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The Murky World of Modic Changes
August 18, 2016 by Dr Matthew D. Long
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The Murky World of Modic Changes
August 18, 2016 by Dr Matthew D. Long
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The Murky World of Modic Changes
August 18, 2016 by Dr Matthew D. Long
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As chiropractors we tend to view the world through a functional lens. Although we do appreciate the importance of structural damage and pathology, our view of the world tends to revolve around the functional deficits that our patients exhibit. While this is clearly important, and obviously our unique professional strength, it is always useful to pause occasionally and reflect upon other possible reasons for patients to present to our clinics.
Whether we like it or not, there will always be a proportion of our patients who simply don’t respond to our care. There are many reasons for this, with a vast array of possible contributors all receiving attention in the research literature. These would include central sensitisation, a distorted body schema, altered sensorimotor integration, limbic vigilance and conditioned behaviours. But what about other mechanisms? Could there be something far more ‘pathological’ that might perpetuate lower back pain in some of our patients? According to some recent work on the nature of Modic changes, this may well be the case.
Modic changes were first classified and described in detail back in 1988 (1). Ever since, their significance has been debated and research interest has waxed and waned, depending upon whatever new discoveries may have been in vogue at the same time. Modic changes can only be visualised on MRI scans, and are seen as changes within the bone marrow of the vertebral body on either side of a damaged intervertebral disc. This will typically announce itself as an alteration to the signal intensity within the vertebral body and endplates.
To summarise the essence of Modic changes, they are divided into 3 subtypes:
Whether we like it or not, there will always be a proportion of our patients who simply don’t respond to our care. There are many reasons for this, with a vast array of possible contributors all receiving attention in the research literature. These would include central sensitisation, a distorted body schema, altered sensorimotor integration, limbic vigilance and conditioned behaviours. But what about other mechanisms? Could there be something far more ‘pathological’ that might perpetuate lower back pain in some of our patients? According to some recent work on the nature of Modic changes, this may well be the case.
Modic changes were first classified and described in detail back in 1988 (1). Ever since, their significance has been debated and research interest has waxed and waned, depending upon whatever new discoveries may have been in vogue at the same time. Modic changes can only be visualised on MRI scans, and are seen as changes within the bone marrow of the vertebral body on either side of a damaged intervertebral disc. This will typically announce itself as an alteration to the signal intensity within the vertebral body and endplates.
To summarise the essence of Modic changes, they are divided into 3 subtypes:
(a) Type 1 Modic changes in the vertebral body are characterised by an increased signal intensity on T2-weighted MRI sequences, representing oedema within the bone marrow. According to Kääpä et al (2), this area of increased fluid density within the marrow represents an increase in vascularised fibrous tissue and ‘fissuring or disruption in the adjacent endplates’. These areas have also shown increased levels of pro-inflammatory cytokines and increased levels of innervation. Such obvious reactivity around the endplate is highly uncommon in an asymptomatic population (2). Importantly, Type 1 changes appear dark of T1 images (which are biased towards fat-containing tissues).
(b) Type 2 Modic changes are characterised by an increased signal intensity on both T1-weighted and T2-weighted sequences. This represents a fatty degeneration within the bone marrow, as well as proliferation of granular tissue.
(c) Type 3 Modic changes are characterised by a decreased signal intensity on both T1-weighted and T2 weighted sequences which thought to be due to bone marrow sclerosis.
Figure 1. MC type I (arrows): hypointense on T1 (A) and hyperintense on T2 (B). From Zhang et al (3). Springer.
Figure 2. MC type II (arrows): hyperintense on T1 (A) and isointense or hyperintense on T2 (B). From Zhang et al (3). Springer.
In general, research has tended to focus upon the relevance of Type 1 Modic changes, largely due to their clear inflammatory nature and their strong association with back pain (4, 5, 6). Not only are such changes painful, but the mere presence of Type 1 Modic changes suggests a reduced capacity for spontaneous resorption of any associated lumbar disc herniation (7), and a poorer prognosis when nerve root blocks are used to try and control associated sciatica (8). While some studies have found that successful surgical stabilisation through fusion can reverse Modic changes (9), in general, there is no definitive management approach. This probably reflects the fact that we don’t actually understand exactly why Modic changes arise in the first place. To date, most theories about the aetiology of Modic changes have focused upon some form of segmental instability and associated disc degeneration. Segmental instability is known to create abnormal shearing forces across the annulus, leading to internal disc disruption. Associated loss of nucleus pulposus leads to focal pockets of stress upon the adjacent endplate, producing local micro-fractures and bone remodelling. The subsequent inflammatory oedema seen so clearly on T2-weighted MRI sequences suggests that fluid accumulation occurs as a result of migration of nucleus pulposus material into the highly vascularised environment of the subchondral bone. This may establish a long-term immune response, with the migrating nuclear tissue being treated as a foreign invader.
However, a number of studies have looked at an entirely different mechanism to account for Type 1 Modic changes...
Albert et al (11) published a paper in 2013 entitled, "Does nuclear tissue infected with bacteria following disc herniations lead to Modic changes in the adjacent vertebra?”. Their work followed on from a number of prior papers that had noted that patients exhibiting Modic changes on MRI often suffered chronic lower back pain that was unresponsive to other forms of therapy. Interestingly, some of these patients had responded to antibiotic therapy (prescribed for an unrelated condition), with an improvement in their back pain. Such a serendipitous improvement would make no sense unless the patient harboured a bacterial infection that was directly causing their back pain. This prompted some elegant investigative work in which samples of nuclear tissue were taken from patients exhibiting Type 1 Modic change. Within this supposedly sterile and anaerobic environment, the bacterium Propionibacterium acnes (P. acnes) was found in 53% of these patients.
But where did this bacteria come from? There has been some criticism aimed at the original studies, suggesting that the biopsy technique introduced the bacteria through contamination, as P. acnes can usually be found around hair follicles on the skin. However, further studies with rigorous techniques have shown that the bacterium does indeed find its way into the inner confines of a herniated disc, setting up residence and ultimately wreaking havoc upon the adjacent bone. But how would the bacteria find their way into the centre of a contained structure such as the intervertebral disc?
As mentioned above, P. acnes is found on the surface of the skin, and also within the oral cavity. According to Chen et al in their paper "Overview: the role of Propionibacterium acnes in nonpyogenic intervertebral discs" (12),
However, a number of studies have looked at an entirely different mechanism to account for Type 1 Modic changes...
Albert et al (11) published a paper in 2013 entitled, "Does nuclear tissue infected with bacteria following disc herniations lead to Modic changes in the adjacent vertebra?”. Their work followed on from a number of prior papers that had noted that patients exhibiting Modic changes on MRI often suffered chronic lower back pain that was unresponsive to other forms of therapy. Interestingly, some of these patients had responded to antibiotic therapy (prescribed for an unrelated condition), with an improvement in their back pain. Such a serendipitous improvement would make no sense unless the patient harboured a bacterial infection that was directly causing their back pain. This prompted some elegant investigative work in which samples of nuclear tissue were taken from patients exhibiting Type 1 Modic change. Within this supposedly sterile and anaerobic environment, the bacterium Propionibacterium acnes (P. acnes) was found in 53% of these patients.
But where did this bacteria come from? There has been some criticism aimed at the original studies, suggesting that the biopsy technique introduced the bacteria through contamination, as P. acnes can usually be found around hair follicles on the skin. However, further studies with rigorous techniques have shown that the bacterium does indeed find its way into the inner confines of a herniated disc, setting up residence and ultimately wreaking havoc upon the adjacent bone. But how would the bacteria find their way into the centre of a contained structure such as the intervertebral disc?
As mentioned above, P. acnes is found on the surface of the skin, and also within the oral cavity. According to Chen et al in their paper "Overview: the role of Propionibacterium acnes in nonpyogenic intervertebral discs" (12),
"One possible route is that P. acnes inoculates intervertebral discs via the circulation system. As a commensal bacterium residing on skin or in the oral cavity, it may invade the circulatory system when skin or mucosa is broken. It will not be observed during this period, because P. acnes has difficulty surviving and reproducing under the aerobic conditions in the blood. Typically, normal intervertebral discs are enclosed, and vascularisation occurs only in the annulus fibrosus. However neovascularisation will occur around a rupture site when the annulus fibrosus is broken, which provides a pathway for P. acnes to gain access to the nucleus pulposus. There, the anaerobic condition is suitable for P. acnes survival. This hypothesis explains why the positive rate of P. acnes is much higher in breached intervertebral discs than in normal discs.
Another possible route is that macrophages devour P. acnes in the blood, transport them into intervertebral discs via the circulatory system, and release the viable bacterium upon cell death. This hypothesis is supported by the fact that P. acnes survived inside macrophages after phagocytosis, and the devoured P. acnes is proven to be the pathogen for some chronic inflammation diseases, such as sarcoidosis. More importantly, many macrophages will aggregate around the ruptured annulus fibrosis after disc herniation, some of which may contain devoured P. acnes. Therefore, macrophages may act as a transport for P. acnes into the intervertebral discs.”
Another possible route is that macrophages devour P. acnes in the blood, transport them into intervertebral discs via the circulatory system, and release the viable bacterium upon cell death. This hypothesis is supported by the fact that P. acnes survived inside macrophages after phagocytosis, and the devoured P. acnes is proven to be the pathogen for some chronic inflammation diseases, such as sarcoidosis. More importantly, many macrophages will aggregate around the ruptured annulus fibrosis after disc herniation, some of which may contain devoured P. acnes. Therefore, macrophages may act as a transport for P. acnes into the intervertebral discs.”
It does appear that some patients may ultimately succumb to intervertebral disc infection through a simple break in the skin, or even through bleeding gums that might occur during vigorous tooth brushing. Importantly however, simply gaining access to the bloodstream does not pose a threat, as P. acnes does not survive well in aerobic conditions. The other important piece of the puzzle is the necessity for an annular tear to allow access to the inner confines of the disc. According to Zhou (13), “P. acnes was found in the discs in 1/3 patients with visible annular tear, but not seen in the discs without annular tear, suggesting that the breach in outer annulus is a key determinant for P. acnes accessing the disc”.
According to by Albert et al (11), “Studies have shown a dramatic (310%) increase in the frequency of Type 1 Modic changes following a lumbar disc herniation”. Once P. acnes has established itself within the anaerobic nucleus, inflammation in the adjacent bone may be “a secondary effect due to cytokine production or microbial metabolites (e.g. propionic acid) entering the vertebra through normal disc nutrition" (11). Importantly, these patients do not otherwise show signs of systemic illness or the classic evidence of infection (such as fever).
A further study by Albert and colleagues (14) expanded further upon the mechanism by which the bacteria can produce visible inflammatory change with the vertebrae:
According to by Albert et al (11), “Studies have shown a dramatic (310%) increase in the frequency of Type 1 Modic changes following a lumbar disc herniation”. Once P. acnes has established itself within the anaerobic nucleus, inflammation in the adjacent bone may be “a secondary effect due to cytokine production or microbial metabolites (e.g. propionic acid) entering the vertebra through normal disc nutrition" (11). Importantly, these patients do not otherwise show signs of systemic illness or the classic evidence of infection (such as fever).
A further study by Albert and colleagues (14) expanded further upon the mechanism by which the bacteria can produce visible inflammatory change with the vertebrae:
“Propionibacterium acnes bacteria secrete propionic acid, which has the capacity to dissolve fatty bone marrow and bone. We hypothesize that diffusion of propionic acid from the disc into the vertebrae causes the Modic changes. Similarly, as increased TNF-alpha and the growth of PGP-5 unmyelinated nerve fibres have been reported in Type 1 Modic changes, with the inherent slowness of these pathological processes perhaps explaining the delayed onset of improvement observed in this study”.
Over time it appears that P. acnes stimulates and perpetuates chronic inflammation within the adjacent bone and this is strongly associated with chronic lower back pain. Furthermore, the presence of Modic changes have been associated with a significant increase in the rate of disc degeneration (15).
So what are the implications of all of this?
Firstly, we must understand that there is no easily accessible test to determine whether Type 1 Modic changes are due to segmental instability (and mechanical trauma to the endplates), or an insidious infection by a normally skin-dwelling bacterium. While direct biopsy of the affected disc has been done under controlled research conditions, this is not something that is available to the average clinician. A blood test has been promoted as a possible tool for evaluating the presence of infection, although this is again not currently available for widespread use. The actual proportion of patients that have a true infection is therefore unknown and we cannot assume that all patients showing Modic changes are going to be affected. But it is worthwhile keeping the possibility of infection in the back of our mind when we are faced with a patient who is unresponsive to treatment.
A number of studies have used high-dose antibiotics (Amoxicillin-Clavulanate) for 90 days to effect a cure. While this was certainly successful in regards to resolving the patients' back pain, the authors of these studies have all voiced concern about the possible long-term consequences of such an approach. According to Albert (14),
So what are the implications of all of this?
Firstly, we must understand that there is no easily accessible test to determine whether Type 1 Modic changes are due to segmental instability (and mechanical trauma to the endplates), or an insidious infection by a normally skin-dwelling bacterium. While direct biopsy of the affected disc has been done under controlled research conditions, this is not something that is available to the average clinician. A blood test has been promoted as a possible tool for evaluating the presence of infection, although this is again not currently available for widespread use. The actual proportion of patients that have a true infection is therefore unknown and we cannot assume that all patients showing Modic changes are going to be affected. But it is worthwhile keeping the possibility of infection in the back of our mind when we are faced with a patient who is unresponsive to treatment.
A number of studies have used high-dose antibiotics (Amoxicillin-Clavulanate) for 90 days to effect a cure. While this was certainly successful in regards to resolving the patients' back pain, the authors of these studies have all voiced concern about the possible long-term consequences of such an approach. According to Albert (14),
“High-dose long-term antibiotics should not be prescribed without due consideration. Clearly in a condition as chronic lower back pain there is a potential community as well as individual hazard if used indiscriminately. However, as many patients, as in this trial, are on sick leave, at risk of losing their jobs and have a high analgesic intake, we suggest that antibiotics, when applied along the lines of this MAST protocol may be appropriate in this subgroup, i.e. chronic lower back pain with Modic Type 1 changes. We do not support the proposition that all patients with lumbar pain should have a trial course of antibiotics. The criteria in this study were very clear: chronic lower back for more than 6 months, Modic Type 1 changes in the adjacent vertebrae following a previous disc herniation. As we do with other drugs, we rely on our fellow colleagues to use clear evidence-based criteria and to avoid excessive antibiotic use.”
The use of antibiotics in the treatment of Type 1 Modic changes has not yet reached any sort of tipping point. Indeed, very few clinicians are even aware of the possibility of an underlying infection. However, some authors have suggested that the realisation that chronic low back pain may sometimes be due to infection may parallel the gradual realisation that stomach ulcers were actually caused by infection (helicobacter pylori), and not simply the product of stress. It took many years for the role or bacteria in the genesis of stomach ulcers to receive widespread acceptance, and there is probably a long way to go before the same can be said for Type 1 Modic changes. However, it is certainly something for you to think about….
Dr Matthew D. Long
BSc (Syd) M.Chiro (Macq)
Dr Matthew D. Long
BSc (Syd) M.Chiro (Macq)
References:
1. Modic MT, Sternberg PM, Ross JS, et al. Degenerative disk disease: assessment of changes in vertebral body marrow with MR imaging. Radiology 1988;166:193–99
2. Kääpä, E., Luoma, K., Pitkäniemi, J., Kerttula, L., & Grönblad, M. (2012). Correlation of size and type of modic types 1 and 2 lesions with clinical symptoms: a descriptive study in a subgroup of patients with chronic low back pain on the basis of a university hospital patient sample. Spine, 37(2), 134–139. http://doi.org/10.1097/BRS.0b013e3182188a90
3. Zhang, Y.-H., Zhao, C.-Q., Jiang, L.-S., Chen, X.-D., & Dai, L.-Y. (2008). Modic changes: a systematic review of the literature. European Spine Journal, 17(10), 1289–1299. http://doi.org/10.1007/s00586-008-0758-y
4. Jensen, O. K., Nielsen, C. V., Sorensen, J. S., & Stengaard-Pedersen, K. (2014). Type 1 Modic changes was a significant risk factor for 1-year outcome in sick-listed low back pain patients: a nested cohort study using magnetic resonance imaging of the lumbar spine. The Spine Journal, 14(11), 2568–2581. http://doi.org/10.1016/j.spinee.2014.02.018
5. Järvinen, J., Karppinen, J., Niinimäki, J., Haapea, M., Grönblad, M., Luoma, K., & Rinne, E. (2015). Association between changes in lumbar Modic changes and low back symptoms over a two-year period. BMC Musculoskelet Disord, 16(1), 193–17. http://doi.org/10.1186/s12891-015-0540-3
6. Määttä, J. H., Wadge, S., MacGregor, A., Karppinen, J., & Williams, F. M. K. (2015). ISSLS Prize Winner: Vertebral Endplate (Modic) Change is an Independent Risk Factor for Episodes of Severe and Disabling Low Back Pain. Spine, 40(15), 1187–1193. http://doi.org/10.1097/BRS.0000000000000937
7. Shan, Z., Fan, S., Xie, Q., Suyou, L., Liu, J., Wang, C., & Zhao, F. (2014). Spontaneous Resorption of Lumbar Disc Herniation Is Less Likely When Modic Changes Are Present. Spine, 39(9), 736–744. http://doi.org/10.1097/BRS.0000000000000259
8. Peterson, C. K., Pfirrmann, C. W. A., & Hodler, J. (2014). Are Modic changes related to outcomes in lumbar disc herniation patients treated with imaging-guided lumbar nerve root blocks? European Journal of Radiology, 83(10), 1786–1792. http://doi.org/10.1016/j.ejrad.2014.06.008
9. Hutton, M. J., Bayer, J. H., & Powell, J. M. (2011). Modic Vertebral Body Changes. Spine, 36(26), 2304–2307. http://doi.org/10.1097/BRS.0b013e31821604b6
10. Nguyen, C., Poiraudeau, S., & Rannou, F. (2015). From Modic 1 vertebral-endplate subchondral bone signal changes detected by MRI to the concept of 'active discopathy'. Annals of the Rheumatic Diseases, 74(8), 1488–1494. http://doi.org/10.1136/annrheumdis-2015-207317
11. Albert, H. B., Lambert, P., Rollason, J., Sorensen, J. S., Worthington, T., Pedersen, M. B., et al. (2013). Does nuclear tissue infected with bacteria following disc herniations lead to Modic changes in the adjacent vertebrae? European Spine Journal, 22(4), 690–696. http://doi.org/10.1007/s00586-013-2674-z
12. Chen, Z., Cao, P., Zhou, Z., Yuan, Y., Jiao, Y., & Zheng, Y. (2016). Overview: the role of Propionibacterium acnes in nonpyogenic intervertebral discs. International Orthopaedics, 1–8. http://doi.org/10.1007/s00264-016-3115-5
13. Zhou, Z., Chen, Z., Zheng, Y., Cao, P., Liang, Y., Zhang, X., et al. (2015). Relationship between annular tear and presence of Propionibacterium acnes in lumbar intervertebral disc. European Spine Journal, 24(11), 2496–2502. http://doi.org/10.1007/s00586-015-4180-y
14. Albert, H. B., Sorensen, J. S., Christensen, B. S., & Manniche, C. (2013). Antibiotic treatment in patients with chronic low back pain and vertebral bone edema (Modic type 1 changes): a double-blind randomized clinical controlled trial of efficacy. European Spine Journal, 22(4), 697–707. http://doi.org/10.1007/s00586-013-2675-y
15. Kerttula, L., Luoma, K., Vehmas, T., Grönblad, M., & Kääpä, E. (2012). Modic type I change may predict rapid progressive, deforming disc degeneration: a prospective 1-year follow-up study. European Spine Journal, 21(6), 1135–1142. http://doi.org/10.1007/s00586-012-2147-9
1. Modic MT, Sternberg PM, Ross JS, et al. Degenerative disk disease: assessment of changes in vertebral body marrow with MR imaging. Radiology 1988;166:193–99
2. Kääpä, E., Luoma, K., Pitkäniemi, J., Kerttula, L., & Grönblad, M. (2012). Correlation of size and type of modic types 1 and 2 lesions with clinical symptoms: a descriptive study in a subgroup of patients with chronic low back pain on the basis of a university hospital patient sample. Spine, 37(2), 134–139. http://doi.org/10.1097/BRS.0b013e3182188a90
3. Zhang, Y.-H., Zhao, C.-Q., Jiang, L.-S., Chen, X.-D., & Dai, L.-Y. (2008). Modic changes: a systematic review of the literature. European Spine Journal, 17(10), 1289–1299. http://doi.org/10.1007/s00586-008-0758-y
4. Jensen, O. K., Nielsen, C. V., Sorensen, J. S., & Stengaard-Pedersen, K. (2014). Type 1 Modic changes was a significant risk factor for 1-year outcome in sick-listed low back pain patients: a nested cohort study using magnetic resonance imaging of the lumbar spine. The Spine Journal, 14(11), 2568–2581. http://doi.org/10.1016/j.spinee.2014.02.018
5. Järvinen, J., Karppinen, J., Niinimäki, J., Haapea, M., Grönblad, M., Luoma, K., & Rinne, E. (2015). Association between changes in lumbar Modic changes and low back symptoms over a two-year period. BMC Musculoskelet Disord, 16(1), 193–17. http://doi.org/10.1186/s12891-015-0540-3
6. Määttä, J. H., Wadge, S., MacGregor, A., Karppinen, J., & Williams, F. M. K. (2015). ISSLS Prize Winner: Vertebral Endplate (Modic) Change is an Independent Risk Factor for Episodes of Severe and Disabling Low Back Pain. Spine, 40(15), 1187–1193. http://doi.org/10.1097/BRS.0000000000000937
7. Shan, Z., Fan, S., Xie, Q., Suyou, L., Liu, J., Wang, C., & Zhao, F. (2014). Spontaneous Resorption of Lumbar Disc Herniation Is Less Likely When Modic Changes Are Present. Spine, 39(9), 736–744. http://doi.org/10.1097/BRS.0000000000000259
8. Peterson, C. K., Pfirrmann, C. W. A., & Hodler, J. (2014). Are Modic changes related to outcomes in lumbar disc herniation patients treated with imaging-guided lumbar nerve root blocks? European Journal of Radiology, 83(10), 1786–1792. http://doi.org/10.1016/j.ejrad.2014.06.008
9. Hutton, M. J., Bayer, J. H., & Powell, J. M. (2011). Modic Vertebral Body Changes. Spine, 36(26), 2304–2307. http://doi.org/10.1097/BRS.0b013e31821604b6
10. Nguyen, C., Poiraudeau, S., & Rannou, F. (2015). From Modic 1 vertebral-endplate subchondral bone signal changes detected by MRI to the concept of 'active discopathy'. Annals of the Rheumatic Diseases, 74(8), 1488–1494. http://doi.org/10.1136/annrheumdis-2015-207317
11. Albert, H. B., Lambert, P., Rollason, J., Sorensen, J. S., Worthington, T., Pedersen, M. B., et al. (2013). Does nuclear tissue infected with bacteria following disc herniations lead to Modic changes in the adjacent vertebrae? European Spine Journal, 22(4), 690–696. http://doi.org/10.1007/s00586-013-2674-z
12. Chen, Z., Cao, P., Zhou, Z., Yuan, Y., Jiao, Y., & Zheng, Y. (2016). Overview: the role of Propionibacterium acnes in nonpyogenic intervertebral discs. International Orthopaedics, 1–8. http://doi.org/10.1007/s00264-016-3115-5
13. Zhou, Z., Chen, Z., Zheng, Y., Cao, P., Liang, Y., Zhang, X., et al. (2015). Relationship between annular tear and presence of Propionibacterium acnes in lumbar intervertebral disc. European Spine Journal, 24(11), 2496–2502. http://doi.org/10.1007/s00586-015-4180-y
14. Albert, H. B., Sorensen, J. S., Christensen, B. S., & Manniche, C. (2013). Antibiotic treatment in patients with chronic low back pain and vertebral bone edema (Modic type 1 changes): a double-blind randomized clinical controlled trial of efficacy. European Spine Journal, 22(4), 697–707. http://doi.org/10.1007/s00586-013-2675-y
15. Kerttula, L., Luoma, K., Vehmas, T., Grönblad, M., & Kääpä, E. (2012). Modic type I change may predict rapid progressive, deforming disc degeneration: a prospective 1-year follow-up study. European Spine Journal, 21(6), 1135–1142. http://doi.org/10.1007/s00586-012-2147-9