Whiplash is not a homogenous condition; rather the patient population consists of subgroups that display varying degrees of pain and disability. Many patients demonstrate functional improvement and a reduction of symptoms by 6 months postinjury.1–3 At the other end of the spectrum is a group of patients (∼25%) that continue to present clinically with moderate to severe levels of painful symptoms in the long-term.1,2 Reasons for this transition to and maintenance of chronic pain and poor functional recovery are poorly understood.
The process of determining who is likely to recover and who may be at risk of chronicity could possibly benefit from the identification of quantitative pathological markers that (1) are not dependent on a cognitive response from the patient and (2) could be used to better classify individuals with whiplash injury. However, the presence of relevant pathological findings (that expand beyond what would be considered normal variants) on commonly used tests, such as conventional imaging, remains inconsistent and elusive.4–8 Most radiological studies have focused on the identification of specific injury to discs, ligaments and facet joints with little or no attention provided to neuromuscular tissues.4–10
Recent findings from magnetic resonance imaging (MRI) studies have provided interesting observations, such as the presence of intramuscular fatty infiltrates and altered cross-sectional area (CSA, in mm2) in the cervical spine muscles of female subjects with chronic whiplash-associated disorders (WAD; established by ≥3 months postinjury).11–13 A consistent pattern of larger CSA was observed in the WAD multifidus muscle at each segment (C3–C7), but this contrasted to inconsistent group CSA measures for the superficial muscles, such as semispinalis cervicis and capitis and splenius capitus.12 By nature of the two-dimensional measure, CSA tends to be highly variable, which may be because of the fact that the measure does not accurately differentiate between the types of tissues within the defined region of interest. Higher fat content, for example, is likely to alter and expand the musculofascial borders thereby producing CSA measures reflecting a pseudohypertrophy.12,14 This suggests that measures of CSA of the cervical musculature with conventional measures should be interpreted with caution at least in persons with a chronic WAD.12 On the contrary, conventional measures of MR fatty infiltration seem to be more sensitive markers as they take into account the different signal intensities of fat and soft-aqueous tissues. Accordingly, measures of muscle fatty infiltrate may be the better marker of altered neuromuscular processes in traumatic whiplash.
Specifically, fatty infiltrates on T1-weighted imaging (consistent with denervation, disuse or other musculoskeletal injury-related pathologies),15–18 have been observed to occur in widespread fashion in all of the neck extensors11 and flexors13 of patients with chronic WAD but not in those with nontraumatic neck pain, suggesting traumatic factors play a role in their development. It is hypothesized that these quantifiable muscle changes represent one physiologic basis for the transition to chronic pain in this population. However, the regulatory neuro-psycho-biology behind their development and their role in this transition is not yet entirely clear. As such, causal inference between muscle fatty infiltrates and poor recovery cannot yet be drawn from the results of previous studies. The presence of muscle fatty infiltrates could however represent an objective marker of injury (that is not dependent on a cognitive response from the patient) as well as provide some prognostic value in determining long-term functional recovery. Current investigations have set focus on determining the precise underlying mechanisms governing the development of fatty infiltrates and their role in the contribution to and maintenance of painful symptoms after whiplash injury.
Although neck pain is a common symptom after acute whiplash injury, there also exists a myriad of complex signs/symptoms in some patients that could pose a challenge for the clinical decision making of even the most perceptive clinician. These include but are not limited to; sensory and motor deficits, dizziness, loss of balance, and widespread hyperalgesia, all of which could imply injury to either peripheral and/or central structures.5,19–24 Consistent findings of salient structural lesions in peripheral and/or central tissues on standard radiography and MRI are however, rarely present, and this may have contributed (or continues to contribute) to the scepticism underlying the genesis of persistent symptoms after whiplash.7,25,26
Support for pain originating from structural lesions can be found from animal models whereby controlled injuries to peripheral tissues incite inflammatory responses in the dorsal ganglia and spinal cord, leading to chronic widespread pain, including exaggerated responses to painful stimuli.23,27 Some patients with WAD also present with widespread sensory hyperalgesia to painful stimuli, which suggests the development and maintenance of increased sensitivity of dorsal horn sensory neurons.19 However, this does not clearly explain the findings of muscle degeneration that are also prevalent in those who transition to chronicity.11,13
It is not the intent of this commentary to ignore the clinical presence of widespread hyperalgesia in some patients; rather the focus is set primarily on discussions related to the potential neuromuscular mechanisms underlying the development of muscular degeneration and the transition from acute to chronic pain after the injury event. Preliminary evidence that altered spinal cord biochemistry and neck muscle water diffusion are present in chronic WAD—both of which may implicate central mechanisms—will be provided. The potential psychological influence on biological changes at the muscle level must however also be considered. In this overall context, hypotheses are generated to support potential mechanisms underpinning the development of muscle degeneration and the transition from acute to chronic whiplash-related pain and disability.
PREVIOUS AND PRELIMINARY EVIDENCE
Recent results demonstrate fatty infiltrates of neck muscles develop between 4-weeks and 3-months postinjury, but only in those with more severe levels of pain and disability. Subjects with mild or recovered symptoms do not develop fatty infiltrates (Figure 1).28 As such, these muscle changes may embody one neurophysiologic basis for the development and maintenance of chronic pain in this group. However, the exact (and early) mechanisms for their development remain mostly unknown.
A relationship with higher initial and ongoing pain levels seems likely because muscle changes do not feature in patients with lower levels of chronic nontraumatic neck pain.20 The widespread fatty infiltrates in both the cervical extensor and flexor muscles in patients with whiplash suggest that disuse or possibly denervation atrophy could be contributing factors.29,30 Future investigations should aim to confirm or refute the presence of denervation atrophy as an established protocol is available for the upper cervical musculature31 and should be expanded to include other cervical extensor and flexor muscles.
In addition, the presence of induced stress has shown to impart a detrimental influence on overall systemic and muscle function in other chronic pain populations, likely secondary to activation of the sympathetic nervous system (SNS).32 Post-traumatic stress symptoms are common to WAD33 and have shown to be associated with poor recovery.2,34,35 Our previous cross-sectional work demonstrated a significant but weak relationship with symptoms of post-traumatic stress and the total content of neck muscle fatty infiltrates in chronic WAD.5
Our group has also recently discovered that symptoms of post-traumatic stress (a psychological manifestation) mediate the relationship between initial pain intensity and the development of muscle fatty infiltrates (a physical pathology) on conventional T1-weighted MRI measures at 6 months postinjury.28 This is an interesting finding and may be the result of excessive outflow from the SNS including vasoconstriction and altered muscle metabolism. Under such conditions, intramyocellular oxidative stresses may contribute to the observed muscular degeneration,36–38 and possibly the development and maintenance of long-term pain. The persistent presence of oxidative, ischemic stress could also dramatically affect the contractility of skeletal muscle as well as induce fibrotic degeneration, commonly seen in other painful conditions (e.g., fibromyalgia) and possibly the fatty changes observed in our prospective study, suggesting a relationship between muscle dysfunction and pain.
This may be especially important for some cases of traumatic whiplash when considering the potential for even greater consequences on overall health resulting from post-traumatic stress disorders,34,39,40 which could activate other biological processes including the release of cortisol by the adrenal glands. The negative consequenes of hypercortilosemia could include skeletal muscle degeneration,41 increased autonomic nervous system functioning, insomnia, misperception of symptoms and lowered immunity.42 A potential conclusion to be drawn on the basis of such preliminary information is that neck muscle degeneration may be related to alterations of the neuroendocrine system in some patients after whiplash, suggesting a neuro-psycho-biological link with poor outcomes. This requires further investigation in prospective fashion before strong definitive conclusions can be offered.
Notwithstanding the influence of psychological factors, the single most consistent predictor of chronicity remains initial pain intensity.43,44 As stated, neck muscle fatty infiltrates are observed to be present soon after the injury event (between 4-weeks and 3-months postinjury) and are related to higher levels of pain, reduced cervical spine range of movement and symptoms of post-traumatic stress.28 However, the exact underlying central and/or peripheral neural mechanisms governing their development and whether they are the cause or consequence of ongoing painful symptoms remain unknown.
An unresolved issue in whiplash is the extent to which injury of specific tissues is associated with the transition to chronicity. Minor injury to the spinal cord could be possible and as such may align with both widespread sensory and motor changes commonly observed in whiplash.2,45 There exists data from a single-case to imply injury to the spinal cord24 and animal studies demonstrate the immediate presence of pressure gradient changes in the spinal canal after whiplash loading.46 More specifically, postmortem histological analyses reveal coagulative necrosis in the ventral horn of the spinal cord (but only in one subject after a minor whiplash)24 and the presence of nervous tissue damage markers also feature in the cerebrospinal fluid (CSF) in those patients with neurological compromise after incomplete spinal cord injury and traumatic whiplash.21 Such trauma could lead to neuronal necrosis followed by a secondary axonal degeneration and further neural cell apoptosis, both of which could last days to months postinjury.21
Interestingly, intramuscular fat in the lower extremity muscles has shown to develop at 6 weeks in patients with nonwhiplash related incomplete spinal cord injury.47 It is possible that mild cord injury in some patients with whiplash contributes to the macroscopic neck muscle changes observed in previous works11 and ultimately, the transition from acute to chronic pain. Preliminary results using magnetic resonance spectroscopy of the cervical spinal cord (Figure 2) in a small sample of subjects with chronic pain and fatty infiltrates after whiplash are interesting and suggest the possibility of either an initial mild cord injury and/or persistent abnormal afferent input after injury to peripheral structures with the subsequent production of neural cell death. Five subjects with chronic WAD (>3 months postinjury) revealed significantly lower N-acetylaspartate (NAA) and Creatine (Cr) ratios (NAA/Cr) when compared to seven healthy controls (P = 0.02).48 This is interesting as NAA is a maker for neuronal integrity and reduced NAA/Cr on MRS has been associated with damaged axons in other neurological disorders,49,50 traumatic brain and spinal cord injury,51,52 and cervical myelopathy.53 The reduction of NAA/Cr in patients was surprising similar to the reported values for patients with cervical myelopathy.53 Although the presentation and timing of clinical symptoms as well as the patterns of involvement for the two conditions may vary, the reductions in NAA/Cr on MRS suggests neuronal loss and cell death in the spinal cord in both cervical myelopathy and a small sample of chronic WAD.48 Support for such a position can be obtained from animal studies that have demonstrated the development of cellular alterations within the cell bodies of the dorsal root ganglion (DRG) and dorsal horn secondary to prolonged sensistization.54 Larger scaled prospective MRS studies involving human subjects with varying levels of pain after whiplash injury are required and are well underway.
Additional findings involving the same five subjects described above support the position that the observed changes in neck muscle structure may result from nervous system damage. Diffusion weighted imaging (DWI) is an emerging tool for measuring muscle physiology that can provide for a noninvasive glance into the extra- and intramyocellular environment.55,56 Specifically, DWI provides a method of studying the diffusion of water molecules in many different tissues, including but not limited to, brain, spinal cord, kidneys, heart, lumbar intervertebral disc and prostate. Normal water diffusion is affected by the presence of tissue barriers (e.g., proteins, myelin sheaths, and lipids). Minute movements of water diffusion can be calculated via the apparent diffusion coefficients (ADC). The ADC can be divided bi-exponentially into fast and slow components, believed to represent movements in the extra- and intracellular spaces, respectively.55,57 Denervated animal and human muscle on DWI has shown to be associated with an increased ADC and these changes manifest before any electrophysiological evidence is available to confirm denervation.55
Figure 3 highlights the DWI data from subjects with WAD (>6 months postinjury). Significantly faster ADCs in the fast component for the cervical multifidus were found when compared to healthy controls (P = 0.01) and there was a trend for slower slow component ADC (P = 0.3). This suggests atrophic muscle changes are associated with increased fast diffusion and the reduced slow water ADC may result from restrictive diffusion barriers (e.g., lipids).48
Although, it should be clear that the above findings are preliminary and represent data obtained from a small sample of chronic WAD patients.48 Prospective studies are now underway to determine the usefulness of a DWI measure for determining any temporal changes to muscle fiber structure after whiplash injury and whether such changes are unique to those who transition to chronicity. Future studies should also include correlates to electrophysiological testing31 to further establish whether denervation plays a role in altered ADCs of neck muscle and ultimately, ongoing pain. Such knowledge could inform clinical decision-making.
A potential conclusion to be drawn on the basis of this information is that the mechanisms behind the transition from acute to chronic pain and the development of muscle degeneration after whiplash seem to involve a combination of neuro-psycho-biological factors, including higher pain levels and subsequent post-traumatic stress. Larger scaled studies are required before making strong clinical conclusions into the underlying mechanisms governing muscular degeneration after whiplash and their influence on long-term recovery and painful symptoms.
In summary, for the accurate clinical assessment and management of whiplash to continue to advance, interdisciplinary investigation of the precise mechanisms underlying the transition to chronic pain through the implementation of state-of-the-art technology is mandatory. Considering the recent preliminary advancements in advanced imaging applications, we may be well positioned to provide new evidence to further optimize the assessment and accurate classification of patients with varying levels of pain and disability. In particular, those at risk for transitioning to chronic pain. Although there remain many questions for today's clinicians and researchers, there also remains a plethora of opportunities for scientific inquiry that if/when answered could help limit the numbers of patients who transition to a chronic state.
- Changes in muscle structure have been observed in whiplash-injury patients presenting with chronic head and neck pain.
- Muscle fatty infiltrates occur soon after injury but only in those with higher levels of pain and symptoms of post-traumatic stress.
- It is possible that the MRI markers of muscle fatty infiltrates are associated with poor functional recovery and may represent an initial injury involving peripheral, central, or both structures.
- The presence of post-traumatic stress disorder could also contribute to the morphological features of muscle degeneration and this requires further prospective investigation.
1. Rebbeck T, Sindhusake D, Cameron ID, et al. A prospective cohort study of health outcomes following whiplash
associated disorders in an Australian population. Inj Prev 2006;12:93–8.
2. Sterling M, Jull G, Kenardy J. Physical and psychological factors maintain long-term predictive capacity post-whiplash
3. Walton DM, Pretty J, MacDermid JC, et al. Risk factors for persistent problems following whiplash
injury: results of a systematic review and meta-analysis. J Orthop Sports Phys Ther 2009;39:334–50.
4. Borchgrevink G, Smevik O, Haave I, et al. MRI
of cerebrum and cervical columna within two days after whiplash
neck sprain injury. Injury 1997;28:331–5.
5. Elliott J, Sterling M, Noteboom JT, et al. The clinical presentation of chronic whiplash
and the relationship to findings of MRI
fatty infiltrates in the cervical extensor musculature: a preliminary investigation. Eur Spine
6. Krakenes J, Kaale BR, Moen G, et al. MRI
assessment of the alar ligaments in the late stage of whiplash
injury—a study of structural abnormalities and observer agreement. Neuroradiology 2002;44:617–24.
7. Myran R, Kvistad KA, Nygaard OP, et al. Magnetic resonance imaging assessment of the alar ligaments in whiplash
injuries: a case-control study. Spine
8. Ronnen HR, de Korte PR, Brink PR, et al. Acute whiplash
injury: is there a role for MR imaging?—A prospective study of 100 patients. Radiology 1996;201:93–6.
9. Krakenes J, Kaale BR. Magnetic resonance imaging assessment of craniovertebral ligaments and membranes after whiplash
10. Vetti N, Krakenes J, Damsgaard E, et al. MRI
of the alar and transverse ligaments in acute whiplash
-associated disorders 1-2—a cross-sectional controlled study. Spine
(Phila Pa 1976) 2011;36:E434–40.
11. Elliott J, Jull G, Noteboom JT, et al. Fatty infiltration in the cervical extensor muscles in persistent whiplash
-associated disorders: a magnetic resonance imaging analysis. Spine
(Phila Pa 1976) 2006;31:E847–55.
12. Elliott J, Jull G, Noteboom JT, et al. MRI
study of the cross-sectional area for the cervical extensor musculature in patients with persistent whiplash
associated disorders (WAD). Man Ther 2008;13:258–65.
13. Elliott JM, O’Leary S, Sterling M, et al. Magnetic resonance imaging findings of fatty infiltrate in the cervical flexors in chronic whiplash
(Phila Pa 1976)2010;35:948–54.
14. Lovitt S, Moore SL, Marden FA. The use of MRI
in the evaluation of myopathy. Clin Neurophysiol 2006;117:486–95.
15. Fleckenstein JL, Watamull D, Conner KE, et al. Denervated human skeletal muscle
: MR imaging evaluation. Radiology 1993;187:213–18.
16. Gerber C, Schneeberger AG, Hoppeler H, et al. Correlation of atrophy and fatty infiltration on strength and integrity of rotator cuff repairs: a study in thirteen patients. J Shoulder Elbow Surg 2007;16:691–6.
17. Kamath S, Venkatanarasimha N, Walsh MA, et al. MRI
appearance of muscle
denervation. Skeletal Radiol 2008;37:397–404.
18. Murphy WA, Totty WG, Carrol JE. MRI
of normal and pathologic skeletal muscle
. Am J Roentgenol 1986;146:565–74.
19. Banic B, Petersen-Felix S, Andersen OK, et al. Evidence for spinal cord hypersensitivity in chronic pain
injury and in fibromyalgia. Pain
20. Elliott J, Sterling M, Noteboom JT, et al. Fatty infiltrate in the cervical extensor muscles is not a feature of chronic, insidious-onset neck pain
. Clin Radiol 2008;63:681–7.
21. Guez M, Hildingsson C, Rosengren L, et al. Nervous tissue damage markers in cerebrospinal fluid after cervical spine
injuries and whiplash
trauma. J Neurotrauma 2003;20:853–8.
22. Kaneoka K, Ono K, Inami S, et al. Motion analysis of cervical vertebrae during whiplash
23. Lee KE, Davis MB, Winkelstein BA. Capsular ligament involvement in the development of mechanical hyperalgesia after facet joint loading: behavioral and inflammatory outcomes in a rodent model of pain
. J Neurotrauma 2008;25:1383–93.
24. Martin D, Schoenen J, Lenelle J, et al. MRI
-pathological correlations in acute traumatic central cord syndrome: case report. Neuroradiology 1992;34:262–6.
25. Ferrari R, Kwan O, Russell AS, et al. The best approach to the problem of whiplash
? One ticket to Lithuania, please. Clin Exp Rheumatol 1999;17:321–6.
26. Joslin CC, Khan S, Bannister GC. Long-term disability after neck injury: a comparative study. J Bone Joint Surg [Br] 2004;86:1032–4.
27. Lee KE, Winkelstein BA. Joint distraction magnitude is associated with different behavioral outcomes and substance P levels for cervical facet joint loading in the rat. J Pain
28. Elliott J, Pedler A, Kenardy J, et al. The temporal development of Fatty infiltrates in the neck muscles following whiplash
injury: an association with pain
and posttraumatic stress. PLoS One 2011;6:e21194.
29. Ingemann-Hansen T, Halkjaer-Kristensen J. Lean and fat component of the human thigh. The effects of immobilization in plaster and subsequent physical training. Scand J Rehabil Med 1977;9:67–72.
30. Manini TM, Clark BC, Nalls MA, et al. Reduced physical activity increases intermuscular adipose tissue in healthy young adults. Am J Clin Nutr 2007;85:377–84.
31. Hallgren RC, Andary MT, Wyman AJ, et al. A standardized protocol for needle placement in suboccipital muscles. Clin Anat 2008;21:501–8.
32. Passatore M, Roatta S. Influence of sympathetic nervous system on sensorimotor function: whiplash
associated disorders (WAD) as a model. Eur J Appl Physiol 2006;98:423–49.
33. Sullivan MJ, Thibault P, Simmonds MJ, et al. Pain
, perceived injustice and the persistence of post-traumatic stress symptoms during the course of rehabilitation for whiplash
34. Kongsted A, Bendix T, Qerama E, et al. Acute stress response and recovery after whiplash
injuries. A one-year prospective study. Eur J Pain
35. Williamson E, Williams M, Gates S, et al. A systematic literature review of psychological factors and the development of late whiplash
36. Jenkins RR. Exercise and oxidative stress methodology: a critique. Am J Clin Nutr 2000;72:670S–4S.
37. Nishikawa H, Manek S, Barnett SS, et al. Pathology of warm ischaemia and reperfusion injury in adipomusculocutaneous flaps. Int J Exp Pathol 1993;74:35–44.
38. Sjogaard G, Sogaard K. Muscle
injury in repetitive motion disorders. Clin Orthop Relat Res 1998:21–31.
39. Hoge CW, McGurk D, Thomas JL, et al. Mild traumatic brain injury in U.S. Soldiers returning from Iraq. N Engl J Med 2008;358:453–63.
40. Marshall RD, Garakani A. Psychobiology of the acute stress response and its relationship to the psychobiology of post-traumatic stress disorder. Psychiatr Clin North Am 2002;25:385–95.
41. Paddon-Jones D, Sheffield-Moore M, Cree MG, et al. Atrophy and impaired muscle
protein synthesis during prolonged inactivity and stress. J Clin Endocrinol Metab 2006;91:4836–41.
42. Nemeroff CB, Bremner JD, Foa EB, et al. Posttraumatic stress disorder: a state-of-the-science review. J Psychiatr Res 2006;40:1–21.
43. Cote P, Cassidy JD, Carroll L, et al. A systematic review of the prognosis of acute whiplash
and a new conceptual framework to synthesize the literature. Spine
(Phila Pa 1976) 2001;26:E445–58.
44. Scholten-Peeters GG, Verhagen AP, Bekkering GE, et al. Prognostic factors of whiplash
-associated disorders: a systematic review of prospective cohort studies. Pain
45. Sterling M, Jull G, Vicenzio B, et al. sensory hypersensitivity occurs soon after whiplash
injury and is associated with poor recovery. Pain
46. Svensson MY, Aldman B, Bostrom O, et al. Nerve cell damages in whiplash
injuries. Animal experimental studies. Orthopade 1998;27:820–6.
47. Gorgey AS, Dudley GA. Skeletal muscle
atrophy and increased intramuscular fat after incomplete spinal cord injury. Spinal Cord 2007;45:304–9.
48. Elliott JM, Pedler AR, Cowin G, et al. Spinal cord metabolism and muscle
water diffusion in whiplash
. Spinal Cord 2011; doi: 10.1038/sc.2011.17. Accessed March 8, 2011.
49. Blamire AM, Cader S, Lee M, et al. Axonal damage in the spinal cord of multiple sclerosis patients detected by magnetic resonance spectroscopy. Magn Reson Med 2007;58:880–5.
50. Kendi AT, Tan FU, Kendi M, et al. MR spectroscopy of cervical spinal cord in patients with multiple sclerosis. Neuroradiology 2004;46:764–9.
51. Brenner T, Freier MC, Holshouser BA, et al. Predicting neuropsychologic outcome after traumatic brain injury in children. Pediatr Neurol 2003;28:104–14.
52. Erschbamer M, Oberg J, Westman E, et al. (1) H-MRS in spinal cord injury: acute and chronic metabolite alterations in rat brain and lumbar spinal cord. Eur J Neurosci 2011;33:678–88.
53. Holly LT, Freitas B, McArthur DL, et al. Proton magnetic resonance spectroscopy to evaluate spinal cord axonal injury in cervical spondylotic myelopathy. J Neurosurg Spine
54. Zimmermann M. Pathobiology of neuropathic pain
. Eur J Pharmacol 2001;429:23–37.
55. Holl N, Echaniz-Laguna A, Bierry G, et al. Diffusion-weighted MRI
of denervated muscle
: a clinical and experimental study. Skeletal Radiol 2008;37:1111–17.
56. Zaraiskaya T, Kumbhare D, Noseworthy MD. Diffusion tensor imaging in evaluation of human skeletal muscle
injury. J Magn Reson Imaging 2006;24:402–8.
57. Sehy JV, Ackerman JJ, Neil JJ. Evidence that both fast and slow ADC components arise from intracellular space. Magn Res Med 2002;48:765–70.