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| Degenerative Disc Disease Unlike other tissues of the body, the intervertebral disc under goes an early and often severe form of aging and degeneration (6 ,8,14,151,152 ). In most humans, this aging/degeneration process is slow and steady, but in some the process rapidly accelerates and may lead to catastrophic failure of the disc; which in turn may lead to chronic pain and disability. This 'accelerated' form of aging/degeneration may be called Degenerative Disc Disease (DDD), although the term is commonly and erroneously used to describe any form of disc degeneration. Research has strongly linked DDD to back pain, and sciatica (201,206,219,227), although not in every case, for it is well known that DDD, disc protrusion, and stenosis do occur in completely asymptomatic people (100-106), but for about 10% of the population, DDD will result in permanent chronic pain and disability (250-253). Technically it's not the actual process of DDD that results in pain; it's the evil 'end-phases' of the disease that have the potential to generate back pain. These end-phases include anular tears (aka: Internal Disc Disruption or IDD) (203,209,216,231); disc protrusions (227); nerve in-growth (900,904,905,906); and the ultimate end-phase, stenosis. The diagnosis of DDD is best made on T2-weighted MRI imaging (27), although some of the late appearances of DDD (disc collapse, osteophytosis, and sclerosis) may also be seen on CT scan and X-ray. The MRI appearance of DDD is easy to spot, even for the layperson, and is characterized by a loss of 'signal intensity' (loss of whiteness) of discal tissue, which makes the disc appear black instead of bright white. Technically, this 'Blackening' of the disc occurs because the disc has greatly lost its water content and become dehydrated. This 'blackening' is called disc 'Desiccation'. Since the MRI signal intensity (whiteness) is directly related the disc's water content (215,226), any loss of discal water will proportionally decrease the 'whiteness' of that disc on T2-weighted MRI. So, in layman's terms, the dryer the disc, the blacker and more degenerated it will look on MRI. Why some discs prematurely degenerate (DDD) and cause chronic pain and others don't is still somewhat controversial, however, it is becoming clearer that poor genetics (397-399,403,413a); a past history of moderate to severe spinal trauma; or have an occupation that is heavy, and labor-intensive are the main risk factors (201,16). These factors will be discussed in depth below. Warning: In order to really understand DDD and disc aging, you must understand a few basic principles of disc physiology. I'm going to assume that you understand normal disc physiology and anatomy. If you don't please go (here) and learn your basic structures, and more importantly, learn the basics physiology of the disc. You will need to know why water (hydrostatic pressure) is so very important for normal disc function (allows the nucleus to support the axial load of the body), and how the cells of the disc maintain discal water content (via proteoglycan aggrecan production) In order to understand DDD, we must first understand the natural disc aging process, or the 'normal pathway' of degeneration, which occurs in all humans to varying degrees and does NOT lead to pain. Natural Disc Aging: (NDA) The most common and striking feature of disc aging and degeneration is the loss of the proteoglycan molecule from the nucleus of the disc (333, 26). Other findings of aging include a progressive dehydration (18), a progressive thickening (via cross-linking, glycation and CML formation), brown pigmentation formation (66) and increased 'brittleness' of the tissues of the disc (62). There are two main factors that are involved in the aging process of the disc and both of these factors are amplified because of the already poor vascular supply of the disc: 1) Idiopathic blood vessel/nutrient loss and dehydration: The short explanation: For unknown reasons the nucleus of the disc losses much of its vital blood supply during the first decade of life (6). Without sufficient nutrients (which are contained in the blood) the cells of the disc begin to die (500) and the disc (especially the nucleus) becomes depleted of water. The drop in water/proteoglycan content is one or the classic signs of disc aging (333). Because of this dehydration of the nucleus, there is ultimately a 'weight-bearing shift' that occurs from the nucleus onto the outer anulus, ring apophysis, and the zygapophyseal joints. This increase stress upon the preceding posterior structures may lead to further more severe forms of aging, i.e., DDD. The long version: Under the physiology section we have learned how important disc nutrition is in maintaining a normally functioning disc. To recap; as long as the cells of the disc receive an adequate nutrient supply (which is obtain from the diffusion of oxygen, glucose, and amino acids from capillary beds just above the end-plates, into the disc), they will happily manufacture the proteoglycan molecule, which combines within the disc to form the larger aggrecan and aggregate molecules. It is these aggrecan molecules that trap and hold water within the disc. A fully hydrated disc will have a very high hydrostatic pressure (osmotic pressure) which makes the nucleus pulposus (which is 80% water in a normal disc) incredibly strong and able support the lion's share of the axial load from the body. Without an adequate supply of nutrients, the cells of the disc will die. The preceding fact was substantiated by the 2001 Volvo Award winning study of Horner and Urban (500), who studied the viability of living human disc cells under different conditions. They concluded that if the cells of the disc failed to get proper nutrients - such as oxygen, or glucose - or if the pH level of the disc rose (because waste is not being diffused out of the disc), disc cells would die and stop producing the vital proteoglycan molecule; without proteoglycans, the disc losses its water content (dehydrates) and losses its hydrostatic pressure (osmotic pressure) (241). This lost proteoglycan content is the most striking feature of disc aging and degeneration (333). Other research has confirmed this cell death as well. In 1982, Trout and Buckwalter discovered that by adulthood over 50% of the cells of the disc were dead (321). So what's killing the disc cells and resulting in this loss of proteoglycan content? Starvation! It seems that the human disc becomes 'nutritionally compromised' from the moment we begin to stand and walk. In 2002, Boos et al. observed an idiopathic "obliteration" of portions of the nutrient-providing capillary beds, which lie just above the vertebral end-plates. (Remember that these capillary beds are the ONLY source of nutrients for the cells of the inner anulus and nucleus.) Amazingly, this 'auto-destruction' begins within the first two years of life, and worsens over the next 8 years. Specifically, they stated that between the ages of 3 and 10 there was "a dramatic decrease of physiologic vessels in the end-plate..and an abundance of areas with obliterated vessels. and a substantial increase in (disc) cell death." (6) THESE FINDINGS WERE THE 'SMOKING GUN' that scientists had been waiting for and suggested that the initial causation of disc aging and degeneration was 'nutritional compromise', secondary to an idiopathic loss of the discal blood supply above the vertebral end-plates. Needless to say, Boos and company won the '2002 Volvo Award in Basic Science' for this most shocking discovery. Other factors affecting disc nutrition via diffusion rates of nutrients through the vertebral end-plates include end-plate calcification (506, 537, 538, 552,), the effects of changes in blood flow patterns secondary to arterial stenosis (522, 524-527), smoking, diabetes, and exposure to vibration (500, 517). The Vicious Cycle of Degeneration: This progressive loss of proteoglycan and dehydration begins to 'snowball' out of control. Not only because of the progressive loss of nutrients, but also because of the fact that decreased hydrostatic pressure also slows the production of proteoglycan by the disc cell (11). Here's what this vicious cycle looks like: As the nutrient supply within the disc drops (because of blood vessel obliteration and later end-plate mineralization), the disc cells start to die. Because there are fewer available disc cells around to make proteoglycan, there is a drop in the amount of circulating proteoglycan aggrecan molecules. This decrease in the aggrecan molecule, (which is what holds water within the disc) results in both dehydration, and a decrease in hydrostatic pressure within the nucleus. The loss of hydrostatic pressure has two negative effects on the disc: a) it will cause a further decrease in the amount of circulating proteoglycan aggrecan molecules, for we know from the work of Handa et al. that disc cells need a constant hydrostatic pressure level of 3 atm to function normally (11). Any increase or decrease in hydrostatic pressure caused a reduction proteoglycan production, which in turn decreases hydrostatic pressure even more - hence the vicious cycle. b) Now, these biochemical changes begin to change the biomechanics of the disc: With the decrease of hydrostatic pressure the nucleus, like a deflating beach-ball, can no longer carry the full axial-load (weight) of the body. A 'shift' in the axial-load distribution begins to occur, with the periphery of the disc (outer anulus, ring apophysis, and zygapophyseal joints) taking on more and more of the load and stress. Experimentally, the anulus of a degenerated disc shows a very high 'stress-load' on the anulus and NOT the nucleus (17 ,12 ). We will later learn that this 'load-shift' can be greatly accelerated if the volume of the nucleus is increased by trauma-induced structural damage to either the end-plate (compression fracture) and/or tearing of the inner anulus. 2.) Non-Enzymatic Glycation & the aging process: Glycosylation (aka: Glycation) Glycation (aka: Glycosylation, or non-enzymatic glycation) is a biochemical reaction which occurs when reduced sugars (like glucose) come in contact with proteins (like disc collagen) in an avascular environment. The more avascular the tissue, the more severe this reaction occurs. Since the disc is the largest avascular tissue in the body, the glycation process thrives within its substance and results in a slow but steady transformation of disc collagen into a thicker and more brittle substance. Specifically, this reaction occurs between the protein molecules within the collagen, and free floating glucose (reduced sugar). This reaction is called 'posttranslational protein modification' or simple Glycation. Here's how it work. In the absents of oxygen, reduced sugars start to 'rub against' (bind) the proteins within the collagen. The proteins can only take so much 'rubbing', and soon are transformed into what is called an 'Advanced Glycation End-Product' or AGE. These converted discal collagen strands (AGEs) become much more brittle and also much more 'sticky', i.e., they love to combine with their glycated neighbors in a process called 'cross-linking'. This 'cross-linking' phenomenon makes the disc thicker, more fibrous and more susceptible to the development of DDD (62). It also stains the discal tissue a distinct shade of brown (66). Finally the unstable AGEs molecules, which produce another evil biochemical called the 'free radical', oxidize into a much more stable structure called a CML (N-Carboxymethyl-lysine). CML formation has been found to be an excellent indication of discal aging (15). In fact Andreas and Boos won the 1997 Volvo Award for their work in using the presents of CML-modified discal protein as an indicator for the various stages of aging (15). I'm not going to review this study for it's out of our scope, but for those of you who need-to-know, his paper is an excellent read. That about does it for the natural aging process. Now lets learn how and why things 'go wrong' with this natural aging process. DDD: It seems that about 10% of us humans will develop chronic, life-long, back pain as a result of an accelerated form of natural disc aging which is to some degree, is traumatically induced. We may call this Degenerative Joint Disease (DDD), although keep in mind that many doctors use the term DDD and natural disc aging interchangeable. DDD includes all of the mechanisms of natural disc aging that we have discussed above but goes a step farther and includes often painful anular tears (216), disc protrusions (303) arrant nerve ingrowth (900), and stenosis. The Risk Factors: There are two major risk factors that increase the chance of someone developing debilitating DDD: 1) Traumatically induced 'Structural Damage' to either the anulus fibrosus or the vertebral end-plate (12 ,59,16 ). 2) Inheritance and/or Poor Genetics, which research has demonstrated to be the single greatest risk-factor for DDD (505,411). Let's explore the major risk factors more in depth: 1) DDD induced by 'Structural Damage' to the Disc: The 'Structural Damage Theory' (as I call it) of DDD, is based on the fact that any sudden loss of nuclear hydrostatic pressure (as a result of end-plate fracture/micro-fracture, and/or inner anular disruption) will result in a sudden and devastating 'axial-load-shift' (weight bearing shift) from the 'deflated' nucleus, onto the posterior anulus, ring apophysis, and zygapophyseal joints (12,59,16). This extra pressure upon the posterior anulus results in biochemical changes (MMP-3 secretion) which encourage the break down (degradation) and weakening of the anulus, hence encouraging painful anular tears (IDD) which may lead to disc herniation (19). Let's discuss this in more depth: The Vertebral End-Plate: The Achilles' Heal of the disc. The vertebral end-plates are definitely the 'Achilles' Heal' of the motion segment (16) (two vertebrae and the disc in-between), and are easily damaged by 'axial over-load injuries'; such as a fall on the buttock, lifting something that is way too heavy, or from repetitively lifting something moderately heavy (fatigue failure) (16). It has been repeatedly demonstrated that when the motion segment is experimentally compressed to point of 'failure', it's almost always the end-plates that 'breaks' first, NOT disc (30-33). It's also known that it doesn't take much end-plate damage to trigger this 'axial load-shift'. Adams et al. has experimentally determined that only "minor compressive damage to a middle-age vertebra" will result in a "large and progressive" axial load-shift, that always upon the posterior anulus (16). Abnormal Hydrostatic Pressure accelerates disc degeneration: Both Handa et al. (11) as well as Ishihara (20) have concluded experimentally that disc cells are very picky about the amount of hydrostatic pressure that they can function in. They thrive at 3 atm of hydrostatic pressure, which just happens to be the normal pressure of a non-degenerated disc. Any variation in that pressure, EITHER higher (>30 atm) or especially lower (< 1 atm) will stop that disc from functioning (making proteoglycan which hold water within the disc). Another Vicious Cycle: When the vertebral end-plates or inner anulus become disrupted, the 'volume' of the nucleus is increased (the nucleus has gained extra space), which in turn causes an immediate and sudden drop in the hydrostatic pressure within that nucleus (23). In order to get that nuclear pressure back up, the disc cells would have to kick into 'over-drive' and make proteoglycan (which would suck up more water and resort hydrostatic pressure). Unfortunately, as noted in the above paragraph, the cells of the human the disc cells turn OFF in response to lowered hydrostatic pressure (< 1 atm) (11,20) instead of ON, so there is no chance to 'pump that nucleus back up'. To make matters even worse, since many disc cells are no longer making proteoglycan, the hydrostatic pressure falls even lower which turns off even more cells and a vicious cycle is born. This vicious cycle shifts more and more 'axial-load' onto the posterior anulus, hence worsening the degradation of the anulus even more. 2) Inheritance and Poor Genetic: The number 1 risk factor of DDD. There are three areas of study in this sub-field of disc degeneration: Familial associations, unspecific genetic twin studies, and specific gene studies. A) Familial Risk factors for DDD: IF IT'S IN THE FAMILY WATCH OUT: There are two studies that strongly indicate that genes for DDD do exists and carry a significantly high risk factor for the passage of DDD and its evil end-phases (disc herniation in these studies) to the off-spring. In 1998, Matsui L et al. (398) demonstrated for the first time that moderate to severe disc degeneration was strongly associated with a family history of past disc surgery. This study evaluated two groups of patients (gender and age matched) that were suffering from lower back pain and/or unilateral leg pain. The first group (study group) all had immediate family members (first degree) that had previously undergone lumbar disc surgery. The second group (control group) had no immediate family members that had under disc surgery. Both groups had the same level and duration of back/leg pain entering into the study. MRIs were performed on all the members of both groups. RESULTS: The 'study' group had a much higher incidence of moderate and severe disc degeneration (DDD) on MRI than the control group. Specifically, there was about a 50% greater chance of developing severe disc degeneration in the relatives of past disc surgery patients. Matsui concluded that paper by saying, "There may be a genetic factor and familial predisposition in the development of lumbar disc herniation as an expression of disc degeneration." Other studies have found similar results (397,399) to that of Matsui. This same 50% increased chance of developing DDD was also seen in a study by Kellgren JH, et al. where they found first-degree relative are twice (50%) as likely as population-controls, to have generalized osteoarthritis involving many joints of the body (396). So, if you have someone in your family who has crippling arthritis, or who has had back or neck surgery as the result of the end-phases of DDD, there is a chance that you may be at risk to suffer their fate as well. B) Gene Mutations and DDD: Even more striking than DDDs connection to familial factors, is that between certain gene mutations and DDD. Based on a fairly recent, 'Volvo Award Winning' Twin study, 'inheritance' has been determined to be the largest single 'risk-factor' of a person developing DDD (403) and this inheritance is at least partly genetic in nature (413a). It now seem likely that there may well be 'genetic weaknesses' in the collagen framework of the disc and/or genetic influences on blood supply and disc metabolism (413a). There may also be 'genetic susceptibility' that may indirectly lead to DDD such as genetically small discs, a heavy torso, or small internal levers. The latter factors may all over-whelm the disc and lead to DDD. Gene mutations occurring within the structural make-up of the disc have also been recently discovered. Here are some of these recent and exciting mutations: Two mutations (polymorphisms) have been found within the genes that produce discal collagen (type IX collagen). These gene mutations have been named COL9A2 and COL9A3. Although the occurrence of this type of gene mutation is rare, when it does occur, the association with disc degeneration and sciatica are extremely strong (406,407, 408). Another gene mutation has been associated with the discal proteoglycan aggrecan molecule (409, 410). You remember how important aggrecan molecules are right? Remember that they attract and hold water within the disc, which disc the disc high hydrostatic pressure. This particular devastating gene mutation produces a non-water absorbing aggrecan! Yikes! This gene ultimately results in severe disc dehydration and greatly increases the chance for IDD, and disc herniation (409, 410). Recently, a mutation within the Vitamin D receptor gene has been associated with DD although the mechanism is still not clear (411a, 412, 413,414). Other gene mutations have been strongly associated with disc bulging, anular tearing (IDD) and osteophytosis (412, 417). I'm sure we will hear a lot more about this fascinating research area in the near future. In future there may a blood test that will warn you if your susceptible for the development of DDD and its 'evil end-phases'. This could help you chose a line of work that was conducive to the strength of you discs and maybe help prevent a middle aged catastrophe! C. Other Risk Factors of DDD: Occupation: In 2000, Luoma et al. (201) conducted an excellent study on the relationship between DDD, pain, and occupation. They found that occupation type was strongly related to lower back pain and sciatica, however, DDD was only somewhat associate with these pains. Here's the study in a 'nut-shell': A moderate sized (50 - 60) group of construction workers [heavy lifting], heavy equipment operators [vibration & prolonged sitting], and office workers [sit & stand light work] were followed for four years via questionnaire & nurse interview. At the end of the four years a MRI, interview, and final questionnaire was done on each participant. Results: Over the last year, and over the last four years the heavy equipment operators has about 50% more sciatica (nonspecific) than the construction workers, and 66% more sciatica than the office worker. The office workers did the best and had about 25 to 30% less back/leg pain over the four year period. Interesting, despite all this sciatica (over 50% of the heavy equipment operators had complained of leg pain) there were NO disc herniation found in any of the groups! So, lower back pain and leg pain does seem to be related to occupation. DDD (defined at disc bulging and a black nucleus on T2-weighted MRI) was also associated with back pain and sciatica not nearly as strongly as was occupation was. Cigarette Smoking: Cigarette smoking with a disc condition is just a bad idea! In 1991, Battie et al. (28) won the Volvo Award for her discovery that smoking increased spinal disc degeneration (across all discs!) by nearly 20%! She did this by using twin pairs that were discordant (one twin smoked with the other twin didn't) for smoking. I personally know several spinal surgeons who will NOT perform surgery unless the patient is 'smoke-free' for at least three months. It has been theorized that smoking damages the already compromised capillary beds (which reduces nutrient supply to the disc and dehydrates the disc) above the vertebral end-plates. The 'Evil' End-Phases of DDD: As I've mentioned back at the beginning of this paper, it's not the beginning phases of DDD that are painful. The pain begins when the intervertebral disc becomes disrupted and disorganized. Let's discuss some of the possible 'end-phases' of DDD: #1) Internal Disc Disruption (IDD) and Disc Herniations: The outer 1/3 of the disc and perianuluar tissue is filled with tiny pain-sensitive nerve fiber (701-705). Because of the 'vicious cycle' of DDD that was discussed above (here) clefts and fissures begin to form in the nucleus and anulus of the disc. With time these may grow into larger anular fissures that eventually may completely rip through the disc. is 'structural disruption' of the disc, or Internal Disc Disruption (IDD) (aka: radial anular tear). Because of the structural disruption within the anulus fibrosus (via genetics, trauma, and the 'axial-load shift), nuclear material is force outward, through anuluar fissures and into the pain sensitive outer 1/3 of the anulus. This scenario may well cause extreme lower back pain, and even sciatic (discogenic sciatica). I've got three pages on the subject of IDD, and anular tears for you to further study. Disc herniations are born when the final layers of the anulus rupture and allow nuclear material to either collect behind the posterior longitudinal ligament (PLL) (this would be called a 'contained herniation' or 'protrusion'), or extrude into the peridural space (this would be called an extrusion or non-contained herniation) and compress the sensitive posterior nerve roots, dura of the cauda equina, dorsal root ganglion (DRG), and/or spinal nerve root. Now, the patient may develop 'true' radicular pain (true sciatica) which is often worse than the lower back pain. These topics will be covered separately on another page. Nerve In-growth: There is mounting evidence that a diseased disc (DDD) may be generating pain from deep within its own tissue (900,904,905,906)! For years it's been taught that the nucleus, inner and central anulus are completely avascular and aneural (have no blood or nerves), and that only the very outer layers of the posterior and anterolateral anulus contain nerve fiber (701-705). There is now strong evidence that pain carrying nerve fibers can grow inward, deep into the middle anulus and even nucleus in some cases! These nerve fibers have now been liked with chronic discogenic pain and must be considered when making a diagnosis. IDD is so important that I have devoted a several pages to it. I'll just briefly say here that natural disc aging (dehydration, stiffening, and brittleness) will predispose the to 'tearing'. Traumatic injury, and/or repetitive trauma to the spine over prolonged periods of time (strenuous occupation) can cause the disc to tear open from the inside out, which in turn may allow nuclear material to be forced Stenosis as a result of DDD: The extra axial load which is placed upon the outer structures of the disc, not only affects the anulus but also affects facet joints, especially when/if the disc begins to thin (12, 13). Human bone, as in the facet joints, responds to mechanical stress (i.e., the extra weight bearing duty) by making more bone in the areas of highest stress. This bony thickening is called hypertrophy. Stress induced hypertrophy is a good thing, for it makes the bone stronger and less apt to break under any newly imposed stress. Unfortunately, the facet joints just happen to form the posterior boarder a bony tunnel called the intervertebral foramen (IVF), in which the delicate and sensitive spinal nerve roots reside. IF our over-stressed facet joints just happen to hypertrophy (thicken) too much, and in the anterior direction, a narrowing (aka: encroachment) of the already narrow IVF will occur. The sensitive spinal nerves will slowly be crushed by the thickening facet, which leads to back pain, leg pain, and a decrease in the muscle power (motor power) in the lower limbs. This syndrome of facet joint hypertrophy into the IVF is called 'Stenosis', (lateral stenosis to be exact) and is a major concern for the elderly, i.e., it's the number one disabling spinal disorder in people over 65 (1). Bony thickening may also occur within the posterior ring apophysis, and if severe, may compress the front portion of the spinal cord (cauda equina). This type of stenosis is called 'central stenosis', and can also cause pain, motor loss, and bowel and bladder dysfunction (cauda equina syndrome). Stenosis often does very poorly with conservative care and may ultimately force the person into decompressive surgery. Now lets answer some commonly asked questions about disc degeneration:
Can the disc degeneration process be stopped or reversed? No! Once the 'train leaves the station' it is on its way; meaning that once the process of disc desiccation (dehydration) begins, there is no way to stop its progression! To understand this we need to go over some simple disc physiology; its time to get technical!! The future: Biological therapies to the rescue? NOT Researchers are futilely working on all sorts of ways to rejuvenate the dying disc via both biological based therapy and gene related therapy - based on tissue engineering (21 ,24,25,47 ). I'm not even going to bother to go into all of the theories, for their efforts will at best, only buy some additional time for the disc. The reason for my blanket condemnation? Any new implanted modified disc tissue or any gene injected to create new disc tissue, will immediately be starved for food, dehydrate, and die; just as the original disc cells did! Doh!! THERE NOT PAYING ATTENTION TO FACT THAT THE DISC CAN'T GET FOOD THROUGH THE NOW DISCOMBOBULATED VERTEBRAL END-PLATES. If you don't feed things, they die! It's not just me who believes their work is in vain. Famed researcher, author and multi-timed Volvo Award Winner, Dr. Norbert Boos, also politely insinuates that this line of research is 'doomed for failure' and advices the researchers to focus their efforts on ways of "tackling the discal inflammatory reactions (which seem to be the real 'ignition switch' of back and leg pain) at a molecular level instead of attempting tissue repair." (6) References: 1) Spivak J, "Degenerative Spinal Stenosis" J Bone Joint Surg - 1998; 80:1053-1066 2) Gruber, H.E. and Hanley, E.N., Jr. (1998) Analysis of aging and degeneration of the human intervertebral disc. Comparison of surgical specimens with normal controls. Spine 1998; 23(7):751-7 3) Sward L, et al. "Disc Degeneration and associated abnormalities of the spine in elite gymnasts; a MRI study." Spine, 1991 ;16:437 -43 4) Salminen JJ, et al. "Recurrent low back pain and early disc degeneration in the young." Spine 1999; 24: 1316-21
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