W & Iwata H (1998) The involvement of matrix metalloproteinasesand inflammation in lumbar disc herniation. Spine 23: 863–868.

McCarron RF, Wimpee MW, Hudkins PG & Laros GS (1987) The inflammatory effect of nucleuspulposus. A possible element in the pathogenesis of low-back pain. Spine 12: 760–764.

Meller ST & Gebhart GF (1994) Spinal mediators of hyperalgesia. Drugs 47:10–20.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: 153–156.Miller JA, Schmatz C & Schultz AB (1988) Lumbar disc degeneration: correlation with age, sex, and

spine level in 600 autopsy specimens. Spine 13: 173–178.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. Anexperimental study in the rabbit. Spine 23: 870–876.

Mixter WJ & Barr JS (1934) Rupture of the intervertebral disc with involvement of the spinal canal.N Engl J Med 211: 210–215.

Miyamoto H, Saura R, Harada T, Doita M & Mizuno K (2000) The role of cyclooxygenase-2 andinflammatory cytokines in pain induction of herniated lumbar intervertebral disc. Kobe J Med Sci46: 13–28.

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: 193–199.

Modic MT, Ross JS, Obuchowski NA, Browning KH, Cianflocco AJ & Mazanec DJ (1995) Contrast-enhanced MR imaging in acute lumbar radiculopathy: a pilot study of the natural history.Radiology 195: 429–435.

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 functionof anular ruptures and disc degeneration. A re-analysis of 833 discograms. Spine 19: 1968–1974.

Muramoto T, Atsuta Y, Iwahara T, Sato M & Takemitsu Y (1997) The action of prostaglandin E2 andtriamcinolone acetonide on the firing activity of lumbar nerve roots. Int Orthop 21: 172–175.

Nachemson A (1969) Intradiscal measurements of pH in patients with lumbar rhizopathies. ActaOrthop Scand 40: 23–42.

Naftulin S, Fast A & Thomas M (1993) Diabetic lumbar radiculopathy: sciatica without discherniation. Spine 18: 2419–2422.

Naylor A (1974) Late results of laminectomy for lumbar disc prolapse. A review after ten to twenty-five years. J Bone Joint Surg [Br] 56: 17–29.

83

Nelson CL, Janecki CJ, Gildenberg PL & Sava G (1972) Disk protrusions in the young. Clin Orthop88: 142–150.

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 16:265–268.

Nitta H, Tajima T, Sugiyama H & Moriyama A (1993) Study on dermatomes by means of selectivelumbar spinal nerve block. Spine 18: 1782–1786.

Norlen G (1944) On the value of the neurological symptoms in sciatica for the localisation of a lumbardisc herniation. Acta Chir Scand (Suppl) 95: 1–96.

Nygaard OP & Mellgren SI (1998) The function of sensory nerve fibers in lumbar radiculopathy. Useof quantitative sensory testing in the exploration of different populations of nerve fibers anddermatomes. Spine 23: 348–352.

Nykvist F, Hurme M, Alaranta H & Einola S (1989) A prospective 5-year follow-up study of 276patients hospitalized because of suspected lumbar disc herniation. Int Disabil Stud 11: 61–67.

Ohnmeiss DD, Vanharanta H & Guyer RD (1995) The association between pain drawings andcomputed tomographic/discographic pain responses. Spine. 20: 729–733.

Ohnmeiss DD, Vanharanta H & Ekholm J (1997) Degree of disc disruption and lower extremity pain.Spine. 22: 1600–1605.

Ohnmeiss DD, Vanharanta H & Ekholm J (1999a) Relation between pain location and discpathology: a study of pain drawings and CT/discography. Clin J Pain 15: 210–217.

Ohnmeiss DD, Vanharanta H & Ekholm J (1999b) Relationship of pain drawings to invasive testsassessing intervertebral disc pathology. Eur Spine J 8: 126–131.

Ojala R, Vähälä 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 thenutritional supply to the porcine cauda equina. J Spinal Disord 3: 25–29.

Olmarker K (1991) Spinal nerve root compression. Nutrition and function of the porcine cauda equinacompressed in vivo. Acta Orthop Scand (Suppl) 242: 1–27.

Olmarker K, Rydevik B & Nordborg C (1993) Autologous nucleus pulposus inducesneurophysiologic and histologic changes in porcine cauda equina nerve roots. Spine 18: 1425–1432.

Olmarker K, Byröd G, Cornefjord M, Nordborg C & Rydevik B (1994) Effects ofmethylprednisolone on nucleus pulposus-induced nerve root injury. Spine 19: 1803–1808.

Olmarker K, Blomquist J, Strömberg J, Nannmark U, Thomsen P & Rydevik B (1995)Inflammatogenic properties of nucleus pulposus. Spine 20: 665–669.

Olmarker K, Nordborg C, Larsson K & Rydevik B (1996) Ultrastructural changes in spinal nerveroots induced by autologous nucleus pulposus. Spine 21: 411–414.

Olmarker K, Brisby H, Yabuki S, Nordborg C & Rydevik B (1997) The effects of normal, frozen, andhyaluronidase-digested nucleus pulposus on nerve root structure and function. Spine 22: 471–475.

Olmarker K & Larsson K (1998) Tumor necrosis factor alpha and nucleus-pulposus-induced nerveroot injury. Spine 23: 2538–2544.

Olmarker K & Myers RR (1998) Pathogenesis of sciatic pain: role of herniated nucleus pulposus anddeformation of spinal nerve root and dorsal root ganglion. Pain 78: 99–105.

Olmarker K & Rydevik B (2001) Selective inhibition of tumor necrosis factor-α prevents nucleuspulposus-induced thrombus formation, intraneural edema, and reduction of nerve conductionvelocity. Possible implications of future pharmacologic treatment strategies of sciatica. Spine 26:863–869.

84

Osti OL, Vernon-Roberts B & Fraser RD (1990) 1990 Volvo Award in experimental studies. Anulustears and intervertebral disc degeneration. An experimental study using an animal model. Spine15: 762–767.

Osti OL, Vernon-Roberts B, Moore R & Fraser RD (1992) Annular tears and disc degeneration in thelumbar spine. A post- mortem study of 135 discs. J Bone Joint Surg [Br] 74: 678–682.

Otani K, Arai I, Mao GP, Konno S, Olmarker K & Kikuchi S (1999) Nucleus pulposus-induced nerveroot injury: relationship between blood flow and motor nerve conduction velocity. Neurosurgery45: 614–619.

Özaktay AC, Kallakuri S & Cavanaugh JM (1998) Phospholipase A2 sensitivity of the dorsal rootand dorsal root ganglion. Spine 23: 1297–1306.

Paajanen H, Alanen A, Erkintalo M, Salminen JJ & Katevuo K (1989a) Disc degeneration inScheuermann disease. Skeletal Radiol 18: 523–526.

Paajanen H, Erkintalo M, Kuusela T, Dahlström S & Kormano M (1989b) Magnetic resonance studyof disc degeneration in young low-back pain patients. Spine 14: 982–985.

Paassilta P, Pihlajamaa T, Annunen S, Brewton RG, Wood BM, Johnson CC, Liu J, Gong Y, WarmanML, Prockop DJ, Mayne R & Ala-Kokko L (1999) Complete sequence of the 23-kilobase humanCOL9A3 gene. Detection of Gly-X-Y triplet deletions that represent neutral variants. J Biol Chem274: 22469–22475.

Paassilta P, Lohiniva J, Göring HH, Perälä M, Räinä S, Karppinen J, Hakala M, Palm T, Kröger H,Kaitila I, Vanharanta H, Ott J & Ala-Kokko L (2001) First common genetic risk factor for lumbardisc disease. JAMA 285: 1843–1849.

Pihlajamaa T, Perälä 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 274:22464–22468.

Porter RW, Hibbert CS & Wicks M (1978) The spinal canal in symptomatic lumbar disc lesions. JBone Joint Surg [Br] 60–B: 485–487.

Powell MC, Wilson M, Szypryt P, Symonds EM & Worthington BS (1986) Prevalence of lumbar discdegeneration observed by magnetic resonance in symptomless women. Lancet 2: 1366–1367.

Puranen J & Orava S (1991) The hamstring syndrome – a new gluteal sciatica. Ann Chir Gynaecol80: 212–214.

Redford EJ, Hall SM & Smith KJ (1995) Vascular changes and demyelination induced by theintraneural injection of tumour necrosis factor. Brain 118: 869–878.

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: 288–294.

Ridley MG, Kingsley GH, Gibson T & Grahame R (1988) Outpatient lumbar epidural corticosteroidinjection in the management of sciatica. Br J Rheumatol 27: 295–299.

Riew KD, Yin Y, Gilula L, Bridwell KH, Lenke LG, Lauryssen C & Goette K (2000) The effect ofnerve-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: 1589–1593.

Riihimäki H (1985) Back pain and heavy physical work: a comparative study of concretereinforcement workers and maintenance house painters. Br J Ind Med 42: 226–232.

Riihimäki H, Wickström G, Hänninen K & Luopajärvi T (1989) Predictors of sciatic pain amongconcrete reinforcement workers and house painters – a five-year follow-up. Scand J Work EnvironHealth 15: 415–423.

Riihimäki H, Viikari-Juntura E, Moneta G, Kuha J, Videman T & Tola S (1994) Incidence of sciaticpain among men in machine operating, dynamic physical work, and sedentary work. A three-yearfollow-up. Spine 19: 138–142.

85

Roberts S, Menage J & Urban JP (1989) Biochemical and structural properties of the cartilage end-plate and its relation to the intervertebral disc. Spine 14: 166–174.

Rothoerl RD, Woertgen C, Holzschuh M, Rueschoff J & Brawanski A (1998) Is there a clinicalcorrelate to the histologic evidence of inflammation in herniated lumbar disc tissue? Spine 23:1197–1200.

Russell LB, Gold MR, Siegel JE, Daniels N & Weinstein MC (1996) The role of cost-effectivenessanalysis in health and medicine. Panel on Cost-Effectiveness in Health and Medicine. JAMA 276:1172–1177.

Rydevik B, Brown MD & Lundborg G (1984) Pathoanatomy and pathophysiology of nerve rootcompression. Spine 9: 7–15.

Rydevik BL, Myers RR & Powell HC (1989) Pressure increase in the dorsal root ganglion followingmechanical compression. Closed compartment syndrome in nerve roots. Spine 14: 574–576.

Saal JA, Saal JS & Herzog RJ (1990a) The natural history of lumbar intervertebral disc extrusionstreated nonoperatively. Spine 15: 683–686.

Saal JS, Franson RC, Dobrow R, Saal JA, White AH & Goldthwaite N (1990b) High levels ofinflammatory phospholipase A2 activity in lumbar disc herniations. Spine 15: 674–678.

Saal JS (1995) The role of inflammation in lumbar pain. Spine 20: 1821–1827.Salminen JJ, Erkintalo MO, Pentti J, Oksanen A & Kormano MJ (1999) Recurrent low back pain and

early disc degeneration in the young. Spine 24: 1316–1321.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: 923–944.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. ActaNeuropathol (Berl.) 68: 15–21.

Shackleford IM & Mulholland RC (1994) Can we improve the technique of nerve root infiltrationwith the aid of a nerve stimulator? Presented at the Annual Meeting of the International Societyfor 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: 191–194.

Shubayev VI & Myers RR (2000) Upregulation and interaction of TNFalpha and gelatinases A andB in painful peripheral nerve injury. Brain Res 855: 83–89.

Smyth MJ & Wright J (1958) Sciatica and the intervertebral disk. An experimental study. J Bone JointSurg 40-A: 1401–1418.

Snoek W, Weber H & Jorgensen B (1977) Double blind evaluation of extradural methyl prednisolonefor herniated lumbar discs. Acta Orthop Scand 48: 635–641.

Spangfort EV (1972) The lumbar disc herniation. A computer-aided analysis of 2,504 operations.Acta Orthop Scand (Suppl) 142: 1–95.

Spengler DM, Ouellette EA, Battie M & Zeh J (1990) Elective discectomy for herniation of a lumbardisc. Additional experience with an objective method. J Bone Joint Surg [Am] 72: 230–237.

Stadnik TW, Lee RR, Coen HL, Neirynck EC, Buisseret TS & Osteaux MJ (1998) Annular tears anddisk herniation: prevalence and contrast enhancement on MR images in the absence of low backpain or sciatica. Radiology 206: 49–55.

Stanley D, McLaren MI, Euinton HA & Getty CJ (1990) A prospective study of nerve root infiltrationin the diagnosis of sciatica. A comparison with radiculography, computed tomography, andoperative findings. Spine 15: 540–543.

Stefanovic-Racic M, Morales TI, Taskiran D, McIntyre LA & Evans CH (1996) The role of nitricoxide 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 ofmechanical compression and hypoxia on nerve root and dorsal root ganglia. An analysis of ectopicfiring using an in vitro model. Spine 21: 2089–2094.

Takahashi H, Suguro T, Okazima Y, Motegi M, Okada Y & Kakiuchi T (1996) Inflammatorycytokines in the herniated disc of the lumbar spine. Spine 21: 218–224.

Takahashi K, Miyazaki T, Ohnari H, Takino T & Tomita K (1995) Schmorl's nodes and low-backpain. Analysis of magnetic resonance imaging findings in symptomatic and asymptomaticindividuals. Eur Spine J 4: 56–59.

Taneichi H, Abumi K, Kaneda K & Terae S (1994) Significance of Gd-DTPA-enhanced magneticresonance imaging for lumbar disc herniation: the relationship between nerve root enhancementand clinical manifestations. J Spinal Disord 7: 153–160.

Tertti MO, Salminen JJ, Paajanen HE, Terho PH & Kormano MJ (1991) Low-back pain and diskdegeneration in children: a case-control MR imaging study. Radiology 180: 503–507.

Tervonen O, Lähde S & Vanharanta H (1991) Ultrasound diagnosis of lumbar disc degeneration.Comparison with computed tomography/discography. Spine 16: 951–954.

Tetlow LC, Adlam DJ & Woolley DE (2001) Matrix metalloproteinase and proinflammatorycytokine production by chondrocytes of human osteoarthritic cartilage: associations withdegenerative changes. Arthritis Rheum 44: 585–594.

Thelander U, Fagerlund M, Friberg S & Larsson S (1992) Straight leg raising test versus radiologicsize, shape, and position of lumbar disc hernias. Spine 17: 395–399.

Thelander U, Fagerlund M, Friberg S & Larsson S (1994) Describing the size of lumbar discherniations using computed tomography. A comparison of different size index calculations andtheir relation to sciatica. Spine 19: 1979–1984.

Thomas M, Grant N, Marshall J & Stevens J (1983) Surgical treatment of low backache and sciatica.Lancet 2(8365-66): 1437–1439.

Toyone T, Takahashi K, Kitahara H, Yamagata M, Murakami M & Moriya H (1993) Visualisationof symptomatic nerve roots. Prospective study of contrast-enhanced MRI in patients with lumbardisc herniation. J Bone Joint Surg [Br] 75: 529–533.

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: 391–404.

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 105–122.

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 discdeterioration as seen by CT/discography. Spine. 12: 295–298.

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: 1349–1351.

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: 321–324.

Vanharanta H, Sachs BL, Ohnmeiss DD, Aprill C, Spivey M, Guyer RD, Rashbaum RF, HochschulerSH, Terry A & Selby D (1989) Pain provocation and disc deterioration by age. A CT/discographystudy in a low-back pain population. Spine. 14: 420–423.

Varlotta GP, Brown MD, Kelsey JL & Golden AL (1991) Familial predisposition for herniation of alumbar 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 spinalpathology in cadaveric material in relation to history of back pain, occupation, and physicalloading. Spine 15: 728–740.

Videman T, Leppävuori J, Kaprio J, Battie MC, Gibbons LE, Peltonen L & Koskenvuo M (1998)Intragenic polymorphisms of the vitamin D receptor gene associated with intervertebral discdegeneration. Spine 23: 2477–2485.

Videman T & Battie MC (1999) The influence of occupation on lumbar degeneration. Spine 24:1164–1168.

Videman T, Gibbons LE, Battie MC, Maravilla K, Vanninen E, Leppävuori J, Kaprio J & PeltonenL (2001) The relative roles of intragenic polymorphisms of the vitamin d receptor gene in lumbarspine degeneration and bone density. Spine 26: E7–E12.

Vroomen PC, de Krom MC, Wilmink JT, Kester AD & Knottnerus JA (1999) Lack of effectivenessof bed rest for sciatica. N Engl J Med 340: 418–423.

Vroomen PC, de Krom MC, Slofstra PD & Knottnerus JA (2000) Conservative treatment of sciatica:a systematic review. J Spinal Disord 13: 463–469.

Vucetic N, Määttänen H & Svensson O (1995) Pain and pathology in lumbar disc hernia. Clin Orthop320: 65–72.

Vucetic N, Åstrand P, Guntner P & Svensson O (1999) Diagnosis and prognosis in lumbar discherniation. Clin Orthop 361: 116–122.

Waddell G, Morris EW, Di Paola MP, Bircher M & Finlayson D (1986) A concept of illness testedas an improved basis for surgical decisions in low-back disorders. Spine 11: 712–719.

Wagner R & Myers RR (1996a) Endoneurial injection of TNF-alpha produces neuropathic painbehaviors. Neuroreport 7: 2897–2901.

Wagner R & Myers RR (1996b) Schwann cells produce tumor necrosis factor alpha: expression ininjured and non-injured nerves. Neuroscience 73: 625–629.

Wagner R, Janjigian M & Myers RR (1998) Anti-inflammatory interleukin-10 therapy in CCIneuropathy decreases thermal hyperalgesia, macrophage recruitment, and endoneurial TNF-alphaexpression. Pain 74: 35–42.

Watanabe H, Nakata K, Kimata K, Nakanishi I & Yamada Y (1997) Dwarfism and age-associatedspinal degeneration of heterozygote cmd mice defective in aggrecan. Proc Natl Acad Sci U S A.94: 6943–6947.

Watts RW & Silagy CA (1995) A meta-analysis on the efficacy of epidural corticosteroids in thetreatment of sciatica. Anaesth Intensive Care 23: 564–569.

Weber H (1983) Lumbar disc herniation. A controlled, prospective study with ten years ofobservation. Spine 8: 131–140.

Weber H, Holme I & Amlie E (1993) The natural course of acute sciatica with nerve root symptomsin 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 withcytokine inhibitors. Evidence for a role of interleukin-1. Spine 21: 931–935.

Weiner BK & Fraser RD (1997) Foraminal injection for lateral lumbar disc herniation. J Bone JointSurg [Br] 79: 804–807.

Weinstein SM, Herring SA & Derby R (1995) Contemporary concepts in spine care. Epidural steroidinjections. Spine 20: 1842–1846.

Weir BK (1979) Prospective study of 100 lumbosacral discectomies. J Neurosurg 50: 283–289.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: 661–666.

88

White AH (1983) Injection techniques for the diagnosis and treatment of low back pain. Orthop ClinNorth Am 14: 553–567.

Wiesel SW, Tsourmas N, Feffer HL, Citrin CM & Patronas N (1984) A study of computer-assistedtomography. I. The incidence of positive CAT scans in an asymptomatic group of patients. Spine9: 549–551.

Wilppula E & Jussila P (1977) Spinal nerve block. A diagnostic test in sciatica. Acta Orthop Scand48: 458–460.

Wrocklage C, Wassmann H & Paulus W (2000) COL9A2 allelotypes in intervertebral disc disease.Biochem Biophys Res Commun 279: 398–400.

Wu JJ & Eyre DR (1989) Covalent interactions of type IX collagen in cartilage. Connect Tissue Res20: 241–246.

Yabuki S & Kikuchi S (1995) Nerve root infiltration and sympathetic block. An experimental studyof intraradicular blood flow. Spine 20: 901–906.

Yabuki S, Kikuchi S, Olmarker K & Myers RR (1998a) Acute effects of nucleus pulposus on bloodflow and endoneurial fluid pressure in rat dorsal root ganglia. Spine 23: 2517–2523.

Yabuki S, Kawaguchi Y, Nordborg C, Kikuchi S, Rydevik B & Olmarker K (1998b) Effects oflidocaine on nucleus pulposus-induced nerve root injury. A neurophysiologic and histologic studyof the pig cauda equina. Spine 23: 2383–2389.

Yabuki S, Igarashi T & Kikuchi S (2000) Application of nucleus pulposus to the nerve rootsimultaneously reduces blood flow in dorsal root ganglion and corresponding hindpaw in the rat.Spine 25: 1471–1476.

Yabuki S, Onda A, Kikuchi S & Myers R (2001) Prevention of compartment syndrome in dorsal rootganglia caused by exposure to nucleus pulposus. Spine 26: 870–875.

Yamashita K, Hiroshima K & Kurata A (1994) Gadolinium-DTPA – enhanced magnetic resonanceimaging of a sequestered lumbar intervertebral disc and its correlation with pathologic findings.Spine 19: 479–482.

Yasuma T, Arai K & Yamauchi Y (1993) The histology of lumbar intervertebral disc herniation. Thesignificance of small blood vessels in the extruded tissue. Spine 18: 1761–1765.

Yoshizawa H, Kobayashi S & Morita T (1995) Chronic nerve root compression. Pathophysiologicmechanism of nerve root dysfunction. Spine 20: 397–407.

Yrjämä M, Tervonen O, Kurunlahti M & Vanharanta H (1997) Bony vibration stimulation testcombined with magnetic resonance imaging. Can discography be replaced? Spine. 22: 808–813.

Yrjämä M, Tervonen O & Vanharanta H (1996) Ultrasonic imaging of lumbar discs combined withvibration pain provocation compared with discography in the diagnosis of internal anular fissuresof the lumbar spine. Spine 21: 571–575.

Yrjämä M & Vanharanta H (1994) Bony vibration stimulation: a new, non-invasive method forexamining intradiscal pain. Eur Spine J 3: 233–235.

Yu SW, Haughton VM, Ho PS, Sether LA, Wagner M & Ho KC (1988a) Progressive and regressivechanges in the nucleus pulposus. Part II. The adult. Radiology 169: 93–97.

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 indetecting radial tears of the anulus: a postmortem study. AJNR Am J Neuroradiol 10: 1077–1081.

Zamani MH and MacEwen GD (1982) Herniation of the lumbar disc in children and adolescents. JPediatr Orthop 2: 528–533.

Zitting P, Rantakallio P & Vanharanta H (1998) Cumulative incidence of lumbar disc diseasesleading to hospitalization up to the age of 28 years. Spine 23: 2337–2343.