Safety of laronidase delivered into the spinal canal for treatment of cervical stenosis in mucopolysaccharidosis I.

Enzyme replacement therapy with laronidase (recombinant human alpha-l-iduronidase) is successfully used to treat patients with mucopolysaccharidosis type I (MPS I). However, the intravenously-administered enzyme is not expected to treat or prevent neurological deterioration. As MPS I patients suffer from spinal cord compression due in part to thickened spinal meninges, we undertook a phase I clinical trial of lumbar intrathecal laronidase in MPS I subjects age 8 years and older with symptomatic (primarily cervical) spinal cord compression. The study faced significant challenges, including a heterogeneous patient population, difficulty recruiting subjects despite an international collaborative effort, and an inability to include a placebo-controlled design due to ethical concerns. Nine serious adverse events occurred in the subjects. All subjects reported improvement in symptomatology and showed improved neurological examinations, but objective outcome measures did not demonstrate change. Despite limitations, we demonstrated the safety of this approach to treating neurological disease due to MPS I.

Topical application of tacrolimus prevents epidural fibrosis in a rat postlaminectomy model: histopathological and ultrastructural analysis.

AIM: Postlaminectomy epidural fibrosis is the formation of scar tissue over the dura mater following posterior spinal surgery. This devastating complication is responsible for the substantial amount of failed back syndromes. MATERIAL and METHODS: Twenty male Wistar-Albino rats each weighing 350-400 grams were used. Following L3-L5 laminectomy, the rats were randomly divided into 2 groups, with 10 rats in each group. In the control group, only a laminectomy was performed. In the drug group, 5 mg/ml tacrolimus was topically applied with a cotton pad soaked with the drug solution for 5 minutes. The animals were killed on the 30th postoperative day injecting a lethal dose (250 mg/kg) of pentobarbital and the involved dural segments were removed for histopathological and ultrastructural evaluations. RESULTS: Epidural scar thickness and the density were significantly lower in the animals treated with tacrolimus than those of the control group. CONCLUSION: Promising evidence regarding the anti-scar potential of tacrolimus merits further research to optimize the dosage and the usage of the drug.

Periduroscopy: general review of clinical features and development of operative models.

BACKGROUND: Myeloscopy is a useful approach for both diagnosis and treatment of back pain. However clinicians have underestimated its potential. From the nineties myeloscopy has been used only as a diagnostic tool, without any improvement of the technique. Racz's method is nowadays still used for the lysis of adherence by applying medical solutions without a direct vision inside the spinal channel. In 1998 we showed the limitations of Racz's approach, and in 1999 we developed a new technique, introducing a Fogarty balloon to remove the occlusions of the spinal canal and the resaflex for the lysis of adherence at low temperature (Raffaeli-Righetti technique). In this paper we report a general review of our experience with periduroscopy for the treatment of failed back surgery syndrome (FBSS) and spinal stenosis. METHOD: A Fogarty balloon was used to remove fat and/or mild fibrosis occluding the spinal canal, reducing by 50% the volume of the saline solution used in periduroscopy. The Resaflex was subsequently used to lyse adherence and to allow reaching the site of pain origin, using a low temperature (> 50°C). FINDINGS: the fibrosis morphologies of epidural space (ES) were grouped on the basis of common macroscopic and organizational characteristics, which were revealed during myeloscopy. A year after myeloscopy, 59% of FBSS patients, and 67% of patients with stenosis reported a general improvement of their painful pathology, with a pain reduction above 50 in 56% of patients. Forty-eight percent of patients used minor analgesics and 67% of patients went back to work. Only few complications were observed (4%). CONCLUSIONS: myeloscopy technique enlightens pain-triggering mechanisms otherwise unrevealed; it has specific therapeutic value, whereas on the diagnostic side it has not revealed relevant pathologies. Its effectiveness in FBSS patients is high, with the advantage of its relatively easy implementation, limited invasiveness and repeatability.

Changes in cross-sectional area of spinal canal and vertebral body under 2 years of teriparatide treatment: results from the EUROFORS study.

The treatment of osteoporotic patients with teriparatide is associated with a significant increase in bone formation and gain of bone mass. The purpose of this post hoc analysis was to determine if the cross-sectional area (CSA) of the spinal canal and the vertebral body is affected by teriparatide treatment. Narrowing of the spinal canal might represent a safety problem, while widening of the vertebral CSA might improve mechanical stability. High-resolution computed tomography (HRCT) scans of vertebra T12 were obtained at baseline and after 6, 12, and 24 months of teriparatide treatment (20 microg/day) from 44 postmenopausal women with established osteoporosis participating in the prospective, randomized EUROFORS study. The CSA of the spinal canal did not decrease but increased marginally by 0.9% (2.6 mm(2)) over 24 months (P < 0.001), with a range from -0.5% (-2 mm(2)) to 3.1% (+8 mm(2)). Even when analyzing the spinal CSA on a slice-by-slice basis, no clinically relevant narrowing of the spinal canal was observed. For vertebral bodies, the CSA increased by 0.7% (5.7 mm(2)) over 24 months (P < 0.001), with a range from -0.4% (-3 mm(2)) to 1.6% (+14 mm(2)). Our data do not provide evidence for safety concerns regarding spinal canal narrowing. On the other hand, the increases observed for vertebral CSA apparently also only minimally contribute to the mechanical strengthening of the vertebral body under teriparatide treatment.

Effectiveness of a mucolythic agent as a local adjuvant in revision lumbar spine surgery.

Aim of this prospective randomized trial was to analyze the effectiveness of MESNA in chemical dissection of peridural fibrosis in patients who underwent revision lumbar spine surgery. Between January 2003 and October 2006, 30 patients who underwent revision lumbar spine surgery were enrolled in the study. Patients were randomly assigned to one of two groups: a study group (A) and a control group (B). Once peridural fibrosis was exposed, MESNA (Uromixetan MESNA, 50 mg/ml) was intraoperatively applied on the fibrous tissue (Group A) to ease tissue dissection and enter the canal. In patients of Group B, saline solution was used. Surgical time, preoperative and 1 week postoperative hemoglobin (Hb), length of hospitalization (days), and incidence of perioperative complications were evaluated. The blinded surgeon assigned the surgeries to one of four categories as none, minimal, moderate, and severe basing on intraoperative difficulty in dissecting the fibrous tissue and intraoperative bleeding. Statistical analysis used chi-square analysis to evaluate the difference in surgery difficulty and the incidence of intraoperative complications between the two groups. The analysis of surgical time and hemoglobin levels was performed using a one-sample Wilcoxon test and Mann-Whitney U test. Patients in whom MESNA was used intraoperatively (Group A) presented better intraoperative and perioperative parameters with respect to the control group. Average surgical time and decrease in Hb postoperatively were more in the saline group (B) respect to MESNA (A) (P = 0.004 and P = 0.001, respectively), while no difference in average hospital stay was reported between the two groups. Surgeon-blinded intraoperative report on surgical difficulty showed a significant difference between the two groups (P < 0.05). Postoperatively, no complications directly attributable to the use of MESNA were experienced. The incidence of dural tears and intraoperative bleeding from epidural veins were significantly less in Group A with respect to the control group. MESNA contributed significantly to reduce the operative complications, with a diminution of the surgical time and the grade of difficult for the surgeon, confirming its ability as chemical dissector also for epidural fibrosis in revision lumbar spine surgery.

Preventing peridural fibrosis with nonsteroidal anti-inflammatory drugs.

Peridural fibrosis is one of the more frequent complications of lumbar surgery. Nonsteroidal anti-inflammatory drugs inhibit the inflammatory and fibroblastic response. We performed lumbar laminectomies in 24 rabbits, divided into two groups. The experimental group received 5 mg/kg/day of aceclofenac for 7 days and the control group received 1 cm(3) of physiological saline. The samples were stained using immunohistochemical methods. The cellular populations in the inflammatory reaction and the thickness of the fibrous membrane were quantified. The mean of the fibrous area was always less in the rabbits of the experimental group compared to controls (47% less at 2 weeks and 41% less at 4 weeks). We observed an 8% decrease in the number of fibroblasts with antivimentin monoclonal antibodies in the experimental group. In this model, aceclofenac inhibits the presence of inflammatory cells in the fibrous scar in the early stages and reduces the extension of adhesions without adverse reactions.

Neurologic deficit following percutaneous vertebral stabilization.

STUDY DESIGN: A retrospective review. OBJECTIVE: The purpose of this study is to document a series of cases of neurologic deficit following percutaneous vertebral stabilization, to identify patterns of neurologic injury, and to describe potential methods for avoiding these injuries. SUMMARY OF BACKGROUND DATA: Percutaneous vertebral stabilization procedures, including vertebroplasty and kyphoplasty, have become a widely used for the treatment of osteoporotic vertebral compression fractures, primary and metastatic vertebral tumors, and traumatic burst fractures. Despite an increasing array of indications, there have been few reports of adverse events. Neurologic complications associated with vertebroplasty and kyphoplasty have been described previously as case reports and have generally been considered as infrequent and minor in severity. METHODS: The clinical course of 14 patients with documented loss of neurologic function following percutaneous vertebral cement augmentation was retrospectively reviewed. RESULTS: The average patient age was 74.9 years (range, 46-88 years) with 3 male and 11 female patients. Four patients underwent a vertebroplasty procedure while 10 were treated with kyphoplasty. Six patients developed neurologic deficits acutely (<24 hours of procedure). The remaining 8 patients developed neurologic symptoms at an average of 37.1 days (range, 3-112 days) postprocedure. Neurologic deficits were recorded as ASIA A in 4 patients, ASIA B in 2 patients, ASIA C in 1 patient, and ASIA D in 7 patients. Twelve of 14 patients (85.7%) required revision open surgical intervention for treatment of their neurologic injury. CONCLUSION: Percutaneous vertebroplasty and kyphoplasty have been reported to be safe options for the treatment of painful osteoporotic vertebral fractures. Although complications are infrequent, there remains the potential for catastrophic neurologic injury. Physicians performing these procedures need to be aware of these potential complications and be prepared to respond in an emergent manner (surgically) if a need arises.

Controlling bone morphogenetic protein diffusion and bone morphogenetic protein-stimulated bone growth using fibrin glue.

STUDY DESIGN: An in vitro and in vivo study. OBJECTIVE: To evaluate the ability of fibrin glue to limit diffusion of recombinant human bone morphogenetic protein (rhBMP)-2 and its ability to protect spinal nerves from rhBMP-2 stimulated bone growth. SUMMARY OF BACKGROUND DATA: Studies have shown bone morphogenetic protein (rhBMP-2) stimulated bone growth can encroach on the spinal canal and nerves, causing neural compression. More recently, rhBMP-2 use in the cervical spine has been associated with life-threatening swelling. Fibrin glue has been used as a biologic carrier but has not been evaluated for its ability to limit rhBMP-2. METHODS: In phase 1 of the study, rhBMP-2 soaked absorbable collagen sponges (ACS) were encapsulated in fibrin glue and immediately incubated in physiologic lactated ringers solution at 38 degrees C. Samples of solution were tested for rhBMP-2 concentration. In phase 2 of the study, rats were surgically treated with laminectomy and placement of rhBMP-2/ACS versus laminectomy and placement of fibrin glue before placement of rhBMP-2/ACS. After 8 weeks, animals were euthanized and imaged using micro-computerized tomography. RESULTS: The diffusion study showed a significant limitation in rhBMP-2 diffusion when encapsulated in fibrin glue. The laminectomy study revealed blockage of bone formation by fibrin glue and protection of the spinal canal. CONCLUSIONS: Fibrin glue can limit the diffusion of rhBMP-2, and, thus, it can be used to help protect the spinal canal and nerve roots from rhBMP-2 stimulated bone growth.

Recombinant human bone morphogenic protein-2-enhanced anterior spine fusion without bone encroachment into the spinal canal: a histomorphometric study in a thoracoscopically instrumented porcine model.

STUDY DESIGN: A thoracoscopically assisted 5-level anterior spinal fusion and instrumentation model analyzing new bone formation when using recombinant human bone morphogenic protein-2 (rhBMP-2) with a collagen hydroxyapatite-tricalcium phosphate (HA/TCP) composite sponge carrier. OBJECTIVE: To determine whether new bone formation extends beyond the posterior confines of the vertebral body encroaching into the spinal canal when rhBMP-2 is used to enhance anterior fusion. SUMMARY OF BACKGROUND DATA: A possible concern regarding the use of rhBMP-2 to enhance spinal fusion is the risk of unwanted bone formation leading to inadvertent fusion of adjacent levels or compression of neural elements. The safety of rhBMP-2 in one spinal application does not ensure similar results in other applications. Therefore, the expanded use of rhBMP-2 should occur only after carefully monitored preclinical and clinical studies for each new application. METHODS: Eighteen pigs underwent thoracoscopically-assisted instrumentation and fusion of 5 contiguous levels (T5-T10) and randomly assigned to 4 treatment groups: group 1 (n = 6): rh-BMP-2 on a HA/TCP-collagen sponge (Medtronic Sofamor Danek, Memphis, TN); group 2 (n = 4): iliac crest autograft; group 3 (n = 4): empty; group 4 (n = 4): HA/TCP-collagen sponge (Medtronic Sofamor Danek) only. In groups 1 and 4, the HA/TCP collagen sponge was morselized into small granules and pushed through a bone delivery funnel for implantation into the disc. At 4 months after surgery, spines were sectioned longitudinally through the midsagittal plane and underwent undecalcified processing. Bone formation extending beyond the margins of the original discectomy and the confines of vertebral body were evaluated histomorphometrically at each operative level. RESULTS: Recombinant human bone morphogenic protein-2 on a HA/TCP-collagen sponge induced significant new bone formation extending anterior to the confines of the vertebral body compared with the other treatment groups (P < 0.05). In addition, rhBMP-2 on a HA/TCP-collagen sponge induced significant new bone formation extending posterior to the original margins of the discectomy (P < 0.05). However, there was no new bone formation beyond the confines of the posterior vertebral body. The total bone volume in the rhBMP-2-HA/TCP-collagen sponge group was significantly greater compared with all other groups in both the discectomy fusion area and beyond the discectomy area (P < 0.05). CONCLUSIONS: Recombinant human bone morphogenic protein-2 on a HA/TCP-collagen sponge enhanced anterior spinal fusion and induced significant new bone formation extending beyond the margins of the original discectomy and anterior vertebral body, most likely secondary to migration of some morselized carrier fragments from the disc space. However, the new bone formation did not extend beyond the posterior confines of the vertebral body to encroach into the spinal canal because of the intact posterior anulus and/or posterior longitudinal ligament.

Cobb syndrome in an infant: treatment with endovascular embolization and corticosteroid therapy: case report.

OBJECTIVE AND IMPORTANCE: Cobb syndrome is a rare clinical entity characterized by the combination of a vascular skin nevus and an angioma in the spinal canal at the same metamere. We present a case report of an infant with Cobb syndrome. CLINICAL PRESENTATION: A 5-month-old girl presented with cutaneous hemangioma of the thoracolumbar region (T5-T12) and paraparesis. The infant was examined by magnetic resonance imaging and aortography and was diagnosed with Cobb syndrome. INTERVENTION: The patient received orally administered prednisolone therapy and underwent endovascular embolization of paravertebral and spinal angiomas with the use of n-butyl-2-cyanoacrylate. Her symptoms improved by combined treatment with liquid embolization and corticosteroid therapy. CONCLUSION: Although Cobb syndrome has been reported in older children, it is extremely rare in infants. To our knowledge, this is the first report of an infant with Cobb syndrome treated with endovascular embolization and corticosteroid therapy. The combined treatment with corticosteroid therapy and endovascular embolization of cutaneomeningospinal angioma in Cobb syndrome seems effective in alleviating symptoms and minimizing morbidity.

Roentgenographic evaluation of ossification and calcification of the lumbar spinal canal after intradiscal betamethasone injection.

There have been reports of lumbar spinal canal ossification and calcification after triamcinolone intradiscal injection therapy. Our objective was to observe the roentgenographic changes after betamethasone intradiscal injection therapy for lumbar disc diseases. The subjects were 183 patients (498 discs; 130 men and 53 women) who underwent discography and betamethasone intradiscal injection therapy and were followed for a mean of 5 years and 7 months. Ossification and calcification appeared de novo (three patients, three discs) or enlarged (four patients, five discs) in the outer layer of the posterior annulus fibrosus or posterior longitudinal ligament in eight discs among seven patients (3.8%). The incidence and degree of ossification and calcification in our patients were significantly lower than those reported in previous studies, and a long time elapsed before ossification and calcification appeared or enlarged. Intradiscal injection of betamethasone did not appear to confer any incremental relative risk for lumbar spinal canal ossification and calcification based on review of follow-up roentgenographs.

Effects of nitric oxide availability on responses of spinal wide dynamic range neurons to excitatory amino acids.

The role of nitric oxide (NO) in responses of spinal dorsal horn neurons to excitatory amino acids and to cutaneous mechanical stimuli was examined. Extracellular recordings were made from wide dynamic range neurons excited with iontophoretically applied excitatory amino acid agonists, N-methyl-D-aspartate (NMDA) and (R,S)-alpha-amino-3-hydroxy-5-methyl-isoxazole-4-propionic acid (AMPA) or kainic acid. Nitric oxide availability was decreased by iontrophoretic application of NO synthase inhibitors, N omega-nitro-L-arginine methyl ester (L-NAME) or L-N5-(1-iminoethyl)ornithine (L-NIO), or elevated by the NO donating compound, S-nitroso-N-penicillamine (SNAP). When cells were excited with successive application of NMDA and non-NMDA excitatory amino acid receptor agonists, application of NO synthase inhibitors led to a decrease in responses to NMDA in 60% of neurons. In more than a third of the cells tested, inhibition of NO synthase caused reciprocal changes in responses to glutamate receptor agonists: NMDA-evoked responses were significantly decreased whereas responses to the non-NMDA receptor agonists (AMPA or kainic acid) were increased. Application of the NO donating compound, S-nitroso-N-penicillamine, revealed an opposite tendency, increasing responses to NMDA in more than half of the neurons tested. In approximately 40% of the cells, reciprocal changes in responses to excitatory amino acid receptor agonists of NMDA versus non-NMDA types were observed after application of S-nitroso-N-penicillamine, such that the increase in NMDA responses was accompanied by decreases in the responses to kainic acid.(ABSTRACT TRUNCATED AT 250 WORDS)

Synthesis and structure-activity relationships of 2-(4-benzhydryl-1-piperazinyl)-1-phenylethanols as new calcium blockers.

A series of 2-(4-benzhydryl-1-piperazinyl)-1-phenylethanols (4) was synthesized and evaluated for calcium entry-blocking activity, assessed as inhibitory activity on calcium current in rat hippocampal pyramidal neurons by using a patch-clamp technique (10(-5) M), and cerebral vasodilating activity, assessed in terms of increase of vertebral blood flow after intravenous administration (1 mg/kg) in anesthetized dogs. Alkoxy substituents on the phenyl ring of the phenylethanol moiety conferred potent calcium entry-blocking activity and potent cerebral vasodilating activity. Among these compounds, 4i (NC-1100) was selected as the best analog. Some pharmacological properties of 4i are presented.

[Changes in CSF resorption resistance. Experimental studies]. / Zmiennosc oporu resorpcji. Badania doswiadczalne.

Lumbar infusion tests (IT) with different infusion rates (0.06 ml/min-1.2 ml/min) were used in order to investigate the intracranial pressure (ICP) and CSF outflow resistance (R) changes. Two groups of animals were studied: control group and animals with an 0.8 ml epidural balloon. In control group (without balloon) significant differences in ICP and R values between the increasing and decreasing IT curve were found. The most pronounced changes were noticed right after the highest infusion rate (40% for ICP value and 49% for R value). The results in the balloon group were very similar and the only difference were delayed ICP and R changes. The results obtained suggest that the determined R values are specific for the applied infusion rate and this phenomenon has to be taken into account in all human studies.

The effect of 0.5% ropivacaine on epidural blood flow.

Twenty patients scheduled for elective abdominal surgery received epidural analgesia with 20 ml 0.5% ropivacaine or 0.5% bupivacaine. Epidural blood flow was measured by an epidural 133Xe clearance technique on the day before surgery (no local anaesthetic) and again 1 h before surgery, 30 min after injection of the local anaesthetic during continuous infusion (8 ml/h). Median initial blood flow was 5.0 ml/min and 6.0 ml/min per 100 g tissue in patients receiving ropivacaine and bupivacaine, respectively. After epidural bupivacaine, blood flow increased in 8 of 10 patients to 6.9 ml/min per 100 g tissue (P less than 0.05) in contrast to a decrease in 9 of 10 patients to 3.3 ml/min per 100 g tissue after ropivacaine (P less than 0.05), (P less than 0.01 between groups). The median level of sensory analgesia was T3.5 and T4.5 in the ropivacaine and bupivacaine group, respectively (P greater than 0.05). The demonstrated vasoconstrictor effect of epidural ropivacaine may influence the duration of its local anaesthetic effect.

Microscopic epidural lesions in goats given repeated epidural injections of morphine: use of a modified autopsy procedure.

Epidural catheterization was performed in six goats. Five days later either saline or 20 mg (5 mg/ml) preservative free morphine was injected epidurally once daily for 8 days. The goats were sacrificed 4, 24 or 48 hours after the last injection. The lumbar part of columna was removed in toto for microscopic examination of the spinal cord and the entire epidural space after decalcification and transverse sectioning. After saline, minimal changes including a fibrous membrane surrounding the catheter, scattered fat cell necrosis, scattered small focal cell infiltrations and occasionally focal haemorrhages were seen. After morphine the changes were considerably more severe including diffuse cellular inflammatory reaction in the epidural space, fat cell necrosis, occasionally focal exudative inflammation and chronic inflammatory reaction in the vicinity of the fibrous membrane demarcating position of the catheter. It is concluded that the present modified autopsy procedure permits microscopic examination of the epidural space. It has been shown that repeated administration of morphine caused tissue damage in the epidural space of goats. The human predictability of the results obtained is unknown. However, the results are encouraging for investigations with similar procedure in humans.