The LSS represents a narrowing of the spinal canal in the lumbar region that can be acquired (degenerative) or congenital (developmental). The narrowing of the spinal canal can be caused by degenerative changes such as marked hypertrophy of the facet joints, formation of osteophytes, hypertrophy or thickening of the LF, and disc herniation. Also, any space occupying lesion, including abscess and tumors can lead to the LSS. However, it is well established that degenerative LSS represents a condition of spinal stenosis usually due to changes in the LF, hypertrophy of the facet joints or due to buckling of the LF secondary to disk height loss, and as such, LSS and LDH are regarded as two different conditions [15]. As the LF covers most of the posterior and lateral part of the lumbar spinal canal, morphological and histological changes merit special attention in the development of LSS. Many studies examined histological changes of the LF in patients with LSS, and in majority of cases control group consisted of the patients with LDH in which it is assumed that the changes in LF are not so pronounced [9, 16,]. Since degenerative changes in the LF are also increasing with age, especially fibrosis, e.g., the amount of elastic fibers decrease with age and these fibers are replaced by fibrous collagen tissue, compering histological appearance of LF in patients with LDH and LSS can be a methodological pitfall [17, 18]. The first part of our study was to show clinical and radiological/morphological differences between groups with LDH and group with LSS, in order to make a clear distinction between these two conditions. There were no significant demographic differences between the two examined groups, e.g., groups did not differ in terms of gender, level of education, job difficulty, sitting time at work nor in smoking cigarettes. On the other hand, groups differ significantly in age, with LSS patients being older. Also, patients with LSS had significantly higher body mass index (BMI), as well as more comorbidities than patients with LDH. Groups differ significantly in clinical findings, e.g., patients with LDH and patients with LSS had significantly different chief complaints, with sciatica/radicular pain being the main complaint in patients with LDH and spinal claudication’s being the most common symptom in patients with LSS. Also, groups differ in the duration of main symptoms, with LSS patients having symptoms in a significantly longer period of time. Differences between examined groups were also significant regarding neurological status e.g., LDH patients more often had a positive Lazarević sign as well as Bragard sign. Also, differences were significant in the type of reflexes, but there were no significant differences of motor strength and presence of paresthesia’s. Finally, groups didn’t show difference in the health-related quality of life determined by the EuroQol EQ-5D questioner, which suggests that the severity of the disease or the impact of the disease on patient’s life is similar between groups. Morphological/radiological investigation showed significant differences of several factors, including scoliosis angle which was more pronounced in the LSS group, as well as ligamentous interfacet distance, laterolateral diameter, and anteroposterior diameter of dural sac, as well as dural surface, which had higher values in patients with LDH comparing to patients with LSS. Interestingly, groups differ significantly in the value of average facet joint angle with higher values in patients with LDH. Most importantly, thickness of the LF on both sides differed significantly between groups, with significantly thicker LF in patients with LSS. According to our study, a clear distinction can be made between the two entities, e.g., LDH and LSS, and thus LDH patients can be a control group for a group of patients with LSS in the study of histological differences in the LF. We believe this is a unique aspect in methodology and significant improvement over previous studies that investigated LF.
According to literature, stenotic changes are most prevalent at the L4/L5 level, followed by the L3/L4 and L5/S1 levels, and about 95% of disc herniation’s occur at L4/L5 or L5/S1 [19]. Our findings are in accordance with this data. Groups did not differ from each other regarding gender but differ in age with LDH patients being significantly younger, which is another positive factor in our methodology, since degenerative changes of LF are age related, e.g., LF tends to thicken with increasing age [20].
Normal LF is composed of about 80% elastic and 20% collagen fibers. Upon thickening and hypertrophy, LF shows elastic fibers loss and an increase in amount of collagen fibers, resulting in fibrosis. Previous studies indicated that LF hypertrophy was characterized by fibrosis, loss of elastic fibers, increased collagen fibers, calcium depositions, ossification, degeneration of elastic fibers with disturbance of tissue architectonics, and chondrometaplasia [8, 21]. In our study there was significant difference between degree of LF fibrotic changes, e.g., in patients with LSS LF showed more pronounced and severe fibrosis with significant loss of elastic fibers and increase in amount of collagen fibers all of which is followed by significantly damaged architecture of the remaining elastic fibers. Described histological changes are similar to scarring during the post-inflammatory repair process in other tissues [21]. Sairyo et al. postulated so called scar-repair-scar theory in which mechanical stress produces damage of LF which is the initial trigger for an inflammatory reaction and subsequent development of tissue scarring [22]. It is also postulated that cells of LF interact with macrophage-like cells to produce angiogenesis-related factors, and that activated LF cells exposed to macrophages can impact the stimulus of angiogenesis-related factors. This implies that fibrosis and scarring, triggered by an inflammatory reaction, is the major mechanism of hypertrophy of LF. So, inflammatory reactions are initiated by trauma such as mechanical stress and are followed by the repair process. Further on, hypertrophied and thickened LF, containing less elastic and more collagen fibers is vulnerable to repetitive flexion-extension motion resulting in a vicious cycle of scar-repair-scar process [21]. Reduced elasticity is certainly contributed by calcification or ossification of the LF, which is also seen as part of pronounced degenerative changes in patients with LSS, especially in increasing age [16]. However, our study did not show difference in calcium deposition between examined groups.
It is postulated by Chokshi et al. that inflammatory changes surrounding the degenerative facet joints may be the inciting etiology of LF thickening [15].Also, several studies revealed leakage of inflammatory cytokines from degenerating facet joints, implicating these molecules as causes of both LF thickening and pain generation in the adjacent nerve fibers [23]. It is well established that interleukin-1 (IL-1), a cytokine produced by chondrocytes and other cells in the joint, plays an important role in cartilage degradation by stimulating the synthesis of degradative enzymes that inhibit the production of proteoglycans. Other cytokines that appear to act synergistically with IL-1 to promote matrix breakdown are interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha). All of these cytokines are routinely found in inflamed joints [13, 24]. In our study an increased presence of inflammation cells, i.e., macrophages in LF were shown in patients with LSS, but statistical significance, although close, was not achieved, probably due to the relatively small number of samples. However, these overall findings suggest chronic inflammation that may be the cause of LF thickening in patients with LSS.
The major symptom of LSS is neurogenic (spinal) intermittent claudication’s with a decrease in walking distance. Besides claudication’s, low back and leg pain can be seen in patients with LSS [9]. This was also seen in our study with neurogenic (spinal) intermittent claudication’s as the main complaint in patients with LSS.
Although many studies have been performed, clear understanding of the specific pathophysiological mechanism of neurogenic claudication’s remains challenging. The main theories propose that neurovascular compression plays an important role. The neuro-ischemic theory suggests that poor blood and oxygen supply to the spinal nerve roots results in claudication’s. In contrast, the venous stasis theory proposes that a combination of low blood oxygen levels and metabolite buildup are responsible due to venous backup at the nerves of cauda equine. Increasing pain, numbness and gait disturbance with walking may be explained by the corresponding increase in nerve root oxygen requirements [25]. The third and most recent theory implies that chronic inflammation itself leads to the appearance of pain, as a result of the inflammatory response. Several studies confirmed that inflammation and degeneration due to osteoarthritis of facet (zygapophyseal) joint play’s important role in pathogenesis of LSS and neurogenic claudication’s, e.g., a cytokine Interleukin-1 (IL-1) produced by chondrocytes, macrophages and other cells in the joint, plays an important role in cartilage degradation by stimulating the synthesis of degradative enzymes that inhibit the proteoglycans production. All of these molecules i.e. inflammatory cytokines are consistently found in inflamed joints. Enzymes secreted by the chondrocytes are released into the extracellular matrix and degrade the matrix proteins and decompose structure. Most important enzymes that have been identified as playing a major role in collagen and proteoglycan degradation are the matrix metalloproteinase (MMPs), and many others. Under normal condition, these destructive enzymes activation is held in check by inhibitors, such as plasminogen activator inhibitor-7 (PAI-7) and tissue inhibitor of metalloproteinase (TIMP). These enzyme inhibitors work by making complexes that inactivate the action of degradative enzymes. Chondrocytes are responsible for maintaining the natural balance between these degradative enzymes and their inhibitors. In osteoarthritis, there is an imbalance between the levels of these destructive and degradative enzymes such as MMPs, and their inhibitors, such as PAI-7 and TIMP. Osteoarthritis affects the articular cartilage and underlying bone, as well as adjacent joint structures. As the cartilage becomes eroded, small fragments may become loose and float within the capsule of joint. Progressive cartilage degeneration results in narrowing of the joint space which is frequently seen in LSS patients. Areas of bone stripped of cartilage have significant loss of the shock-absorbing mechanism which leads to contact of bone on bone. This causes underlying subchondral bone to form a new articulating surface in the joint and become polished and smooth. In subchondral plane, osteoblasts begin to form new bone tissue and osteophytes in response to messenger molecules secreted by the chondrocytes, which leads to bone remodeling and formation of cartilaginous and bony overgrowths and osteophytes especially in non-weight-bearing joint areas. These changes that occur within the joint are due to inflammatory response and inflammation [23]. New and recent studies have revealed higher production and leakage of inflammatory cytokines from degenerating zygapophyseal joints, implicating these molecules as causes of both LF thickening as well as pain generation in the adjacent nerve fibers [25]. This inflammation theory has its root in the fact that the symptoms of degenerative spine pathology, especially in patients with LSS are often disproportionate to the underlying extent of the disease, e.g., the degree of spinal stenosis does not always correlate with the severity of symptoms and claudication’s [18]. In our study the overall histological appearance of LF in patients with LSS resembles histological appearance similar to tissue scarring during the post-inflammatory repair process in other organs, which is in favor of the inflammatory theory of spinal claudication’s.
In recent years, Banditz et al. studied the phenomenon of nociceptive nerve fiber sprouting, called sensory hyper-innervation which was found in different diseases with inflammatory and non-inflammatory origin such as rheumatoid arthritis, Achilles tendinosis, Crohn's disease, Dupuytren contracture, chronic Charcot foot, and anterior knee pain. They summarize that sensory hyper-innervation is common in many musculoskeletal diseases. They also found a higher density of sensory nerve fibers in LF of LSS patients. These findings support the role of LF in associated low back pain. Density of sensory nerve fibers was positively correlated with typical markers of clinical pain and functional disability. Inflammation as estimated by macrophage infiltration and higher vascularity didn’t play a marked role in LF in their LSS patients [18]. In our study, patients with LSS showed increased presence of inflammation cells, i.e., macrophages in LF butstatistical significance, although close, was not achieved. Same as in study of Banditz et al. we did not find higher vascularity of LF in patients with LSS, but we showed that patients with LSS have more myelinated nerve fibers in LF than patients with LDH. Recently, a sprouting of autonomic sympathetic fibers into the upper dermis of the skin, an area that is normally devoid of them, was found in the skin following chronic inflammation of the rat hindpaw. Longo et al. showed that that transmitters released from the sprouted sympathetic fibers in the synovial membrane and upper dermis contribute to the pain associated with arthritis. Blocking sympathetic fiber sprouting may provide a novel therapeutic approach to alleviate pain [26]. This phenomenon of nociceptive nerve fiber sprouting in LF of patients with LSS can be result of chronic inflammation, since overall histological appearance of LF is similar to tissue scarring during the post-inflammatory repair process in other organs with significant decrease in the number of elastic and increase in the number of collagen fibers with impaired tissue architecture. In our study symptoms in patients with LSS lasted significantly longer than in patients with LDH which also speaks in favor of long-acting chronic smoldering inflammation.