Pathophysiology of low back pain

Pathophysiology of Discogenic Low Back

Pain

Dr. Sushil Paudel

Low back pain is the most common musculoskeletal disorder in industrialized societies.

AAOS, Dept of Research and Scientific Affairs

Workers’ compensation statistics suggest that disability for back pain is increasing 14 times the population growth.

Aronoff, 1991

Low Back Pain

MRI Analysis of the Lumbar Spine

Lumbar Spinal MRI (n = 131) n (%) of regionIntervertebral disc degeneration 116 (88.5)

Intervertebral disc bulge or herniation 101 (77.1)

Posterior joint degeneration 42 (32.1)

Facet tropism 9 (7.2)

Spondylolisthesis, grade I 6 (5.6)

Congenital narrow central stenosis, L4 and L5 6 (5.4)

Acquired central stenosis, L4 and L5 4 (3.1)

Conjoined nerve root 2 (1.5)

Transitional segmentation 2 (1.5)

Uterine mass 2 (1.5)

Neurofibroma 2 (1.5)

Malignant alteration of bone marrow 1 (0.8)

- Marchiori et al. 2002

The Intervertebral Disc

The intervertebral disc is comprised of:

The nucleus pulposus

The anulus fibrosus The vertebral

endplates

Disc- Derived From:◦ Notochord◦ Somatocoele Mesenchymal Cells

Mesenchymal Cells◦ Dense Celled Zone – Forms the disc◦ Loose Celled Zone – Forms the vertebral bodies◦ Outer Zone – forms fibroblasts

Cotton et al. 1994 Mirza and White, 1995

Embryological Development

10 Weeks◦ Notochord cells disappear from vertebral body

11-20 Weeks◦ Nucleus forms from expansion of the notochord◦ Annular formation begins

After 20 Weeks◦ Notochord cells decrease◦ Collagen fibers form in the annulus

Cotton et al. 1994 Mirza and White, 1995

Disc Change with Maturity

Consists of 15 to 25 layers of fiber bundles Layers are 0.14 to 0.52 mm thick Average interbundle space is 0.22 mm wide

and filled with gelatinous material Structure of the anulus is irregular

◦ 40% of the layers are incomplete in any 20 degree circumferential sector of the disc

◦ Irregularities are most frequent in the posterolateral region of the anulus

Marchand and Ahmed 1990

Anulus Fibrosus

Consists of a clear gelatinous substance Makes up 50% of the disc Moves within the disc with changes in

posture Communicates with the epidural space and

surrounding neural structures Beattie et al. 1994 MacMillan et al. 1991

Nucleus Pulposus

MacMillam et al analyzed 105 discs with methylene blue dye injected in the nucleus◦ 14% showed leaks◦ 93% of the leaks were in the posterolateral region◦ Injected dye showed contact with the adjacent

nerve root in 27% of the leaks MacMillan et al. 1991

The Leaky Disc

The end plate consists of a thin flat layer of hyaline cartilage.

Each EP is composed of parallel lamellae of chondrocytes and collagen fibers

The EP contributes to resilience of the motion segment

Ghosh, 1990

End Plate

Located cephalad in the foramen and bathed in CSF

With SLR, the lumbar nerve roots move 0.5-5 mm and sustain 2-4% strain. – Smith et al. 1993

A more transverse course of the nerve root may be associated with an increased risk of sciatica

Sato and Kikuchi, 1993

Conjoined nerve roots:◦ 2-4% of patients undergoing imaging studies -

Okuwaki et al. 1991

◦ 14% of anatomic studies ◦ May be associated with developmental anomalies

and increased risk of disc herniation - Gomez et al. 1993

Nerve Root

Lumbar region◦ Loosely connected in upper levels◦ Smaller diameter at lower levels

Morphologically associated with herniation◦ Intact PLL - central herniation in upper levels◦ Ruptured PLL - posterolateral extrusion in lower

levels Ohshima et al. 1993

Posterior Longitudinal Ligament

Normal intervertebral foramen is oval shaped

With disc degeneration, foramen assumes an auricular shape

Stephens et al. 1991

Intervertebral Foramen

Provide torsional rigidity and provide structural support in axial loading

Zimmerman et al. 1992

Posterior elements restrict the disc to 80% of its full range of flexion

Degeneration and arthritis of the facet joint is linked with decreased disc height as a result of DDD.

Adams et al. 1994

Facet Joint Pain Related to Disc Disease

The normal disc is avascular Segmental blood vessels contribute to the

capillary bed surrounding the anulus Stairmand et al. 1991

Blood vessels penetrate the subchondral bone of the vertebral body and calcified region of the hyaline cartilage end plate

Invasion of blood vessels from the exterior is seen in people age >50 years

Yasuma et al. 1993

Blood Supply

Blood Supply

- Modified from Postacchini and Rausching, Anatomy, 1999

Anterior annulus is innervated by nerves derived from the ventral rami and gray ramus communicans

Yamashita et al. 1993

The posterior annulus is innervated by the sinuvertebral nerve – McCarthy et al. 1991

No nerve fibers or neuropeptides have been identified in normal nucleus pulposus

Ashton et al. 1994

Nerve Supply


Nerve Supply


Nerve endings in the outer half of the anulus in normal and degenerated discs – Yoshizawa et al. 1980

Nerve fibers may extend 3mm into the anulus of a normal disc

Nerve endings in abnormal discs may reach the nucleus

Ashton et al. 1994

Innervation of the Disc

NP AFWater

Young Disc 85-90 % 78%Older Disc 70% 70%

Solids 10-20% 30-40%Proteoglycans 65% 20%Collagen 20-30% 50-60%Elastin ~1% ~1%

- Gumina and Postacchini, 1998, Mirza and White, 1995

Biochemical Composition of Intervertebral Disc

“It takes approximately 3

years to replace the proteoglycan molecules in the human intervertebral disc.”

- Stathopoulos and Cramer, 1995

Healthy Disc◦ Average daily variation of 1.2 mm

Degenerated Disc◦ Average daily variation of 2.1 mm

Diurnal Variation◦ 13 to 21 mm variation in healthy 22-year olds◦ Prolonged bed rest is associated with 22%

expansion of the disc◦ Increased disc space may increase diffusion

distances Paajanen et al. 1994 LaBlanc et al. 1994

Hydrostatic Pressure

Intradiscal pressure is lowest in supine position

Nachemson, 1960

Intradiscal pressure rises in the sitting, leaning forward position

65% of height loss occurs in the first 6 min after a 10 kg weight is lifted

Krag et al. 1990

Pressure on the Disc

The disc is largely avascular Metabolism is mainly anaerobic Nutrients enter by diffusion via two routes Diffusion through the end plates

◦ Perianular◦ Diffusion distance may be as large as 8 mm

Load dependant◦ Metabolism in bovine discs was highest with 5 to 10

kg loads – Ohshima et al. 1995

◦ A physiologic level (0.33 MPa) of hydrostatic pressure acts in an anabolic fashion, stimulating proteoglycan synthesis – Handa et al. 1997

Metabolism

Maximum cell density of the disc is determined by nutrient supply

Oxygen and glucose levels within the disc may fall to very low levels

Stairmand et al. 1991

Oxygen◦ At the center of the disc O2 is 1/20 to 1/50 of that

at the edge of the disc Lactate

◦ At the center of the disc is 8 to 10 times the plasma concentration

Holm et al. 1981

Oxygen Consumption

Cell Density

Cell Density (x 10-3)/mm3

Age 15 years 18 years 56 years Average

Cartilage end plate 12.6 15.4 17.1 15.0

Anulus fibrosus 6.9 8.4 11.6 9.0

Nucleus pulposus 3.3 4.3 4.7 4.0

- Maroudas et al. 1975

Anular injury can initiate progressive degenerative changes◦ Nucleus becomes small, fibrotic, and develops

yellowish discoloration◦ Replacement of lamellae with granulation tissue◦ Lamellar structure was not restored in the area of

injury 3 to 5 months following injury◦ Development of ventral osteophytes◦ Collagen synthesis and content increased, cross

links decreased, water content decreased Kaapa et al. 1994 Osti et al. 1990

Anular Injury

Degeneration at the L4-5 disc predicted decreased loads on the facet joints, increased intradiscal pressure (by 10%), and increased disc bulge at the L3-4 level in a finite element model

- Kim et al. 1991

Degeneration at one level may effect an adjacent level

Intervertebral disc prolapse is peripheral in origin with the anulus being the site of primary pathological change

Gordon et al. 1991 Bending in addition to axial compression in

predisposing a disc to prolapse Adams, 1994

The normal disc is protected by the posterior elements from overstretching, however not from fatigue failure

Adams et al. 1994

Mechanisms of Disc Injury

Proteoglycan levels decrease with◦ Disc degeneration◦ Age◦ Altered loading◦ A pH decrease from 6.9-7.1 to less than 6.5 May be due to degeneration or smoking

◦ NSAID use Yoo et al. 1992 Ohshima and Urban, 1992 Ohshima et al. 1995 (J Orthop Res)

Disc Composition Changes

Many changes occur before maturity◦ Collagen in the nucleus increases in lumbar regions◦ Collagen in the anulus increases◦ Water content decreases◦ Chondroitin sulfate and polyanion concentrations

decrease◦ Hyaluronic acid and keratan sulfate increase◦ Increase in elastin to proteoglycan ratio◦ Decrease in elastin to collagen ratio

Scott et al. 1994

Maturation of the Disc

Aging leads to loss of anular integrity Bernick et al. 1991

In persons over 40 years of age◦ Breakdown of lamina and thickening of lamellar layers◦ Fraying, splitting, loss of collagen fibers◦ Spaces filled with proteoglycan◦ Deposition of chondroid material in the anulus◦ Amyloid deposition in the anulus◦ Circumferential and radial ruptures are noted

Ito et al. 1991 Marchand and Ahmed 1990

Changes in The Anulus

Aging may lead to: Calcification and gradual replacement with

bone Bernick et al. 1991

May become separated from subchondral bone and herniate with the anulus◦ In 51.1% of persons aged 77 years, end plate is

separated – Tanaka et al. 1993

Irregularities may become common◦ Bone marrow tissues may penetrate the end plate,

triggering cytokine production leading to matrix degradation

Fujita et al. 1993

End Plate

Aging may lead to: Increased contact forces over the facet

joints due to loss of disc height Shirazie-Adl, 1992

Facet osteoarthritis may occur secondary to mechanical changes resulting from disc degeneration

Butler et al. 1990

Facet Joints

Biological Basis of Risk Factors

Genetic factors have been linked to disc degeneration in identical twins.

Sambrook et al. 1999 Battie et al. 1995

Harrington et al. 2001 analyzed five factors: height, weight, body mass index, disc endplate area, and disc endplate size.

Only disc endplate shape had a strong association with disc herniation occurrence

Disc endplate area had a borderline association with disc herniation occurrence in men.

Genetic Factors

Mechanical factors such as: small discs, a heavy torso, or small internal levers may lead to high internal muscle forces acting on the disc.

Videmann, 2001

Collagen Expression◦Defects in Collagen IX (CLO9A2), a

structural element of the anulus fibrosus, nucleus pulposus, and the endplates, have been associated with dominantly inherited lumbar disc disease.

Paasilta et al. 2001 Annunen et al. 1999 Jones et al. 1998

Lifting

Method of Lifting Relative RiskKnees bent and back straight 0.71

Knees bent and back bent 2.02

Knees straight and back bent 3.95

Lifting starting and ending at floor level 1.84

Lifting starting and ending at waist level

2.53

Lifting started with arms extended 1.87

Twisting while lifting 1.90Adapted from Mundt et al. 1993

Smoking has been linked to disc degeneration in studies of identical twins.

Lebeouf-Yde et al. 1998 Battie et al. 1991

Smoking – increases intradiscal lactate levels, decreases pH, and degrades hyaluronic acid.

Hambly and Mooney, 1992 McDevitt et al. 1985 Holm and Nachemson 1988

Narrows the vascular lumen and reduces the number of vascular buds present in the endplate

Iwahashi et al. 2002

Smoking

Occupational Risk in 57,000 Workers

Other Industrial Workers

Building Workers

Drivers

Farmers

Professional and white collar workers

Suspected Herniation (or sciatica) Documented Herniation

Adapted from Heliovaara, 1987

Stenosis of the ostia of the arteries supplying the disc has been correlated to degree of disc degeneration.

Kauppila et al. 1994

Atherosclerosis

21.5% of herniated discs contain both nuclear and anular material

29% of herniated discs contain only anular material

Lebkowski and Dzieciol 2002 Most recurrent disc herniations and

herniations with multiple extruded fragments contain portions of endplate

Brock et al. 1992

Pathology of Disc Herniation

The prevalence of disc herniation is 1.6% in the US, 2.2% in England, and 1.2% in Finland

The prevalence of low back pain is 15-20% in the US, 25-45% in European countries, with a life-time prevalence exceeding 70%

Disc Herniation

Neovascularization was seen in 12.5% of herniated discs in patients with less than 1 month duration and in 82% of herniated discs in patients with symptoms greater than 6 month duration.

Chitkara, 1991 Neovascularization was seen in 91% of

herniated discs in patients with symptom duration ranging from 5 days to 2.5 years

Sequestered herniations had greater neovascularization than did protrusions

Virri et al., 1996

Neovascularization

In 80% of degenerated discs, solitary free nerve fibers could be seen deeper than the outer third of the annulus

In 20% of degenerated discs, free nerve fibers were discernible in the periphery of the NP

Coppes et al. 1997, COPPES et al. 1990 Freemont et al. 1997 Bogduk et al. 1981

Abnormal Innervation

Mechanisms of Pain Generation

Neuropeptides involved in the transmission of pain have been identified in the intervertebral disc:◦ CGRP, VIP, and SP are present in the outer anulus

of dog discs Chemical events in the disc following injury

may sensitize the DRG and generate pain Weinstein et al. 1988

Disc Pain

Acute compression of the nerve root with disc protrusion is estimated to generate a contact pressure of ~ 400 mm Hg compression.

Spencer et al. 1984 This compression may cause numbness,

parasthesiae, and weakness but not pain.Rydevik et al. 1984, Garfin et al. 1991

5-10 mm Hg of pressure causes impairment in blood flow

50-75 mm Hg of pressure causes increased permeability of blood vessels, edema, increased tissue pressure, altered local ion balance, and altered impulse contraction

Olmarker et al. 1989, Lind et al. 1993

Nerve Root Compression

Compression of an inflamed nerve root may cause pain

Proposed mechanisms of inflammation◦ Lowered pH◦ Breakdown products from nucleus◦ Proteoglycans from disc◦ Autoimmune reaction to exposed disc tissue

Mirza and White, 1995

Nerve Root Pain

The degenerated disc has been shown to contain high levels of inflammatory mediators, thought to regulate the immunological response to injury.

-Guiot and Fessler, 2000

Application of NP to the nerve root reduces blood flow in the DRG and causes vascular changes and hypoxia.

Causes hypersensitivity leading to an increased spontaneous discharge rate.

Excitation and mechanical hypersensitivity may be induced without mechanical compression.

- Takebayashi, et al. 2001

The Effect of NP on the DRG

Inflammatory Mediators GUIOT and FESSLER, 2000

Inflammatory Mediators

Normal Degenerative Disc

Gelatinase 1.05 5.76

Caseinase (Stromelysin) 0.110 0.432

Nitric Oxide (nmol/g) 51.33 132.21

Interleukin -6 174 30401

PG E2 (ng/ml) 1.71 20.85

Nucleus pulposus-induced effects on the nerve root seems to be mediated by disc cell-related cytokines, which in turn have a role in mediation of the immune response.

Brisby et al. 2000

The Role of Cytokines

Proteoglycan Synthesis

Matrix Degeneration

Direct Stimulationand Sensitization

of DRG and

Spinal Nerve Root

Net Loss of Proteoglycan

Disc Degeneration

LOW BACK PAIN RADICULOPATHY

CYTOKINES NITRIC OXIDE

PGE2 OTHER INFLAMMATORY AGENTS

Direct Stimulationand Sensitizationof Nerve Endingsof the Functional

Spine Unit

- Kang et al. 1997

◦ Involved in vasodilation, neurotransmission, cytotoxicity and gene regulation in several organ systems

Hashizume et al. 1997◦ Involved in the inhibition of proteoglycan synthesis

by IL-1 Kang et al. 1997

◦ Synthesis may be stimulated by TNF-a and other cytokines.

Aoki et al. 2002

Nitric Oxide (NO)

◦ Include Collagenase-1 and -3 (MMP-1 and -13) and Gelatinase A and B (MMP-2 and –9)

◦ Involved in the normal turnover and pathologic degradation of extracellular matrix in connective tissues

Borden and Heller, 1997◦ Able to degrade all known matrix components,

including collagen types I, II, and III, which make up 80% of the disc collagen

Roberts et al. 2000

Matrix Metalloproteinases

◦ PGE2 and IL-6 are present in large quantities in the herniated discs

◦ Both are strongly stimulated by IL-1◦ In articular cartilage, IL-6 and PGE2 may be

possible intermediaries in the suppression of proteoglycan synthesis

Kang et al. 1996

Prostaglandin E2 and Interleukin-6

Phospholipase A2◦Lipolytic enzyme which hydrolyzes certain phospholipids and free fatty acids, generating prostaglandins and other eicosanoids which are potent inflammatory mediators

◦Application onto nerve roots in rats resulted in demyelination in the nerve fibers and increased ectopic discharges in response to mechanical stimuli.

Chen et al. 1997

PA2 activity is 20,000 to 100,000 fold more than any other phospholipase activity

PA2 extracted from the human lumbar disc has a powerful inflammatory effect in vivo

Increased PA2 activity is seen in disc tissue◦ 50 times higher than in synovial tissue

Saal et al. 1990

Phospholipase A2

The effect of tumor necrosis factor TNF-a on the nerve root was remarkably similar to the effect of application of the nucleus pulposus itself, indicating that TNF- a may be an “early player” in pathophysiologic reactions resulting from nerve root injury.

Aoki et al. 2002

Tumor Necrosis Factor (TNF- )a

The left L5 nerve root and corresponding DRG were examined with application of TNF-a, as well as on response to pinch and brush stimulation with and without application of TNF-a.◦ Spontaneous discharge of both wide dynamic

range and nociceptive specific neurons increased significantly within 2 hours of application.

◦ Within 2 hours of application, discharge from pinch stimulation became more intense and prolonged.

◦ No change was observed between control and experimental groups in response to brush stimulation.

Onda, et al. 2002

Exogenous Application of TNF- a to the Nerve Root

CT◦ Excellent imaging of bones, inadequate for nerve

roots◦ Less sensitive than MRI for disc pathology

MRI◦ Detailed imaging of discs and nerve roots◦ Detailed imaging of herniation

Discography◦ Necessary for confirmation of the painful disc

Diagnostic Studies

Discograms produce mechanical stimulus Injection may directly stimulate

sensitized nerve fibers in the anulus Weinstein et al. 1988

False-positive rate has been reported as 0%

Gunzburg et al. 1992 Specificity has been reported as 31%

Walsh et al. 1990 Sensitivity has been reported as 81-100%

Nachemson, 1989

Discography

Early degenerative disc disease may exist before there is loss of disc height or signal intensity, therefore appearing normal on MRI

Scheibler et al. 1991 Brightbill et al. 1994

MRI is less specific than discography in detecting disc pathology

Gunzburg et al. 1992

Why is discography necessary?

Confirmation of the exact symptomatic disc level(s): A recent study indicated that normal MRI and T2-weighted MRI with additional Gd-DTPA-enhanced images were superior at identifying posterior annular tears, however could not replace discography in terms of confirming the exact symptomatic disc level(s).

Yoshida et al. 2002

The size of disc herniation in relation to the size of the spinal canal has been reported to provide the best correlation to clinical findings

Sagittal plane ratio of disc herniation to canal size has also been correlated to the degree of sciatic pain.

Thelander et al. 1994

Disc Herniation

Radiological Classification of Disc Herniation

Classification Findings

Bulge Symmetric extension beyond bone

Protrusion Asymmetric extension of anulus beyond bone

Extrusion Focal extension beyond anulus

Free Fragment Herniated material dissociated from the disc

- Modified from Mirza and White, 1995

-Modified from Adams, 2002

Morphological Classification of Disc Pathology

Grade Nucleus Anulus End Plate Vertebral Body

I Bulging Discrete lamellae Uniform thickness

Rounded margins

II Fibrous changes peripherally

Mucinous material between lamellae

Irregular thickness

Pointed margins

III Consolidated fibrous changes

Loss of anular demarcation

Focal defects Chondrophytes

IV Horizontal clefts in the nucleus

Focal disruptions Fibrocartilage <2 mm osteophytes

V Clefts extending into the anulus

Clefts through anulus

Diffuse sclerosis

>2 mm osteophytes

- Modified from Thompson et al. 1990

Paramedian sagittal anatomic section showing a contained herniation.

The outermost lamellae of the AF and the PLL (arrowhead) are intact. Asterisk: nerve root that is penetrating the intervertebral foramen- Modified from Postacchini and Rausching, Pathomorphology, 1999

Midsagittal section of lumbar intervertebral disc

The anterior portion of the sic is considerably larger than the posterior and the anterior annular lamellae have lost their curvature, whereas the posterior lamellae have an increased curvature. A portion of the NP is displaced dorsally with respect to the rest of the nucleus.


Paramedian sagittal section of L5 vertebra and lower 2 lumbar discs in an elderly subject.

The L4-L5 disc is decreased in height and a long radial cleft is visible (arrowhead). The vertebral bodies are no longer covered by the cartilage EPs. The posterior AF bulges and is in contact with the ligamentum flavum (asterisk). The L5-S1 disc is almost completely resorbed and also demonstrates a radial fissure and bulging AF.

- Modified from Postacchini and Rausching, Pathomorphology, 1999

Lateral sagittal section of a cadaver spine at L4-L5 level. The intervertebral disc, of normal height, shows fissures in the posterior AF reaching in proximity to the outermost lamellae. The annulus bulges into the vertebral canal and, in its caudal portion, the prominence has the appearance of a true herniation. Asterisk: ligamentum flavum located ventrally to the facet joint.


Axial section of a cadaveric spine immediately cranial to the L4-L5 disc.

Top: Disc herniation extruded cranially in the posterolateral region and partially in the left intervertebral foramen (arrowhead). The herniation encroaches on the spinal canal, but appears to compress only the root running in the intervertebral foramenBottom: Higher magnification.


Anatomic Section at the Level of the IVD

Combined stenosis of the spinal canal resulting from moderate constitutional narrowing of the canal and thickening of the ligamenta flava (asterisk) associated with mild hypertrophy of the articular processes.


Midsagittal section of the cadaver spine at the L4 level.

The PLL (arrowheads) is adherent to the adjacent discs, but not to the vertebral body. - Modified from Postacchini and Rausching, Anatomy, 1999

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Pathophysiology of low back pain