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Study Design: Systematic review., Objectives: Primary Spinal Intradural Tumours (PSITs) are rare pathologies that can significantly impact quality of life. This study aimed to review patient reported outcomes (PROs) in PSITs., Methods: A systematic search of Pubmed and Embase was performed to identify studies measuring PROs in adults with PSITs. PRO results were categorised as relating to Global, Physical, Social, or Mental health. Outcomes were summarised descriptively., Results: Following review of 2382 records, 11 studies were eligible for inclusion (737 patients). All studies assessed surgically treated patients. Schwannoma was the commonest pathology (n = 190). 7 studies measured PROs before and after surgery, the remainder assessed only post-operatively. For eight studies, PROs were obtained within 12 months of treatment. 21 PRO measurement tools were used across included studies, of which Euro-Qol-5D (n = 8) and the pain visual/numerical analogue scale (n = 5) were utilised most frequently. Although overall QoL is lower than healthy controls in PSITs, improvements following surgery were found in Extramedullary tumours (EMT) in overall physical, social, and mental health. Similar improvements were not significant across studies of Intramedullary tumours (IMT). Overall QoL and symptom burden was higher in IMT patients than in brain tumour patients. No studies evaluated the effect of chemotherapy or radiotherapy., Conclusion: Patients with PSITs suffer impaired PROs before and after surgery. This is particularly true for IMTs. PRO reporting in PSITs is hindered by a heterogeneity of reporting and varied measurement tools. This calls for the establishment of a standard set of PROs as well as the use of registries., (© 2024. Crown.)

Competing Interests: GB has consulting agreements with Nevro, Abbott, Mainstay Medical, Stryker, Saluda Medical, Nalu Medical and Boston Scientific. The other authors declare no conflicts of interest.

Purpose: The ultrasonic bone curette (Bone Scalpel) is a novel technique in neurosurgery for bony dissection. This study aimed to evaluate its use against conventional techniques for primary lumbar decompression., Materials and Methods: This study was a retrospective cohort comparison, using Spine Tango Registry data. All patients undergoing a primary procedure for lumbar decompression secondary to degenerative disease during a 2-year period (2014-2016) were identified, split into age and gender matched cohorts utilising either bone scalpel or conventional techniques intra-operatively., Results: Ninety-three patients were identified within each cohort, which did not differ significantly in terms of age, gender, BMI, number of operative vertebral levels or seniority of the principal surgeon. The incidence of intra-operative blood loss >100 ml was significantly reduced within the bone scalpel cohort (16.1% bone scalpel, 34.4% conventional, p  = 0.04). There was no difference in the incidence of iatrogenic dural breach (9.7% bone scalpel, 16.1% conventional, p  = 0.27). There was no significant difference in pre-operative Core Outcomes Measures Index (COMI) between the cohorts (7.91 bone scalpel, 8.02 conventional, p  = 0.67) and both cohorts demonstrated a significant reduction in mean COMI at 24 months (bone scalpel p  = 0.004, conventional p = <0.001). No difference in mean COMI existed between either cohort at any point across the 24-month post-operative period ( p  = 0.18)., Conclusions: The use of ultrasonic bone curette for primary lumbar decompression is associated with reduced intra-operative blood loss compared to conventional techniques, alongside a comparable safety profile and equivalent patient reported outcomes.

Background: Sciatica is a common condition reported to affect > 3% of the UK population at any time and is most often caused by a prolapsed intervertebral disc. Currently, there is no uniformly adopted treatment strategy. Invasive treatments, such as surgery (i.e. microdiscectomy) and transforaminal epidural steroid injection, are often reserved for failed conservative treatment., Objective: To compare the clinical effectiveness and cost-effectiveness of microdiscectomy with transforaminal epidural steroid injection for the management of radicular pain secondary to lumbar prolapsed intervertebral disc for non-emergency presentation of sciatica of < 12 months' duration., Interventions: Patients were randomised to either (1) microdiscectomy or (2) transforaminal epidural steroid injection., Design: A pragmatic, multicentre, randomised prospective trial comparing microdiscectomy with transforaminal epidural steroid injection for sciatica due to prolapsed intervertebral disc with < 1 year symptom duration., Setting: NHS services providing secondary spinal surgical care within the UK., Participants: A total of 163 participants (aged 16-65 years) were recruited from 11 UK NHS outpatient clinics., Main Outcome Measures: The primary outcome was participant-completed Oswestry Disability Questionnaire score at 18 weeks post randomisation. Secondary outcomes were visual analogue scores for leg pain and back pain; modified Roland-Morris score (for sciatica), Core Outcome Measures Index score and participant satisfaction at 12-weekly intervals. Cost-effectiveness and quality of life were assessed using the EuroQol-5 Dimensions, five-level version; Hospital Episode Statistics data; medication usage; and self-reported cost data at 12-weekly intervals. Adverse event data were collected. The economic outcome was incremental cost per quality-adjusted life-year gained from the perspective of the NHS in England., Results: Eighty-three participants were allocated to transforaminal epidural steroid injection and 80 participants were allocated to microdiscectomy, using an online randomisation system. At week 18, Oswestry Disability Questionnaire scores had decreased, relative to baseline, by 26.7 points in the microdiscectomy group and by 24.5 points in the transforaminal epidural steroid injection. The difference between the treatments was not statistically significant (estimated treatment effect -4.25 points, 95% confidence interval -11.09 to 2.59 points). Nor were there significant differences between treatments in any of the secondary outcomes: Oswestry Disability Questionnaire scores, visual analogue scores for leg pain and back pain, modified Roland-Morris score and Core Outcome Measures Index score up to 54 weeks. There were four (3.8%) serious adverse events in the microdiscectomy group, including one nerve palsy (foot drop), and none in the transforaminal epidural steroid injection group. Compared with transforaminal epidural steroid injection, microdiscectomy had an incremental cost-effectiveness ratio of £38,737 per quality-adjusted life-year gained and a probability of 0.17 of being cost-effective at a willingness to pay threshold of £20,000 per quality-adjusted life-year., Limitations: Primary outcome data was invalid or incomplete for 24% of participants. Sensitivity analyses demonstrated robustness to assumptions made regarding missing data. Eighteen per cent of participants in the transforaminal epidural steroid injection group subsequently received microdiscectomy prior to their primary outcome assessment., Conclusions: To the best of our knowledge, the NErve Root Block VErsus Surgery trial is the first trial to evaluate the comparative clinical effectiveness and cost-effectiveness of microdiscectomy and transforaminal epidural steroid injection. No statistically significant difference was found between the two treatments for the primary outcome. It is unlikely that microdiscectomy is cost-effective compared with transforaminal epidural steroid injection at a threshold of £20,000 per quality-adjusted life-year for sciatica secondary to prolapsed intervertebral disc., Future Work: These results will lead to further studies in the streamlining and earlier management of discogenic sciatica., Trial Registration: Current Controlled Trials ISRCTN04820368 and EudraCT 2014-002751-25., Funding: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment ; Vol. 25, No. 24. See the NIHR Journals Library website for further project information.

Background: The optimal invasive treatment for sciatica secondary to herniated lumbar disc remains controversial, with a paucity of evidence for use of non-surgical treatments such as transforaminal epidural steroid injection (TFESI) over surgical microdiscectomy. We aimed to investigate the clinical and cost-effectiveness of these options for management of radicular pain secondary to herniated lumbar disc., Methods: We did a pragmatic, multicentre, phase 3, open-label, randomised controlled trial at 11 spinal units across the UK. Eligible patients were aged 16-65 years, had MRI-confirmed non-emergency sciatica secondary to herniated lumbar disc with symptom duration between 6 weeks and 12 months, and had leg pain that was not responsive to non-invasive management. Participants were randomly assigned (1:1) to receive either TFESI or surgical microdiscectomy by an online randomisation system that was stratified by centre with random permuted blocks. The primary outcome was Oswestry Disability Questionnaire (ODQ) score at 18 weeks. All randomly assigned participants who completed a valid ODQ at baseline and at 18 weeks were included in the analysis. Safety analysis included all treated participants. Cost-effectiveness was estimated from the EuroQol-5D-5L, Hospital Episode Statistics, medication usage, and self-reported resource-use data. This trial was registered with ISRCTN, number ISRCTN04820368, and EudraCT, number 2014-002751-25., Findings: Between March 6, 2015, and Dec 21, 2017, 163 (15%) of 1055 screened patients were enrolled, with 80 participants (49%) randomly assigned to the TFESI group and 83 participants (51%) to the surgery group. At week 18, ODQ scores were 30·02 (SD 24·38) for 63 assessed patients in the TFESI group and 22·30 (19·83) for 61 assessed patients in the surgery group. Mean improvement was 24·52 points (18·89) for the TFESI group and 26·74 points (21·35) for the surgery group, with an estimated treatment difference of -4·25 (95% CI -11·09 to 2·59; p=0·22). There were four serious adverse events in four participants associated with surgery, and none with TFESI. Compared with TFESI, surgery had an incremental cost-effectiveness ratio of £38 737 per quality-adjusted life-year gained, and a 0·17 probability of being cost-effective at a willingness-to-pay threshold of £20 000 per quality-adjusted life-year., Interpretation: For patients with sciatica secondary to herniated lumbar disc, with symptom duration of up to 12 months, TFESI should be considered as a first invasive treatment option. Surgery is unlikely to be a cost-effective alternative to TFESI., Funding: Health Technology Assessment programme of the National Institute for Health Research (NIHR), UK., (© 2021 Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license.)

Aim: The choice between anterior cervical discectomy & fusion (ACD) or posterior cervical foraminotomy (PCF) for the treatment of cervical brachialgia is controversial. This study aimes to compare clinical outcomes between these two operative inteventions for brachialgia., Methods: Retrospective review of prospectively collected data was performed. Patients receiving a primary ACD or PCF to treat brachialgia, in a single tertiary neurosurgical unit were included. Surgical details, and patient reported outcomes (COMI-Neck questionnaire) were extracted from a prospectively maintained spinal procedure database. Minimum clinically important difference (MCID) was defined as a change in COMI score of -2 at 12 months. The student t-test, Chi-square test, and linear regression were used to compare groups., Results: Between June 2011 ad February 2016 there were 634 ACD procedures (Median age 49; 321 Male), and 54 PCF procedures (Median age 50; 37 Male) perfomed for brachialgia. Age, ASA and pre-operative COMI were similar between the groups (p > .05). Complete outcome data was recorded at twelve months in 312 ACD and 36 PCF patients. Both ACD and PCF were associated with an improvement in COMI at 3 and 12 months (all p < .01). Mean change in COMI at 3 months was -2.38 for ACD, versus -2.31 for PCF (p = .88); at twelve months it was -2.94 for ACD, versus -2.67 for PCF (p = .55). MCID was seen in 59% of ACD cases, versus 58% of PCF cases at twelve months (p = .91)., Conclusion: There was no significant difference between outcomes in the ACD and PCF groups. This is supportive of published literature. The proposed multicenter RCTs may inform further.

Just over half of publicly funded trials recruit their target sample size within the planned study duration. When recruitment targets are missed, the funder of a trial is faced with the decision of either committing further resources to the study or risk that a worthwhile treatment effect may be missed by an underpowered final analysis. To avoid this challenging situation, when there is insufficient prior evidence to support predicted recruitment rates, funders now require feasibility assessments to be performed in the early stages of trials. Progression criteria are usually specified and agreed with the funder ahead of time. To date, however, the progression rules used are typically ad hoc. In addition, rules routinely permit adaptations to recruitment strategies but do not stipulate criteria for evaluating their effectiveness. In this paper, we develop a framework for planning and designing internal pilot studies which permit a trial to be stopped early if recruitment is disappointing or to continue to full recruitment if enrolment during the feasibility phase is adequate. This framework enables a progression rule to be pre-specified and agreed upon prior to starting a trial. The novel two-stage designs stipulate that if neither of these situations arises, adaptations to recruitment should be made and subsequently evaluated to establish whether they have been successful. We derive optimal progression rules for internal pilot studies which minimise the expected trial overrun and maintain a high probability of completing the study when the recruitment rate is adequate. The advantages of this procedure are illustrated using a real trial example.

Background: Sciatica is a common condition reported to affect over 3% of the UK population at any time and is often caused by a prolapsed intervertebral disc (PID). Although the duration and severity of symptoms can vary, pain persisting beyond 6 weeks is unlikely to recover spontaneously and may require investigation and treatment. Currently, there is no specific care pathway for sciatica in the National Health Service (NHS), and no direct comparison exists between surgical microdiscectomy and transforaminal epidural steroid injection (TFESI). The NERVES (NErve Root block VErsus Surgery) trial aims to address this by comparing clinical and cost-effectiveness of surgical microdiscectomy and TFESI to treat sciatica secondary to a PID., Methods/design: A total of 163 patients were recruited from NHS out-patient clinics across the UK and randomised to either microdiscectomy or TFESI. Adult patients (aged 16-65 years) with sciatic pain endured for between 6 weeks and 12 months are eligible if their symptoms have not been improved by at least one form of conservative (non-operative) treatment and they are willing to provide consent. Patients will be excluded if they present with neurological deficit or have had previous surgery at the same level. The primary outcome is patient-reported disability measured using the Oswestry Disability Questionnaire (ODQ) score at 18 weeks post randomisation and secondary outcomes include disability and pain scales using numerical pain ratings, modified Roland-Morris and Core Outcome Measures Index at 12-weekly intervals, and patient satisfaction at 54 weeks. Cost-effectiveness and quality of life (QOL) will be assessed using the EQ-5D-5 L and self-report cost data at 12-weekly intervals and Hospital Episode Statistics (HES) data. Adverse event data will be collected. Analysis will follow the principle of intention-to-treat., Discussion: NERVES is the first trial to evaluate the comparative clinical and cost-effectiveness of microdiscectomy to local anaesthetic and steroid administered via TFESI. The results of this research may facilitate the development of an evidence-based treatment strategy for patients with sciatica., Trial Registration: ISRCTN, ID: ISRCTN04820368 . Registered on 5 June 2014. EudraCT EudraCT2014-002751-25. Registered on 8 October 2014.

Study Design: We analyzed retrospectively whether early surgery for cauda equina syndrome (CES) within 24, 48, or 72 hours of onset of autonomic symptoms made any difference to bladder function at initial outpatient follow-up., Objective: CES potentially causes loss of autonomic control including bladder dysfunction, resulting in significant disability. There is significant debate regarding appropriate timing of surgery., Summary of Background Data and Methods: We conducted a retrospective cohort study of 200 patients between 2000 and 2011 who underwent decompressive surgery for CES at a regional neurosurgical center. Data collected were from clinical admission and at initial follow-up. Presentation was categorized into CES with retention (CESR) and incomplete CES (CESI) and duration of autonomic symptoms before surgical intervention., Results: A total of 200 patients had complete clinical records; 61 cases with CESR and 139 cases with CESI. Average initial follow-up time was 96 days. For the 36 cases with CESI less than 24 hours, normal bladder function was seen at follow-up in all patients except 4 (11.1%), but with 103 cases with CESI more than 24 hours, 48 (46.6%) had bladder dysfunction (Pearson χP = 0.000). For the 64 cases with CESI less than 48 hours, normal bladder function was seen at follow-up in all except 10 (15.6%), but with 75 cases with CESI more than 48 hours, 42 (56%) had bladder dysfunction (Pearson χP = 0.000). For the 35 patients with CESR, operating within 24, 48, or 72 hours made no obvious difference to bladder outcome. Data were also reanalyzed changing the dataset groups to CESI less than 24 hours, 24 to 48 hours, and more than 48 hours to calculate odds ratios regarding normal bladder outcome., Conclusion: We identified that decompressive surgery within 24 hours of onset of autonomic symptoms in CESI reduces bladder dysfunction at initial follow-up, but no statistically significant difference in outcome was observed in CESR regarding timing of operation., Level of Evidence: 3.

Background: The optimal management of odontoid fractures in the elderly population is unclear and management of this group of patients is complicated by multiple co-morbidities. This study aimed to determine the outcomes after conservative management strategies were applied in this patient group., Methods: We carried out retrospective and prospective analyses of all patients with axial cervical spine injuries, at a single centre. We included patients aged over 60 years with type II and III odontoid fractures. Information was gathered on demographics, ASA grading-associated injuries and complications. The outcome measures were rates and type of union, pain and neurological functions, specifically ambulation., Results: Fifty-seven adult patients with a median age of 78 years (range 60-92 years) were included. There were 42 type II and 15 type III odontoid fractures. Three patients required surgical fixation due to displaced fractures, which could not be reduced with manual traction. Twenty-four (41%) patients were managed with a rigid pinned halo orthosis to obtain adequate reduction and immobilisation. The remaining 30 (53%) were managed in a hard cervical collar. Patients managed with a halo were significantly younger and had more associated injuries than patients managed in a collar (age: t-test=4.05, p<0.01, associated injuries: Chi-square=4.38, p<0.05). At a mean follow-up of 25 weeks, 87% of type II and 100% of type III fractures had achieved bony union or stable, fibrous non-union. There were no statistical differences in fracture type, follow-up or neurological outcomes between the halo and collar groups. However, overall more patients managed in a collar developed stable fibrous non-union than bony fusion (Fisher's exact test, p<0.05), although this was not significant when analysed by each fracture type individually. A regression model was constructed and identified fracture type as the only independent predictor of time to union, with type III fractures healing faster than type II., Conclusions: High rates of bony union and stable fibrous non-union with a good functional outcome can be achieved in the elderly population sustaining type II or III odontoid fractures, when managed non-surgically. Halo orthosis may not offer any clear advantage over hard collar in this group. Close follow-up is needed for late complications and there must be a willingness to perform surgery if conservative measures fail.

STUDY DESIGN. Retrospective audit of consecutive patients. OBJECTIve. To investigate the re-operation rate following elective primary lumbar microdiscectomy and to determine whether principal surgeon grade and/or disc space lavage is a factor in recurrence. SUMMARY OF BACKGROUND DATA. Recurrent herniation of disc material following lumbar microdiscecomy surgery is one of the commonest complications of the procedure. Any reduction in the number of revision microdiscectomies performed per year would have a significant impact on patients' lives and on the health service economy. We undertook this study to ascertain whether principal surgeon grade and/or disc space lavage has an impact in reducing the re-operation rate. METHODS. We undertook a retrospective audit of patients who underwent elective primary lumbar microdiscectomy, over a 3-year period (n = 971). RESULTS. The overall re-operation rate for primary elective microdiscectomy was 3.8%, consistent with the published literature. The relative risk of re-operation in patients primarily operated by registrar surgeons was 1.2 fold the risk in patients operated by consultants (95% CI: 0.62, 2.35) although not statistically significant (p = 0.568). The risk of re-operation in the 'non lavage' group was 2.15 times the risk in the 'lavage' group (95% CI: 0.63, 7.34), but it did not reach significance (p = 0.222). CONCLUSIONS. Principal surgeon grade and intervertebral disc lavage have not been found conclusively to be factors in the rate of recurrence. This information is useful to reassure patients that their outcome from such surgery is not dependent on the grade of surgeon performing the operation. There is a possible trend towards intervertebral disc lavage reducing the rate of recurrence.

Study Design: A clinicopathologic study of synovial cysts in the ligamentum flavum (LF) in patients with spinal stenosis., Objective: To investigate the pathogenesis of lumbar juxtafacet cysts., Summary of Background Data: Contradictions in the terminology applied to lumbar juxtafacet cysts arise from the frequent sparsity of synovial lining cells, which has led to synovial cysts often being called "ganglion cysts" despite lacking confirmatory pathology., Methods: A total of 27 consecutive patients with radiologically confirmed stenosis underwent laminectomy. LF/facet joint (FJ) relationships were retained by en bloc excision of the LF and the medial inferior FJ. Controls were LF/FJ specimens from 47 cadaver lumbar spines., Results: The 27 patients yielded 51 LF/FJ specimens containing 28 synovial cysts, 12 of which were unilateral and 8 were bilateral. Fragments of articular cartilage and bone were embedded in the walls of 89% of cysts and in the walls of a bursa-like channel originating from the medial aspect of the FJ capsule and extending into the LF. Communication with the FJ via this channel was observed in 21 (75%) of the 28 synovial cysts. Extending up to 12 mm in length, the channel was present in nearly all control spines at the L4-L5 level but in only about half at the T12-L1 level., Conclusion: Cysts having an extensive or meagre synovial cell lining are common in the LF of patients with symptomatic lateral or central stenosis. The cysts communicate with the FJ by a bursa-type channel within the LF. Advanced osteoarthritis of the FJ causes the liberation of fragments of cartilage and bone into the synovial fluid of the joint space. This enables some fragments to escape from the joint into the channel and become lodged within its wall where they provoke granulation tissue and scar formation. The tissue response to articular debris may block the synovial-lined channel to cause synovial cyst formation.

Lumbar canal stenosis (LCS) is a common condition affecting elderly patients for which a significant number undergo surgery. The validity and safety of simple laminectomy in this condition is not fully understood. Furthermore, the presence of pre-existing spondylolisthesis is controversial with respect to the need for additional spinal stabilization. We prospectively studied a consecutive cohort of 100 patients with clinical and radiological LCS under the care of a single spinal surgeon. Outcome measures (SF-36, visual analogue scores for back and leg symptoms, and the Roland/Morris back pain scores) were assessed preoperatively, 3 months postsurgery and at long-term (median 2 years) follow-up. We have shown a significant improvement in outcome sustained in the long-term with minimal morbidity. Patients with pre-existing spondylolisthesis accounted for 23% of the cohort and, having received identical treatment, showed no significant difference in outcome compared with patients with normal alignment.

Chlormethiazole is a thiazole derivative with a long history of use as a sedative agent. The mode of action of the drug has been partly worked out and has been established with recognition that its mechanism of action involves potentiation of GABA activity, the major intrinsic inhibitory neurotransmitter. Animal models of stroke ranging from rodents to primates have suggested an optimistic role for chlormethiazole in preventing both anatomical and functional deleterious effects of stroke. Phase III clinical trials, therefore, proceeded but unfortunately with very little success. Recently, the animal models have been revisited in an attempt to identify causes for this discrepancy between the results from preclinical and clinical studies. This review studies the pharmacological roots of chlormethiazole from its origin through to its licensed and novel applications. Emphasis is placed on discussing the animal experiments which led to its grooming as a neuroprotective agent and also on the human trials. The review seeks to explain the discrepancies between animal and human studies, which include short survival times of experimental subjects, speed of drug administration and fundamental differences between species. The primate model of stroke perhaps offers the nearest alternative to phase III trials and has recently been used to compare a number of newer neuroprotective agents with greater efficacy than chlormethiazole. In addition, novel approaches involving human neurochemical analyses in vivo are described which may help bridge the gap between animal models and future phase III trials.

Purpose: To assess the capacity of a retrovirus-engineered Schwann cell line (SCTM41), transfected with either a glial cell line-derived neurotrophic factor (GDNF) construct or a brain-derived neurotrophic factor (BDNF) construct, to sustain visual function in the dystrophic Royal College of Surgeons (RCS) rat., Methods: Cell suspensions were injected into the subretinal space of the right eye of 3-week-old dystrophic RCS rats through a transscleral approach. The left eye remained as an unoperated control. Sham-surgery animals received injections of carrier medium plus DNase to the right eye. All animals were placed on oral cyclosporine. At 8, 12, 16, and 20 weeks of age, animals were placed in a head-tracking apparatus and screened for their ability to track square-wave gratings at various spatial frequencies (0.125, 0.25, and 0.5 cyc/deg). At the end of the experiment, the animals were perfused and processed for histologic assessment of photoreceptor survival., Results: Animals with SCTM41-GDNF-secreting cells, on average, head tracked longer than animals with SCTM41-BDNF-secreting cells, and both performed better than those injected with the parent SCTM41 line. All tracked longer than sham-surgery or nonsurgical dystrophic eyes. Each cell type demonstrated preservation of photoreceptors up to at least 4 months of age, over and above the sham-surgery control., Conclusions: Engineered Schwann cells sustain retinal structure and function in the dystrophic RCS rat. Cells overexpressing GDNF or BDNF had a greater effect on photoreceptor survival than the parent line or sham surgery. This study demonstrates that ex vivo gene therapy and subsequent cell transplantation can be effective in preserving photoreceptors from the cell death that normally accompanies retinal degeneration.

Background and Purpose: The goal of this study was to prospectively assess outcome and cost for poor-grade subarachnoid hemorrhage patients presenting to a regional neurosurgical center (Addenbrooke's Hospital, Cambridge, UK) between 1994 and 2001. Outcome measures were clinical outcome at 6 months, number needed to treat (NNT) for favorable outcomes, and cost analysis., Methods: Poor-grade patients (World Federation of Neurological Surgeons grades 4 and 5) were transferred to the neurocritical care unit after intubation and ventilation. After resuscitation and drainage of ventricular cerebrospinal fluid for 24 hours, sedation was stopped, and patients were assessed clinically. Patients with a Glasgow Motor Score (GMS) > or =4 underwent angiography and surgical treatment of culprit aneurysms. Patients with a subsequent GMS of 6 were not deemed poor grade and were discounted from the study., Results: We deemed 166 ventilated patients genuinely poor grade (mean age, 53.4 years; 94 women [56.6%]). Of these, 88 patients (4

We have treated spinal cord injured rats with demyelination plus Schwann cell transplantation and assessed neurite outgrowth in a quantifiable model of axonal regeneration. Axonal injuries of differing severity were induced in the dorsal funiculus of adult rats using a micromanipulator-controlled Scouten knife. Demyelinated regions were produced so as to overlap with the injury site by the injection of galactocerebroside antibodies plus complement one segment cranial to the axonal injury site. Schwann cells were isolated from the sciatic nerve, expanded in vitro, and transplanted into the injury site 1 day later. Animals were killed after an additional 7 days. Schwann cells were evenly distributed throughout the region of demyelination, which extended 6-7 mm cranial to the axonal injury site. The severity of axonal injury was quantified by counting degenerate axons in transverse resin sections. The degree of axonal regeneration was assessed by an electron microscopic analysis of growth cone frequency and distribution relative to the site of axonal injury. Quantification of growth cones at a distance from the site of axonal injury indicated a strong linear relationship (P < 0.001) between the number of growth cones and the number of severed axons; the ratio of growth cones to severed axons was increased by 26.5% in demyelinated plus transplanted animals compared to demyelinated animals without a transplant. Furthermore, only the demyelinated plus transplanted animals contained growth cones associated with myelin in white matter immediately outside of the region of complete demyelination. Growth cones were absent in transplanted-only animals at a distance from the site of axonal injury. These findings indicate that combined demyelination plus Schwann cell transplantation therapy enhances axonal regeneration following injury and suggests that growth cones are able to overcome myelin-associated inhibitors of neurite outgrowth in the presence of trophic support., (Copyright 1999 Academic Press.)

Astrocytes exclude Schwann cells (SCs) from the central nervous system (CNS) at peripheral nerve entry zones and restrict their migration after transplantation into the CNS. We have modeled the interactions between SCs, astrocytes, and fibroblasts in vitro. Astrocytes and SCs in vitro form separate territories, with sharp boundaries between them. SCs migrate poorly when placed on astrocyte monolayers, but migrate well on various other surfaces such as laminin (LN) and skin fibroblasts. Interactions between individual SCs and astrocytes result in long-lasting adhesive contacts during which the SC is unable to migrate away from the astrocyte. In contrast, SC interactions with fibroblasts are much shorter with less arrest of migration. SCs adhere strongly to astrocytes and other SCs, but less well to substrates that promote migration, such as LN and fibroblasts. SC-astrocyte and SC-SC adhesion is mediated by the calcium-dependent cell adhesion molecule N-cadherin. Inhibition of N-cadherin function by calcium withdrawal, peptides containing the classical cadherin cell adhesion recognition sequence His-Ala-Val, or antibodies directed against this sequence inhibit SC adhesion and increase SC migration on astrocytes. We suggest that N-cadherin-mediated adhesion to astrocytes inhibits the widespread migration of SCs in CNS tissue., (Copyright 1999 Academic Press.)

We have developed a novel Schwann cell line, SCTM41, derived from postnatal sciatic nerve cultures and have stably transfected a clone with a rat glial cell line-derived neurotrophic factor (GDNF) construct. Coculture with this GDNF-secreting clone enhances in vitro survival and fiber growth of embryonic dopaminergic neurons. In the rat unilateral 6-OHDA lesion model of Parkinson's disease, we have therefore made cografts of these cells with embryonic day 14 ventral mesencephalic grafts and assayed for effects on dopaminergic cell survival and process outgrowth. We show that cografts of GDNF-secreting Schwann cell lines improve the survival of intrastriatal embryonic dopaminergic neuronal grafts and improve neurite outgrowth into the host neuropil but have no additional effect on amphetamine-induced rotation. We next looked to see whether bridge grafts of GDNF-secreting SCTM41 cells would promote the growth of axons to their striatal targets from dopaminergic neurons implanted orthotopically into the 6-OHDA-lesioned substantia nigra. We show that such bridge grafts increase the survival of implanted embryonic dopaminergic neurons and promote the growth of axons through the grafts to the striatum.