British Journal of Radiology (2004) 77, 885-887
© 2004 British Institute of Radiology
doi: 10.1259/bjr/62051205
Resolution of symptomatic epidural fibrosis following treatment with combined pentoxifylline–tocopherol
C Georges, MD
1
J-L Lefaix, PhD
2 and
S Delanian, MD, PhD
3
1 Médecine Interne, Hôpital Saint-Louis, Paris, 2 DSV/DRR, CEA Fontenay aux Roses and 3 Oncologie-Radiothérapie, Hôpital Saint-Louis, Paris, France
Correspondence: Dr Sylvie Delanian, Service d'Oncologie-Radiothérapie, Hôpital Saint-Louis, 1, Ave Claude Vellefaux, 75010 Paris, France
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Abstract
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Epidural fibrosis (EF) is a major cause of failed back surgery syndrome (FBSS), which induces disabling radiculopathy for which no effective medical treatment exists. Our understanding of the fibrosis mechanisms and our clinical and experimental results for the treatment of radiation-induced fibrosis prompted us to postulate that EF might respond to treatment with combined pentoxifylline (PTX)–tocopherol (Vit.E). 6 weeks after lumbar spine surgery, a 28-year-old man presented with recurrent left L5 sciatica without disc herniation on MRI in December 1993. From 1993 to 1997, he had unrelieved back and leg pain, which became increasingly resistant to intensive medical treatment and to a spinal cord stimulator, and confined him to bed as from December 1997. In 1998, a lumbar CT-scan showed an area of left L4–L5 EF measuring 12 mm x 12 mm, without disc herniation. From April 1998, oral PTX (800 mg day–1) and Vit.E (1000 IU day–1) were administered daily for 3.5 years and well tolerated. Clinical improvement began during the third month of treatment and continued until total regression of clinical symptoms April 2001. Lumbar MRI in November 2001 showed a surface area of residual EF half the size of the initial area. This is the first report to indicate that antifibrotic treatment using combined PTX–Vit.E may be of potential benefit in the treatment of post-operative EF. Additional studies are required to confirm this potential.
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Introduction
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Failed back surgery syndrome (FBSS) is a disabling complication related to the failure of herniated lumbar disc surgery. It is characterized by severe chronic post-operative pain, which is usually resistant to physiotherapy and pharmacological treatment. FBSS is not rare, since 3–14% of patients undergoing lumbar spinal surgery for a prolapsed intervertebral disc suffer from recurrent painful symptoms [1]. FBSS has various causes ranging from demonstrable anatomical lesions to psychosocial aspects of the patients. The most frequent causes are recurrent or residual disc herniation and epidural fibrosis (EF) [2, 3].
FBSS is caused by EF in 8–14% of cases [4, 5], and occurs in 1–2% after discectomy [6]. The resulting post-operative epidural and periradicular fibrosis, located critically near a lumbar root, may induce dynamic neural tension especially during repeated movements, and lead to a recurrent radiculopathy. Numerous treatments are used to control the painful symptoms of FBSS caused by EF, but few give lasting clinical benefit. Moreover, there are no treatments capable of shortening the fibrotic process. On the basis of our understanding of mechanisms of fibrotic process and of our clinical and experimental results for patients with radiation-induced fibrosis, we recently developed an alternative treatment using antioxidants. In the case described here, FBSS resolved completely, thanks to the striking reduction of EF induced by treatment using combined pentoxifylline (PTX)–tocopherol (Vit.E) in a patient with progressive severe EF.
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Case report
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A 33-year-old man underwent lumbosacral spine surgery in September 1993 for resistant left L5 sciatica due to a herniated L4–L5 disc. After an initial post-operative improvement, he began to develop gradually worsening lumbar pain with increasingly severe left L5 sciatica 6 weeks after surgery. In December 1993, lumbar MRI showed no disc herniation, and only limited EF (Figure 1a
). From December 1993 to December 1997, the pain was permanent, non-impulsive and progressively resistant to medical treatment, including usual analgesics (paracetamol-dextropropoxyphene, codeine and tramadol), and neuropathic pain drugs (clonazepam, amitriptyline, fluvoxamine and carbamazepine). Three successive epidural corticosteroid injections were performed, but only alleviated the pain for 2 weeks. Morphine was then introduced, but was limited to low doses (80 mg day–1) because of a hypertonic ureteral disorder. A spinal cord stimulator (Itrel II) was implanted in September 1996, but failed to relieve pain adequately and was removed in August 1999.
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Figure 1. (a) December 1993: post-operative contrast-enhanced axial T1 weighted lumbar MRI (1.5 Tesla) at the L4–L5 level showing epidural fibrosis in the left lateral recess and lateral spinal canal region, but no disc herniation (arrow). (b) May 1998: contrast-enhanced CT scan examination at L4–L5 level showing epidural fibrosis in the left lateral recess. (c) November 2001: axial T1 weighted contrast-enhanced lumbar MRI (1.5 Tesla), showing the reduction of the left epidural fibrosis after 3.5 years of treatment with combined pentoxifylline–tocopherol (arrow).
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In April 1998, the patient presented at the Saint-Louis Hospital with this uncontrolled and disabling pain, which had confined him to bed as from December 1997. Physical examination was limited because the patient could neither stand nor sit. In May 1998, since MRI was not feasible because of the spinal cord stimulator, lumbar CT was performed, which showed a plaque of inhomogeneous enhancing tissue to the left of midline at L4–L5 level, extending in an anteroposterior and lateral direction over an area of 12 mm x 12 mm with an appearance suggesting EF (Figure 1b
). After a 2 week course of 16 mg day–1 methylprednisolone, a daily antifibrotic combination of 800 mg PTX and 1000 IU Vit.E was initiated as from May 1998. The patient then underwent physical examination every 3 months.
There was regular clinically assessable improvement, which began during the third month of combined PTX–Vit.E treatment. After 3 months of this treatment, in August 1998, the radicular pain became intermittent and its intensity diminished allowing morphine to be tapered from 80 mg day–1 to 60 mg day–1 and the patient to stand up. After 6 months of treatment, left sciatica was occasional and the patient was able to walk 500 m. At 12 months of treatment, the radicular pain had totally disappeared and the patient was able to sit down for a meal; however 40 mg morphine daily was still necessary for residual lumbar pain. In September 1999, after 16 months of combined PTX–Vit.E, another lumbar MRI was performed, and showed that fibrosis had diminished by one third. During the period from 18 months of treatment up to 3 years (April 2001), the lumbar pain continued its gradual decline until it totally disappeared and the analgesics, fluvoxamine and clonazepam used, were stopped. The last lumbar MRI, performed in November 2001, after 3.5 years of treatment, showed a small area of residual fibrosis, which measured 6 mm in dimensions and corresponded to a 50% regression of the original fibrotic area (Figure 1c). The PTX–Vit.E treatment stopped after these improvements, without clinical recurrence 12 months later.
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Discussion
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To our knowledge, this is the first report of a case showing an improvement, after antifibrotic treatment, in both the clinical status and radiological features, of the frequently irreversible post-operative complication of severe symptomatic EF. Our patient's pain can be attributed to EF because of the 6 week pain-free interval after lumbar spine surgery, the gradual onset of the disease, its neuropathic characteristics and the fact that disc herniation did not recur, as confirmed by MRI. The pathogenic mechanism of the radicular pain due to EF is not clear. Some patients with demonstrable EF on MRI may be asymptomatic, the others with minor anatomical EF changes may have major pain and disability [7]. Nevertheless, there seems to be a definite correlation between extensive EF and the severity of post-operative disturbances [8, 9].
The literature contains few reports concerning the treatment of EF. Symptomatic treatments such as the administration of major analgesics, tricyclic antidepressants, benzodiazepines, or gabapentin [10] have some effect but it is transitory and not very strong. Corticosteroid injections into the epidural or intradural space are widely used, but have not been demonstrated in controlled studies to be effective in FBSS. The spinal cord stimulator reduced pain by 12% to 88% in some series [11]. However, it is difficult to implant, and sometimes stimulates the dorsal roots, producing discomfort or motor sensations. Complications such as infection, electrode dislocation or fracture can also occur [11]. The results of surgical reintervention for the excision of scar tissue are generally poor with a success rate of only 20–35%, and symptoms worsened in 20% of cases. However, it is difficult to evaluate this surgery, because many studies either included cases of FBSS due to different causes [3], or were conducted before the advent of CT with contrast material injection and MRI [12], so that EF could not be definitely diagnosed.
Today, the physiopathology of EF is better understood, including its vascular and fibrotic mechanisms. It may often involve vascular hypoxia owing to the venous obstruction, which is caused by the severity of the initial degenerative disk disease, and leads to perineural fibrosis and neuronal atrophy [7]. Iterative surgery can expose patients to the risks of fibrosis and adhesions. In addition, the persistence of cotton debris from sponges used during the operation may act as a fibrogenic stimulus [7].
Our experience of the adverse effects of radiotherapy has enabled us to improve our understanding of the physiopathology of the fibrotic process and to manage it by antioxidant administration. In particular, combined PTX–Vit.E treatment of experimental radiation-induced fibrosis led to a 70% reduction in the fibrotic volume, confirmed by histological analysis with a large reduction of transforming growth factor 
1 (TGF-1) gene expression [13]. Moreover, this treatment proved beneficial in a Phase II clinical trial of 50 patients with measurable superficial fibrosis, as it led to a significant mean regression of 53% of the surface lesions at 6 months, and of 66% at 12 months, with a continuous therapeutic effect, which was confirmed by a recent randomized trial and in osteoradionecrosis [14, 15] without side effects. In one of the patients treated in this trial, who had concomitant breast radiofibrosis and FBSS due to EF, there was a surprising clinical improvement in both diseases using the PTX–Vit.E combination. Lastly, PTX was successfully used in an experimental study to prevent the compartment syndrome in dorsal root ganglia caused by exposure to nucleus pulposus [16]. However, although this case report suggests that combined PTX–Vit.E may be useful in the treatment of EF, further studies are required to confirm this effect.
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Conclusion
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FBSS secondary to EF is a clinical condition that is difficult to manage. The continuous treatment with combined PTX–Vit.E used in the case reported here may be considered a potential method of treatment, as it has proved able to reduce EF and reverse the associated progressive lumboradiculalgia completely. A Phase II clinical trial involving EF patients is in progress to evaluate the effectiveness of this treatment.
Received for publication September 24, 2003.
Revision received January 19, 2004.
Accepted for publication February 27, 2004.
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References
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Abstract
Introduction
