Effects of sodium hyaluronate and methylprednisolone alone or in ...

Effects of sodium hyaluronate and methylprednisolone alone or in combination in preventing epidural fibrosis Madhat Shaban1, Yavuz Aras1, Aydin Aydoseli1, Mehmet Osman Akcakaya1, Altay Sencer1, Cicek Bayindir2, Nail Izgi1 1

Department of Neurosurgery, Istanbul School of Medicine, Istanbul University, Istanbul, Turkey, 2Department of Pathology, Istanbul School of Medicine, Istanbul University, Istanbul, Turkey Objective: Epidural fibrosis and leptomeningeal adhesion formation are common causes of failed back surgery syndrome (FBSS). We employed a rat model of lumbar laminectomy to evaluate the histopathological effects of sodium hyaluronate (HA) and methylprednisolone (MP) alone or in combination on post-laminectomy epidural fibrosis. Methods: Thirty-two male Sprague–Dawley rats were divided into four groups. All rats underwent three-level lumbar laminectomy. In the treatment groups, HA solution, MP, or a combination of both was applied locally to the epidural spaces of the laminectomy fields. No neurological deficits or pathological wound site changes were observed in any of the groups. At the end of the sixth week, all rats were sacrificed, and the laminectomy vertebral column areas were removed en-bloc. Specimens were evaluated by an expert neuropathologist according to histopathological criteria. Results: The results of the three treatment groups were separately compared with the control group to assess epidural fibrosis. Minimal reduction in the rate of epidural fibrosis was observed in the groups treated with HA or MP compared with the control group. However, no significant difference in epidural fibrosis was noted between the combined treatment group and the control group. Conclusions: Our study showed that MP and HA, given separately, significantly reduce post-laminectomy epidural fibrosis; however, the combination of these drugs is not effective. Further investigation is needed to address the causative drug interactions.

Keywords: Epidural fibrosis, Laminectomy, Methylprednisolone, Rat, Sodium hyaluronate

Introduction Epidural fibrosis is one of the most common reasons for poor outcome following lumbar disc surgery. Strong adhesions to the nerve roots may lead to recurrent symptoms, referred to as failed back surgery syndrome (FBSS). These adhesions also make subsequent surgeries quite challenging and can result in serious complications, such as nerve root injuries or cerebrospinal fluid fistulas. Therefore, preventing or minimizing epidural scar formation is essential. However, clinical and experimental studies for the prevention of epidural fibrosis have largely failed.1–3 As many as 24% of FBSS patients exhibit epidural fibrosis.4,5 The incidence of epidural fibrosis after herniated disc surgery ranges from 1 to 48%.5–10 Some studies have reported a relationship between extensive epidural fibrosis diagnosed by magnetic Correspondence to: Mehmet Osman Akcakaya, Istanbul Universitesi Istanbul Tıp Fakultesi Norosirurji Anabilim Dalı, Norolojik Bilimler Binası 6.kat C ¸ apa/Fatih/I˙stanbul 34093. Email: [email protected]

ß W. S. Maney & Son Ltd 2013 DOI 10.1179/1743132813Y.0000000219

resonance imaging (MRI) and increasing lower back pain and/or recurrent radicular pain.11,12 In the normal wound healing process after lumbar spinal surgery, fibroblast migration results in the replacement of normal epidural fat with fibrotic tissue. Other factors, including excessive bleeding, excessive root tension, root anomalies, the use of sponges, and foreign tissue reaction, can facilitate epidural fibrosis formation.13,14 Numerous animal and human studies have evaluated synthetic and natural materials such as polytetrafluoroethylene, free fat, protein-based polymer, high molecular weight hyaluronan, Oxiplex/SP, and DuraGen for their ability to prevent or reduce postoperative epidural scar formation.15–21 The aim of this study is to determine the efficacy of sodium hyaluronate (HA), also known as hyaluronic acid or hyaluronan and methylprednisolone (MP) alone or in combination in preventing post-laminectomy adhesion formation.

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Material and Methods All procedures were performed with the permission of the ethics committee of Istanbul University, Istanbul School of Medicine, using animals from the Experimental Research Center of Istanbul University. Thirty-two male Sprague–Dawley rats (300–350 g) were divided into four equal groups. After general anaesthesia, the same individual performed L 4-5-6 total laminectomy on each animal using a standard surgical protocol.

Surgical procedure Under ketamine (60 mg/kg) (Ketalar, Eczacıbas¸ı, Istanbul, Turkey) and xylazine (10 mg/kg) (Rampun, Bayer, Istanbul, Turkey) anaesthesia, the animals were fixed in a prone position on a small arched table. The operation site was shaved and the surgical field was prepared with povidone–iodine soap solution (Batticon, Adeka Pharmaceuticals Istanbul, Turkey). A 3 cm posterior midline skin incision was made down to the lumbosacral fascia to expose the tips of the spinous processes. The paraspinal musculature was subperiosteally dissected to expose the lumbar vertebral segments. L 4-5-6 total laminectomy was performed, and the dura mater and nerve roots were exposed, leaving the spinal cord and cauda equina intact. Only laminectomy was performed on Group 1 (control, n 5 8), HA (1 mg in 0.1 cc) was applied to the epidural space after laminectomy in Group 2 (HA, n 5 8), MP (0.15 mg in 0.015 cc) was applied to the epidural space after laminectomy in Group 3 (MP, n 5 8), a combination of HA (1 mg in 0.1 cc) and MP (0.15 mg in 0.015 cc) was applied to the epidural space after laminectomy in Group 4 (HAzMP, n 5 8). Upon completion of the surgical procedure, the lumbosacral fascia and other layers were sutured with 3-0 Vicryl (Ethicon Inc., Istanbul, Turkey). No other treatments that could reduce the potential effects of the agents were administered. The neurological status of the animals was closely followed during the first 5 days. Post-operative recovery of all the animals was good, and there were no neurological deficits. All the animals were fed a normal diet and housed under

diurnal light conditions during the six-week study period. The animals were sacrificed on the 42nd postoperative day with a lethal dose of pentobarbital (75– 100 mg/kg) (Nembutol, I˙E Ulagay, Istanbul, Turkey).

Histological evaluation The spinal column and the surrounding muscle tissue were removed en-bloc by osteotomy. After fixation in formalin and decalcification procedures, paraffinembedded sections were processed for histopathological analysis. Each block was cut into 5 mm sections for optimal visualisation of the laminectomy site. Sections were stained with haematoxylin-eosin or Masson’s trichrome. Epidural fibrosis was evaluated by an expert neuropathologist blinded to the groups. Epidural fibrosis and adhesions were graded according to the classification described by He and Revel22 as follows: Grade 0: The dura mater was free of scar tissue; Grade 1: Only thin fibrous bands were observed between the scar tissue and dura mater; Grade 2: Continuous adherence was observed, but it occupied less than two-thirds of the laminectomy region; and Grade 3: Scar tissue adherence accounted for more than two-thirds of the laminectomy region, and/or extended to the nerve roots.

Results There were five animals (62.5%) in Group 1 (control) with Grade 3 epidural fibrosis, compared with none in Groups 2 (HA) and 3 (MP) (Tables 1, 2 and 3). Surprisingly, there were six animals (75%) in Group 4 (HAzMP) with Grade 3 epidural fibrosis, which was Table 1 Results of the grades according to He and Revel for epidural ﬁbrosis

Group Group Group Group

Grade 1 (%)

Grade 2 (%)

Grade 3 (%)

0 50 62.5 12.5

37.5 50 37.5 12.5

62.5 0 0 75

1 2 3 4

Table 2 The difference between the control group and the sodium hyaluronate (HA) group Fibrosis Grade 0–1–2 account % Group 1 (control) Group 2 (HA) Total

3 8 11

37.5 100

Fibrosis Grade 3 account % 5 0 5

62.5 0

Total 8 8 16

Table 3 The difference between the control group and the methylprednisolone (MP) group Fibrosis Grade 0–1–2 account % Group 1 (control) Group 3 (MP) Total

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not significantly different from the control group that received no treatment (Table 4). Figs 1a–d and 2a and b show different examples of epidural fibrosis in different groups. Epidural fibrosis was more common in Groups 1 and 4 (Fig. 3).

Discussion The mechanisms leading to epidural scar formation are not clearly understood, although it was first reported by Key and Ford in 1948 following lumbar disc surgery.23 Their suggestion for the possible causative mechanism was the destruction of the annulus fibrosus. Other reports hypothesised that it was due to protein leakage from the disrupted disc, foreign body reaction related to surgical debris, and defective fibrinolysis.15 However, the major structural element of epidural fibrosis is collagen, which is produced by fibroblasts. Currently, fibroblast migration from surrounding soft tissues is generally accepted as the cause of epidural fibrosis. Barbera et al. indicated that collagen arises from the spinal muscles to fill the laminectomy defect, and its amount is correlated with that of scar tissue.24 Epidural scarring after lumbar disc herniation surgery is normally observed to some extent. The post-operative period can be divided into early (0– 6 months) and late (§6 months) stages.25 Epidural soft tissue swelling due to oedema and haemorrhage commonly occur in the very early post-operative period – these symptoms have been visualized on MRI in as many as 80% of patients who have recently undergone lumber disc surgery. The prevalence of these radiological findings decreases to 50% at 2 months after surgery.26 Sodium hyaluronate is a naturally occurring longchain polymer composed of repeated disaccharide units of N-acetylglucosamine and glucuronic acid, which is a major component of the extracellular matrix of connective tissues. Its anti-inflammatory properties are well known; HA is a potent inhibitor of tumour necrosis factors alpha and beta.27 Experimental studies have shown that HA (as viscous solution, sulphated derivatives, gel form, or interpositional membrane) can prevent post-laminectomy epidural fibrosis.28 Songer et al. compared the efficacies of fat grafts, viscous HA solutions, and high molecular weight HA solutions for preventing scar tissue formation after laminectomy, annular fenestration, and nucleotomy. They concluded that the haematoma formed in the early post-operative

Epidural fibrosis

period turns into thick fibrotic tissue and found that HA is more effective in preventing scar tissue formation compared to fat grafts.29 Abitboll et al. also found HA treatment to be more effective than free fat grafts.30 Another experimental study by Massie et al. demonstrated that topical high molecular weight HA gel was found to be beneficial, both for reducing post-laminectomy adhesions and pain, which was assessed with tactile allodynia tests.31 Schimizzi et al.19 and Kato et al.32 indicated that HA significantly decreases inflammatory cell density. We also found that HA effectively prevented epidural scarring. Corticosteroids are well known for their antiinflammatory effects. They can block COX-2 mRNA expression, which results in suppressed prostaglandin production, as well as inhibit interleukins and other inflammatory mediators to reduce pain.33 Foulkes et al. reported that irrigation of the operation field with long-acting dexamethasone decreased the post-operative need for pain medications and reduced hospital stay length. The authors posited that the effects were due to steroid-mediated depression of inflammation and pain mediators.34 A randomised clinical trial by Rasmussen et al. focused on the effect of perioperative epidural steroid use following lumbar disc herniation.33 They found that epidural MPs following lumbar discectomy reduced hospital stay, recovery, leg pain, and neurological deficits, and stated that it reduced clinical signs of nerve adhesion, which may be related to the inhibition of prostaglandin production and interleukin and c-reactive protein responses.33 Another clinical trial by Lundin et al. also indicated that steroids are beneficial for early pain control and decrease post-operative scar formation.35 However, they simultaneously used intramuscular and intravenous MP and epidural MP-soaked fat grafts. Due to their study design, it was not possible to distinguish whether the observed effects were due to local or systemic steroids or the fat graft. They concluded that systemic perioperative corticosteroid use reduces pain, hospital stay, and return time to work. Although many clinical investigations have focused on the effects of peri-operative corticosteroid use, few have assessed epidural fibrosis following local MP administration.35 In the long term, the inhibitory effect of steroids on intercellular proteoglycan and collagen proliferation could reduce adhesion and fibrosis formation.33 In our study, the individual use of MP post-laminectomy

Table 4 The difference between the control group and the combined group Fibrosis Grade 0–1–2 account % Group I (control) Group IV (combined) Total

3 2 5

37.5 25



Total

62.5 75

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the MP group (Hematoxilen-Eosin 610), thickening of dura mater and oedema was observed. The extent of fibrotic tissue was only minimal. (D) Grade 3 fibrosis in the combination group (Hematoxilen-Eosin 610). Extensive fibrosis was observed with widely atrophic muscle tissue and adhesions alongside fibrosis and muscle tissue.

significantly decreased severe epidural fibrosis compared to the control group (P 5 0.026). Although clinical studies in humans have focused on early postoperative pain and included some observational information about the presence of the epidural fibrosis, our results are in favour of the commonly and easily applied local usage of MP, which prevented epidural fibrosis formation in our model. We also applied MP and HA together. To our knowledge, no other investigation has used both these substances to prevent epidural fibrosis in an animal model. We observed a significant decrease in epidural fibrosis in both individual treatment groups compared to the control group, and we expected that the combination of these drugs would exert an additive effect. Instead, the beneficial effects of these drugs appeared to have a subtractive effect; the

Figure 1 (A) Grade 3 fibrosis in control group (HemotoxilenEosin 610), histopathological examination revealed fibrosis, muscle tissue atrophy and thickening of dura mater. (B) Grade 2 fibrosis in the HA group (Hematoxilen-Eosin 610), adhesions between the oedematous and thickened dura mater and nerve roots were present. (C) Grade 2 fibrosis in

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Figure 2 (A) Grade 2 fibrosis in the MP group (Mason Trichrome 620). Laminectomy defect and local increase of the fibrotic tissue with adhesions nearby the bone defect was observed. (B) Grade 3 fibrosis in combination group. (Mason Trichrome 620) Extensive fibrosis was observed epidurally as well as in muscle and adipose tissue.

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investigation is required to address the interaction between these two compounds.

Disclosure The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper.

References Figure 3 Graph shows the difference of epidural fibrosis among all the animal groups. Group 2 (HA) and Group 3 (MP) do not contain any subjects with Grade 3 fibrosis. In Group 1 (control) there are no subjects with Grade 1 fibrosis. Group 4 (combination) shows similarities with Group 1 with mainly Grade 3 fibrosis and significantly less Grade 2 and Grade 1 fibrosis compared to the other two treatment groups.

group treated with both compounds was equal to the control group with regard to epidural fibrosis. To our knowledge, there has been no in vivo or in vitro pharmacological research on the interactions between these substances. Although these two drugs are commonly used in the intrarticular treatment of osteoarthritis and soft tissue injuries, studies usually compare the two drugs.36 However, there are some clinical studies, in which dexamethasone (another corticosteroid) was used in combination with HA. For example, the sudden onset of sensorineural hearing loss is clinically treated with intratympanic administration of this combination, which was found to be effective compared to intravenous therapy.37,38 Therefore, there is a lack of data to explain the interaction we observed between these two drugs. Both these drugs are eliminated through the hepatic cytochrome p-450 enzyme CY3A4, and both inhibit the enzyme’s activity. We did not find any overlap regarding their elimination; HA is degraded by hyaluronidase, which is used mainly in local anaesthesia and interventional pain reducing procedures. In an experimental study investigating specific interactions of drugs used in interventional pain management and local anaesthesia, it was found that cortisone increases hyaluronidase activity.39 Another study found increased hyaluronidase activity in ram sperm following intramuscular dexamethasone treatment.40 Aside from these two studies, we could not find any other explanation for the observed results. We hypothesise that with systemic use, MP increases hyaluronidase activity and decreases HA concentration. However, it is debatable whether this would occur following topical or local use. In conclusion, we found that MP and HA administered separately significantly reduced postlaminectomy epidural fibrosis. However, the combination of these two drugs was ineffective. Further

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