Sciatica

Studies of symptoms, genetic factors, and treatment with periradicular infiltration

Jaro Karppinen

Abstract

The nature of symptoms and signs of sciatica, genetic factors, and efficacy of periradicular infiltration were studied in 160 nonoperated patients with unilateral sciatica of 3 to 28 weeks duration.

Back and leg pain (100-mm VAS), disability (Oswestry), and quality-of-life (NHP) were evaluated. ENMG and 1.5-T MRI were performed on every patient. Presence of the Trp2 and Trp3 alleles of collagen IX was determined from blood samples. After informed consent, patients were randomized for periradicular infiltration with either methylprednisolone–bupivacaine, or saline. The final follow-up assessment was 1 year after the intervention. Economic analysis was based on data gathered from the patients, medical records and the National Insurance Register.

At baseline, symptoms of sciatica did not correlate with the type of displacement of the symptomatic disc in MRI, or the presence of the Trp2 or Trp3 alleles. In the case of the Trp2 allele, there was a non-significant tendency for the presence of a radial tear at the L4–5 level. A significant genotype-phenotype association was found for the Trp3 allele: 15 of 34 (44%) patients with the Trp3 allele were positive for thoracolumbar Scheuermann’s disease in MRI compared to 19% for sciatic patients without the allele (p = 0.003).

Periradicular infiltration with methylprednisolone–bupivacaine produced a significant treatment effect compared to saline at 2 weeks for leg pain, straight leg raising, lumbar flexion and patient satisfaction. At 6 months, saline was superior to steroid in back and leg pain. By 1 year, 18 patients in the methylprednisolone group and 15 in the saline group had received surgical treatment.

Subgroup analysis revealed that the short-term effect of the steroid treatment was most pronounced for contained herniations and symptomatic lesions situated at the L4–5 (or L3–4) disc level. Patients with a contained herniation were less likely to undergo back surgery when receiving the steroid treatment and they also had significantly fewer days on sick leave from 3 to 6 months. Counter-effectiveness was most pronounced for extrusions.

The results indicate that disability among sciatic patients may be present even when MRI findings are minor; and vice versa, prominent MRI findings may not associate with any symptoms. However, MRI seems to be useful for identifying patients with the Trp3 allele. On the basis of the treatment intervention results, periradicular infiltration with a combination of steroid and anaesthetic may be recommended for sciatica as it offers at least short-term pain relief. Furthermore, in the case of contained herniations the steroid injection is cost-effective and may also prevent surgery. However, this subgroup analysis calls for a verification study.

Table of Contents
Acknowledgements
Abbreviations
List of original publications
1. Introduction
2. Review of the literature
2.1. Pathogenesis of sciatic pain
2.1.1. Intervertebral disc herniation (HNP)
2.1.2. Other causes of sciatica
2.2. Pathophysiological mechanisms of sciatica
2.2.1. Compression of nerve roots
2.2.2. Inflammation
2.2.3. Combination of compression and inflammation
2.2.4. Pain sensitization
2.2.5. Effect of methylprednisolone
2.3. Etiognosis of sciatica
2.3.1. Constitutional factors
2.3.2. Environmental and behavioural factors
2.3.3. Genetic factors
2.4. Diagnosis of sciatica
2.4.1. Medical history
2.4.2. Physical signs
2.4.3. Imaging and other diagnostic tests
2.4.4. Associations of symptoms and clinical signs with MRI findings
2.5. Treatment of sciatica
2.5.1. Natural history
2.5.2. Conservative treatment
2.5.3. Surgical treatment
3. Aims of the study
4. Subjects and methods
4.1. Study population
4.2. Evaluation of patients
4.2.1. Demographics and clinical symptoms (I–V)
4.2.2. Genetic analysis (II and III)
4.2.3. Diagnostic evaluation
4.3. Patient information and randomization (IV and V)
4.4. Periradicular infiltration (IV and V)
4.5. Other interventions (IV and V)
4.6. Follow-ups and outcome assessment (IV and V)
4.7. Economic analysis (IV and V)
4.8. Statistical analysis
4.8.1. Calculation of sample size (I–V)
4.8.2. Reliability of MRI findings (I–V)
4.8.3. Associations of MRI findings, clinical tests and symptoms (I)
4.8.4. Evaluation of patients with the Trp2 and Trp3 alleles (II and III)
4.8.5. Estimation of treatment efficacy and cost-effectiveness (IV and V)
4.8.6. Subgroup analysis (V)
5. Results
5.1. Baseline characteristics of the patients
5.2. Correlations of symptoms and signs to MRI findings (I)
5.3. Evaluation of patients with the Trp2 and Trp3 alleles (II and III)
5.3.1. Demographic and clinical characteristics
5.3.2. MRI findings
5.3.3. Thoracolumbar Scheuermann’s disease (TLS)
5.4. Clinical efficacy of periradicular infiltration. Intention-to-treat analysis (IV)
5.5. Clinical efficacy of periradicular infiltration. Subgroup analysis (V)
5.5.1. Contained herniations vs. extrusions
5.5.2. Disc level
5.6. Cost-effectiveness of the treatments in subgroups (V)
5.6.1. Contained herniations
5.6.2. Extrusions
5.6.3. Disc level
6. Discussion
6.1. Study population
6.2. Methods
6.3. MRI findings versus symptoms and signs of sciatica (I)
6.4. Phenotype of patients with the Trp2 allele (II)
6.5. Phenotype of patients with the Trp3 allele (III)
6.6. Intention-to-treat analysis of periradicular infiltration (IV)
6.7. Subgroup analysis of periradicular infiltration (V)
7. Conclusions
References
List of Tables
1. Baseline characteristics of 160 patients with sciatica randomly assigned to receive periradicular infiltration either with methylprednisolone-bupivacaine or saline.*
2. Characteristics of patients with the Trp2 (Trp2 allele +) and Trp3 (Trp3 allele +) alleles compared to patients without the alleles. MeansSD shown unless otherwise stated.
3. Significant determinants of thoracolumbar Scheuermann’s disease in MRI analyzed by stepwise logistic regression analysis. Odds ratios (OR) with 95% Confidence Intervals (CI) and p-values presented.
4. Between-groups treatment differences following periradicular infiltration with steroid or saline in the whole study population (total), and in subgroups of contained herniations, extrusions and disc levels L3–4–5. Positive treatment difference values indicate that the steroid treatment was superior to saline.§
5. Mean cumulative costs ($) of periradicular infiltration per one responder (≥ 75% decrease of leg pain) according to MRI-classification*.
List of Figures
1. A) Cross-section of the spinal cord with a ventral (VR) and dorsal (DR) spinal nerve root. The cell bodies of the motor axons are located in the anterior horn of the gray matter of the spinal cord, whereas the cell bodies of the sensory axons of the dorsal root are located in the dorsal root ganglion (DRG). The ventral and dorsal nerve roots blend just caudal to the DRG, and form the spinal nerve (SN). Nerve roots are covered with root sheath (RS), a continuation of the pia mater covering the spinal cord. The spinal cord and nerve roots are floating freely in the cerebrospinal fluid (CSF) in the subarachnoid space. D=dura. B) Schematic drawing of vascular supply to the spinal cord and nerve roots. The nervous system branch of the segmental artery (SA) joins the nerve root and forms a ganglionic plexus (GP) in the DRG and caudal nerve root arteries (NRA) running in cranial direction. From the vaso corona of the spinal cord, cranial arteries run in caudal direction in the nerve roots. (Reproduced with permission from, Olmarker K, Thesis, Gothenburg 1990).
2. A schematic presentation of collagen IX. It is covalently cross-linked to the surface of collagen II fibril, but a portion of the molecule projects from the fibril surface. Collagen IX is a heterotrimeric protein consisting of three genetically distinct a chains, α1(IX), α2(IX) and α3(IX). Helical domains are interrupted with globular domains (circles). The glycosaminoglycan (GAG) chain is attached to an α3-chain. The defect in α2(IX) leads to a change of codon for glutamine to that for tryptophan, which may interrupt the covalent binding of collagen IX with collagen II.
3. A) Needle placement in the L5 periradicular infiltration. B) Contrast medium extension (neurogram) around the L5 nerve root. C) Needle placement in the S1 infiltration. D) S1 neurogram.
4. Boxplots comparing low-back specific disability measured by Oswestry Index (upper scale) and straight leg raising (SLR, lower scale, shaded boxes) with MRI classification. Note that disability is not associated with the degree of disc displacement, whereas SLR is. The boxplots show the median (50th percentile) and the interquartile (25th to 75th percentile) range. Vertical bars show the minimum and maximum scores. Cont. HNP=contained herniation, noncont HNP=noncontained herniation.
5. Magnetic resonance imaging scans of a 50-year old storeman with right-sided sciatica for 1.5 months. He is homozygous for the Trp3 allele. Left, T1-weighted sagittal scan, right, T2-weighted sagittal scan. Schmorl’s nodes at the L1-2, L2-3, L3-4 and L4-5 levels. Grade 3 disc degeneration at the L1-2, L2-3 and L4-5 levels. Contained herniation at the L4-5 level. He has thoracolumbar Scheuermann’s disease with multiple Schmorl’s nodes and disc degeneration in the thoracolumbar region.
6. Leg pain (mm on VAS, standard deviations indicated with vertical bars) at baseline and at each follow-up assessment after the nerve root infiltration with either methylprednisolone– bupivacaine (     •     ) or saline (— • —). The upper box presents the number of patients at each follow-up assessment. A) intention-to-treat analysis, B) subgroup of contained herniations, C) subgroup of extrusions. * P-value of between-group treatment difference at the respective follow-up <0.05, **p<0.01.
7. Medical costs ($, standard deviations indicated with vertical bars) at each follow-up assessment after the periradicular infiltration with either methylprednisolone–bupivacaine (    •    ) or saline (— • —). The upper box presents the number of patients at each follow-up assessment. A) Subgroups of contained herniations, B) extrusions. * P-value of the between-group treatment difference at the respective follow-up <0.05, **p<0.01.
8. Kaplan-Meier curves for the number of operated patients versus time of operation in weeks after the periradicular infiltration in subgroups of contained herniations and extrusions. Curves are presented separately for both treatments in each subgroup.
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