Inflammation-induced GluA1 trafficking and membrane insertion of Ca2+ permeable AMPA receptors in dorsal horn neurons is dependent on spinal tumor necrosis factor, PI3 kinase and protein kinase A.

Peripheral inflammation induces sensitization of nociceptive spinal cord neurons. Both spinal tumor necrosis factor (TNF) and neuronal membrane insertion of Ca2+ permeable AMPA receptor (AMPAr) contribute to spinal sensitization and resultant pain behavior, molecular mechanisms connecting these two events have not been studied in detail. Intrathecal (i.t.) injection of TNF-blockers attenuated paw carrageenan-induced mechanical and thermal hypersensitivity. Levels of GluA1 and GluA4 from dorsal spinal membrane fractions increased in carrageenan-injected rats compared to controls. In the same tissue, GluA2 levels were not altered. Inflammation-induced increases in membrane GluA1 were prevented by i.t. pre-treatment with antagonists to TNF, PI3K, PKA and NMDA. Interestingly, administration of TNF or PI3K inhibitors followed by carrageenan caused a marked reduction in plasma membrane GluA2 levels, despite the fact that membrane GluA2 levels were stable following inhibitor administration in the absence of carrageenan. TNF pre-incubation induced increased numbers of Co2+ labeled dorsal horn neurons, indicating more neurons with Ca2+ permeable AMPAr. In parallel to Western blot results, this increase was blocked by antagonism of PI3K and PKA. In addition, spinal slices from GluA1 transgenic mice, which had a single alanine replacement at GluA1 ser 845 or ser 831 that prevented phosphorylation, were resistant to TNF-induced increases in Co2+ labeling. However, behavioral responses following intraplantar carrageenan and formalin in the mutant mice were no different from littermate controls, suggesting a more complex regulation of nociception. Co-localization of GluA1, GluA2 and GluA4 with synaptophysin on identified spinoparabrachial neurons and their relative ratios were used to assess inflammation-induced trafficking of AMPAr to synapses. Inflammation induced an increase in synaptic GluA1, but not GluA2. Although total GluA4 also increased with inflammation, co-localization of GluA4 with synaptophysin, fell short of significance. Taken together these data suggest that peripheral inflammation induces a PI3K and PKA dependent TNFR1 activated pathway that culminates with trafficking of calcium permeable AMPAr into synapses of nociceptive dorsal horn projection neurons.

RhBMP-2 use in lumbar fusion surgery is associated with transient immediate post-operative leg pain.

PURPOSE: Supra-physiological rhBMP loads during spinal fusion may trigger local inflammation and post-operative radiculitis. MRI is an effective tool to detect nerve root compression in severe post-operative leg pain. The aim of this study was to determine if recombinant bone morphogenic protein 2 (rhBMP-2) is associated with immediate post-operative leg pain without evidence of root compression using MRI. METHOD: All patients undergoing posterolateral and posterior interbody lumbar spinal fusions with rhBMP-2 between July 2007 and January 2009 at a single surgeon practice were retrospectively reviewed for incidence of severe immediate post-operative leg pain. Patients that presented with immediate post-operative leg pain were interviewed and Oswestry Disability Indices calculated. RESULTS: Sixty-four rhBMP-2 treated patients and 40 controls were included. Pre-operative demographics and diagnoses were similar and inter-body cages were used equally. Immediate post-operative leg pain incidence was 25 and 12.5% in the rhBMP-2 and non-rhBMP-2 groups, respectively. 17.2% of the patients treated with rhBMP-2 had immediate post-operative leg pain without evidence of nerve root compression on MRI versus 7.5% of the patients treated without rhBMP-2. At follow-up, leg pain incidence was 11.6 and 7.6% in rhBMP-2 and non-rhBMP-2 groups, respectively. There was no difference in Oswestry Disability Indices between groups (36.5 ± 31.2 vs. 23.0 ± 25.5). CONCLUSION: RhBMP-2 associated radiculitis presenting as immediate post-operative leg pain without MRI evidence of neuronal compression occurs in 17% of the patients with rhBMP-2 assisted fusion. Patients should be pre-operatively counselled regarding immediate post-operative leg pain with rhBMP-2. LEVEL OF EVIDENCE: III.

Lumbar puncture drainage with intrathecal injection of amphotericin B for control of cryptococcal meningitis.

Cryptococcal meningitis is a disease with high mortality and refractory to intravenous antifungal treatments with agents such as amphotericin B and fluconazole. We investigated lumbar puncture catheter drainage with an intrathecal injection of amphotericin B as a treatment for cryptococcal meningitis. All of the 14 patients enrolled in the treatment group survived with no evidence of relapse during 1-year follow-up. Complications included lumbosacral nerve root irritation in seven patients and urinary retention in seven patients. This study demonstrated that the technique used was effective in controlling the symptoms. The major complications disappeared after discontinuation of intrathecal injection of amphotericin B or with low-dose therapy. Therefore, this technique could be an effective and safe method for the treatment of cryptococcal meningitis.

Histopathologic inflammatory response induced by recombinant bone morphogenetic protein-2 causing radiculopathy after transforaminal lumbar interbody fusion.

BACKGROUND CONTEXT: A significant increase in off-label use of recombinant human bone morphogenic protein-2 (rhBMP-2) in posterior lumbar interbody fusion techniques has been seen in the spine community. Numerous reports have demonstrated complications with use of this proinflammatory agent; however, the in vivo response caused by rhBMP-2 has not been characterized on a cellular level. PURPOSE: To report the case of lumbar radiculopathy and the associated histopathologic findings stemming from the inflammatory response to rhBMP-2 used in transforaminal lumbar interbody fusion (TLIF) surgery. STUDY DESIGN/SETTING: Case report. PATIENT SAMPLE: Single patient case report of rhBMP-2 off-label use causing an inflammatory response that resulted in radiculopathy after TLIF surgery. OUTCOMES MEASURES: Clinical, radiologic, and histopathologic evidence was used to determine outcomes in this report. METHODS: A 27-year-old male presented with low back pain and radiculopathy and radiographic evidence of degenerative disc disease and foraminal stenosis. Four weeks after L4-L5 TLIF surgery augmented with rhBMP-2, the patient developed right-sided lower extremity radiculopathy. Magnetic resonance imaging of the lumbar spine demonstrated bilateral fluid collections with the larger right-sided mass compressing the right L4 nerve root. RESULTS: Surgical decompression of this mass resulted in resolution of his right-sided radicular symptoms. Histologic analysis of the surgical pathology demonstrated diffuse osteoid and woven bone amidst a fibrovascular stroma densely populated by lymphocytes and eosinophils. CONCLUSIONS: Off-label rhBMP-2 use in posterior interbody fusion techniques can lead to complications. This case serves to identify potential hazards of this growth factor and highlight areas for further study to better understand its in vivo behavior.

Recombinant human bone morphogenetic protein-2-induced radiculitis in elective minimally invasive transforaminal lumbar interbody fusions: a series review.

STUDY DESIGN: Retrospective single center analysis. OBJECTIVE: The purpose of our study is to quantify the development of a postoperative radiculitis in our minimally invasive transforaminal lumbar interbody fusion patient population. SUMMARY OF BACKGROUND DATA: The application of recombinant human Bone Morphogenetic Protein-2 (BMP) in spinal surgery has allowed for greater success in spinal fusions. This has led to the FDA approving its use in anterior lumbar interbody fusion. However, its well-recognized benefits have generated its "off-label" use in the cervical, thoracic, and lumbar spine. Despite its benefits, the adverse effects of its inflammatory properties are just starting to get recognized. Some clear adverse reactions have been documented in the literature in the cervical spine. However, we feel that these inflammatory properties may be present in the lumbar spine as well. METHODS: We performed a retrospective chart review of 43 patients who had undergone a minimally invasive transforaminal lumbar interbody fusions. Thirty-five of these patients had BMP and 8 patients did not have BMP. We documented whether there was a preoperative radiculopathy present and whether a radiculopathy was present postoperative. We reviewed radiographic postoperative imaging to establish a structural cause for any radiculopathy. If new or increasing radicular symptoms were present, we attempted to assess the duration of these symptoms. RESULTS: Our analysis, showed that 0 of the 8 patients of the non-BMP group had new radicular symptoms that were not attributed to structural causes. In the BMP group, 4 of the 35 patients (11.4%) had new radicular symptoms without structural etiology. CONCLUSION: Our analysis suggest that patients undergoing minimally invasive transforaminal lumbar interbody fusions procedures have a higher incidence of developing new radicular symptoms that could be attributed to BMP.

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.

Cryptococcal meningoradiculitis: an atypical presentation after initiation of antiretroviral therapy.

Atypical presentations of cryptococcal infection have been described as clinical manifestations of immune reconstitution inflammatory syndrome (IRIS) in HIV-infected patients following commence of antiretroviral therapy (ART). The authors describe a patient presenting with cryptococcal meningoradiculitis two weeks after initiation of ART. In patients with advanced HIV disease, immune reconstitution induced by ART can precipitate onset of atypical clinical manifestations in those patients with latent cryptococcal infection of the central nervous system.

[Radiculopathy following intrathecal baclofen pump implantation]. / Radiculalgie après implantation de pompe à baclofène.

INTRODUCTION: Intrathecally delivered baclofen has been used as a treatment for severe spasticity since 1984. After a successful intrathecal baclofen trial, a programmable drug delivery system was implanted. Few early complications such as infection or hematoma are observed after this surgery. OBJECTIVE: To describe an unusual and unknown complication of intrathecal baclofen therapy. METHOD: We report 2 cases of complications of intrathecal baclofen therapy, radiculalgy, that appeared early after pump implantation. The clinical symptoms and computed tomography (CT) results are described. RESULTS: The first patient described pain, which evoked left S1 radiculopathic features. The second had left L5 radiculopathic involvement. The mean pain level was estimated on a 10-point visual analog scale as 7.5 (range 4-9). Lumbar CT scan showed a conflict between the symptomatic root and the catheter and eliminated other causes of the symptoms. Treatment with analgesic drugs was successful in 1 patient. The other presented with proximal disconnection of the catheter, which led to surgical replacement of the catheter. The pain disappeared after this surgery. CONCLUSION: Intrathecal baclofen therapy with a subcutaneously implanted progammable pump can be complicated by radiculalgy secondary to a conflict between the catheter and symptomatic root. The diagnosis is made by CT lumbar scan. If medical treatment is not sufficient, surgery could be proposed to replace the catheter.

Cervical radiculopathy due to intra-arterial infusion of cisplatin.

A 55-year-old man with cervical radiculopathy (C5-C8) was referred to us following intra-arterial infusion of cisplatin (CDDP) because of a recurrent neck mass of laryngeal cancer. Three hours after the CDDP infusion, he had noticed general weakness of the left upper extremity and hypoaesthesia of the lateral side of the upper and lower arm. The next day he was diagnosed with left cervical radiculopathy of C5 to C8, which improved gradually and had resolved completely six months after the infusion. Even with proper positioning of the infusion catheter to minimize potential complications, for anatomical reasons there are always some risks of neural injury with intra-arterial infusion from branches of the subclavian artery. This procedure should be carefully indicated in the case of a large neck tumour that is perfused from the major branches of the subclavian artery.

Impact of Agent Orange exposure among Korean Vietnam veterans.

In order to determine whether Agent Orange exposure was associated with increased frequency of medical problems, we conducted a cross-sectional epidemiologic study of Korean veterans during 1995-1996. 1,224 Vietnam and 154 non-Vietnam veterans were included in the study. Exposure to Agent Orange was assessed by structured in-depth interview on the participants' history of service in Vietnam. Health outcomes were assessed by a standardized comprehensive clinical investigation by a group of clinical specialists. The differences in the prevalence of various medical diagnoses were assessed by Cochran-Mantel-Haenszel chi-square tests comparing the exposure levels of Vietnam veterans, adjusting for age. Multiple logistic regression was performed to estimate the effect of "service in Vietnam" adjusting for age, smoking, alcohol, body mass index, education, and marital status. Vietnam veterans had an increased frequency of eczema (odds ratio [OR] = 6.54), radiculopathy (OR = 3.98), diabetes (OR = 2.69), peripheral neuropathy (OR = 2.39), and hypertension (OR = 2.29), compared to non-Vietnam veterans, adjusting for potential confounders. In addition, higher levels of exposure among Vietnam veterans were associated with increased frequency of ischemic heart disease (p < 0.01), valvular heart disease (p < 0.01), and retinopathy (p < 0.01). We conclude that exposure to Agent Orange is associated with various health impacts in Korean Vietnam veterans.

Radicular pain after vertebroplasty: compression or irritation of the nerve root? Initial experience with the "cooling system".

STUDY DESIGN: During vertebroplasty (VP), polymethylmethacrylate (PMMA) may leak into the posterior epidural venus plexus, provoking symptoms ranging from radicular pain to medullar compression. OBJECTIVES: To propose and test the feasibility of a procedure (cooling system) to prevent radicular irritation caused by foraminal PMMA leakage. SUMMARY OF BACKGROUND DATA: Foraminal leak of PMMA, as observed during VP, may lead to radiculalgia. Several mechanisms of nerve root irritation have been proposed. Considering heat or local chemical irritation has led us to treat immediately by local periradicular irrigation with a cooling liquid. METHODS: Four consecutive patients with observed foraminal leakage were treated by local fluid injection. Immediately after observation of a foraminal leak, a 20-gauge Chiba needle was positioned to reach the foramen. Ten cubic centimeters of lidocaine (0.2%) was followed by 100-200 cc of pressurized saline perfusion within 10-20 minutes (cooling system). RESULTS: In all patients with foraminal leakage, no radicular pain existed after application of the cooling system. No complications were observed with its use. CONCLUSION: In presence of a foraminal leakage, the immediate application of a cooling irrigation may protect the root from injury, which is explained by the hypothesis that the main mechanism of injury may be more related to heat or chemical irritation of the nerve than compression.

[Two cases of lumbosacral radiculopathy after intra-arterial infusion of cisplatin for treatment of uterine cancer].

A 60-year-old woman (case 1) experienced severe pain in the lower part of her leg and sciatic nerve paralysis the following day after intra-arterial infusion of cisplatin for the treatment of uterine body cancer. The symptoms gradually improved in the next six months. The lesion was not detected on pelvic MRI after two months. A 49-year-old woman (case 2) complained of severe pain in the lower part of her leg three days after intra-arterial infusion of cisplatin for the treatment of uterocervical cancer. Enhancement of the right first sacral root was demonstrated by the pelvic MRI. The symptoms gradually improved with the symptomatic therapy. To our knowledge, this is the first report of lumbo-sacral radiculopathy associated with intra-arterial infusion of cisplatin presenting the enhanced lesion in the root on MRI. It was suggested that lumbo-sacral radiculopathy induced by intra-arterial infusion of cisplatin is not a rare complication and that MRI is useful in confirming the diagnosis. Various precautions should be undertaken to prevent such complications.

Radiation myelitis in a 5-year-old girl.

Myelopathy is an uncommon complication of radiotherapy, particularly in the pediatric age group. A 5-year-old girl with acute lymphoblastic leukemia developed a severe but transient radiculopathy after intrathecal administration of methotrexate and cytarabine for an isolated central nervous system relapse. Chemotherapy was then given through an intraventricular catheter. Owing to a second central nervous system recurrence, she was treated with craniospinal radiation. The whole brain down to the level of C2 received a dose of 2400 cGy. Two months after completion of radiation, the child developed a progressive tetraparesis, and magnetic resonance imaging revealed an enhancing lesion involving the medulla and upper cervical cord. A biopsy was consistent with a treatment-related necrotizing leukoencephalopathy. This case suggests that patients who develop neurologic dysfunction when treated with methotrexate can also be particularly susceptible to radiation-related injury.

Transient radiculopathy after 5% lidocaine or 0.75% bupivacaine spinal anesthesia in 3 surgical positions.

The present study was conducted to compare the incidence of transient radicular irritation (TRI) after spinal anesthesia with 5% lidocaine or 0.75% bupivacaine in the supine, prone, and lithotomy surgical positions. A non-rAndomized survey approach was used. The convenience sample consisted of 243 adults receiving spinal anesthesia for elective surgery at 1 of 3 hospitals. Patients were questioned by telephone postoperatively to determine whether they had experienced TRI. Statistical analysis using the Fisher exact test revealed no significant difference in TRI incidence between local anesthetics in the supine or prone position groups. In the lithotomy position group, the incidence of TRI was significantly higher in patients receiving 5% lidocaine. Further, chi 2 testing revealed no significant difference in TRI incidence between surgical position groups when position alone was considered. The findings suggest that TRI after spinal anesthesia occurs more frequently with 5% lidocaine than with 0.75% bupivacaine only when patients undergo surgery in the lithotomy position. Providers need to consider the risks and benefits of 5% lidocaine when selecting an agent for spinal anesthesia, especially with patients undergoing surgery in the lithotomy position. When lidocaine is used, providers should discuss TRI as a risk of spinal anesthesia with patients during preanesthetic counseling.

Repeated transient neurological symptoms after spinal anaesthesia with hyperbaric 5% lidocaine.

We report a case of repeated delayed pain after cystoscopy under spinal lidocaine anaesthesia, which may be caused by transient radicular irritation. The possible aetiology of the symptoms is discussed.