Félix Scholtes

Delayed GM-CSF treatment stimulates axonal regeneration and functional recovery in paraplegic rats via an increased BDNF expression by endogenous macrophages

Macrophages (monocytes/microglia) could play a critical role in central nervous system repair. We have previously found a synchronism between the regression of spontaneous axonal regeneration and the deactivation of macrophages 3–4 wk after a compression‐injury of rat spinal cord. To explore whether reactivation of endogenous macrophages might be beneficial for spinal cord repair, we have studied the effects of granulocyte‐macrophage colony stimulating factor (GM‐CSF) in the same paraplegia model and in cell cultures. There was a significant, though transient, improvement of locomotor recovery after a single delayed intraperitoneal injection of 2 µg GM‐CSF, which also increased significantly the expression of Cr3 and brain‐derived neurotrophic factor (BDNF) by macrophages at the lesion site. At longer survival delays, axonal regeneration was significantly enhanced in GM‐CSF‐treated rats. In vitro, BV2 microglial cells expressed higher levels of BDNF in the presence of GM‐CSF and neurons cocultured with microglial cells activated by GM‐CSF generated more neurites, an effect blocked by a BDNF antibody. These experiments suggest that GM‐CSF could be an interesting treatment option for spinal cord injury and that its beneficial effects might be mediated by BDNF.—Bouhy, D., Malgrange, B., Multon, S., Poirrier, A. L., Scholtes, F., Schoenen, J., Franzen, R. Delayed GM‐CSF treatment stimulates axonal regeneration and functional recovery in paraplegic rats via an increased BDNF expression by endogenous macrophages. FASEB J. 20, E493–E502 (2006)

Poly(D,L-lactide) foams modified by poly(ethylene oxide)-block-poly(D,L-lactide) copolymers and a-FGF: in vitro and in vivo evaluation for spinal cord regeneration.

The first goal of this study was to examine the influence that poly(ethylene oxide)-block-poly(D,L-lactide) (PELA) copolymer can have on the wettability, the in vitro controlled delivery capability, and the degradation of poly(D,L-lactide) (PDLLA) foams. These foams were prepared by freeze-drying and contain micropores (10 microm) in addition of macropores (100 microm) organized longitudinally. Weight loss, water absorption, changes in molecular weight, polymolecularity (Mw/Mn) and glass transition temperature (Tg) of PDLLA foams mixed with various amounts of PELA were followed with time. It was found that 10wt% of PELA increased the wettability and the degradation rate of the polymer foams. The release of sulforhodamine (SR) was compared for PDLLA and PDLLA-PELA foams in relation with the foam porosity. An initial burst release was observed only in the case of the 90:10 PDLLA/PELA foam. The ability of the foam of this composition to be integrated and to promote tissue repair and axonal regeneration in the transected rat spinal cord was investigated. After implantation of ca. 20 polymer rods assembled with fibrin-glue, the polymer construct was able to bridge the cord stumps by forming a permissive support for cellular migration, angiogenesis and axonal regrowth.

Surgical management of anterior cranial base fractures with cerebrospinal fluid fistulae: a single-institution experience.

OBJECTIVE The management of cerebrospinal fluid (CSF) fistulae after anterior cranial base fracture remains a surgical challenge. We reviewed our results in the repair of CSF fistulae complicating multiple anterior cranial base fractures via a combined intracranial extradural and intradural approach and describe a treatment algorithm derived from this experience. METHODS We retrospectively reviewed the files of 209 patients with an anterior cranial base fracture complicated by a CSF fistula who were admitted between 1980 and 2003 to Liège State University Hospital. Among those patients, 109 had a persistent CSF leak or radiological signs of an unhealed dural tear. All underwent the same surgical procedure, with combined extradural and intradural closure of the dural tear. RESULTS Of the 109 patients, 98 patients (90%) were cured after the first operation. Persistent postoperative CSF rhinorrhea occurred in 11 patients (10%), necessitating an early complementary surgery via a transsphenoidal approach (7 patients) or a second-look intracranial approach (4 patients). No postoperative neurological deterioration attributable to increasing frontocerebral edema occurred. During the mean follow-up period of 36 months, recurrence of CSF fistula was observed in five patients and required an additional surgical repair procedure. CONCLUSION The closure of CSF fistulae after an anterior cranial base fracture via a combined intracranial extradural and intradural approach, which allows the visualization and repair of the entire anterior base, is safe and effective. It is essentially indicated for patients with extensive bone defects in the cranial base, multiple fractures of the ethmoid bone and the posterior wall of the frontal sinus, cranial nerve involvement, associated lesions necessitating surgery such as intracranial hematomas, and post-traumatic intracranial infection. Rhinorrhea caused by a precisely located small tear may be treated with endoscopy.

The effect of treadmill training on motor recovery after a partial spinal cord compression-injury in the adult rat.

Locomotor training on a treadmill is a therapeutic strategy used for several years in human paraplegics in whom it was shown to improve functional recovery mainly after incomplete spinal cord lesions. The precise mechanisms underlying its effects are not known. Experimental studies in adult animals were chiefly performed after complete spinal transections. The objective of this experiment was to assess the effects of early treadmill training on recovery of spontaneous walking capacity after a partial spinal cord lesion in adult rats. Following a compression-injury by a subdurally inflated microballoon, seven rats were trained daily on a treadmill with a body weight support system, whereas six other animals were used as controls and only handled. Spontaneous walking ability in an open field was compared weekly between both groups by two blinded observers, using the Basso, Beattie and Bresnahan (BBB) locomotor rating scale. Mean BBB score during 12 weeks was globally significantly greater in the treadmill-trained animals than in the control group, the benefit of training appearing as early as the 2nd week. At week 7, locomotor recovery reached a plateau in both animal groups, but remained superior in trained rats. Daily treadmill training started early after a partial spinal cord lesion in adult rats, which accelerates recovery of locomotion and produces a long-term benefit. These findings in an animal model mimicking the closed spinal cord injury occurring in most human paraplegics are useful for future studies of optimal locomotor training programs, their neurobiologic mechanisms, and their combination with other treatment strategies.

Repetitive transcranial magnetic stimulation improves open field locomotor recovery after low but not high thoracic spinal cord compression-injury in adult rats

Electromagnetic fields are able to promote axonal regeneration in vitro and in vivo. Repetitive transcranial magnetic stimulation (rTMS) is used routinely in neuropsychiatric conditions and as an atraumatic method to activate descending motor pathways. After spinal cord injury, these pathways are disconnected from the spinal locomotor generator, resulting in most of the functional deficit. We have applied daily 10 Hz rTMS for 8 weeks immediately after an incomplete high (T4–5; n = 5) or low (T10–11; n = 6) thoracic closed spinal cord compression‐injury in adult rats, using 6 high‐ and 6 low‐lesioned non‐stimulated animals as controls. Functional recovery of hindlimbs was assessed using the BBB locomotor rating scale. In the control group, the BBB score was significantly better from the 7th week post‐injury in animals lesioned at T4–5 compared to those lesioned at T10–11. rTMS significantly improved locomotor recovery in T10–11‐injured rats, but not in rats with a high thoracic injury. In rTMS‐treated rats, there was significant positive correlation between final BBB score and grey matter density of serotonergic fibres in the spinal segment just caudal to the lesion. We propose that low thoracic lesions produce a greater functional deficit because they interfere with the locomotor centre and that rTMS is beneficial in such lesions because it activates this central pattern generator, presumably via descending serotonin pathways. The benefits of rTMS shown here suggest strongly that this non‐invasive intervention strategy merits consideration for clinical trials in human paraplegics with low spinal cord lesions.

Endoscopic endonasal resection of the odontoid process as a standalone decompressive procedure for basilar invagination in Chiari type I malformation.

BACKGROUND The expanded endonasal approach of the cranio-cervical junction provides comfortable working space while avoiding some of the disadvantages of the transoral route. We report a purely endonasal endoscopic resection of the odontoid process for basilar invagination in a patient with a Chiari type I malformation, without posterior decompression or fusion. CASE REPORT A 54-year-old female patient presented with cranial nerve and brainstem deficits. CT and MRI showed a Chiari type I malformation and compression of the medulla by basilar invagination of the odontoid process. The tip of the latter was displaced up to the bulbo-pontine sulcus. The odontoid process was resected via the expanded endoscopic endonasal approach, without additional posterior decompression or fusion. The post-operative course was uneventful, including the absence of velopharyngeal insufficiency. Neurological deficits regressed rapidly. The preoperative cervical pain virtually disappeared. At 9 months follow-up, the patient had normal activity with minimal residual neurological deficits. Post-op dynamic radiography and CT showed stability of the cranio-cervical junction. CONCLUSION Decompression of the bulbomedullary junction by purely endoscopic transnasal resection of the odontoid process is well tolerated and efficient. Immediate stabilization is not mandatory in all cases of congenital causes of basilar invagination.

Intraoperative magnetic resonance imaging versus standard neuronavigation for the neurosurgical treatment of glioblastoma: A randomized controlled trial

Background: Although the added value of increasing extent of glioblastoma resection is still debated, multiple technologies can assist neurosurgeons in attempting to achieve this goal. Intraoperative magnetic resonance imaging (iMRI) might be helpful in this context, but to date only one randomized trial exists. Methods: We included 14 adults with a supratentorial tumor suspect for glioblastoma and an indication for gross total resection in this randomized controlled trial of which the interim analysis is presented here. Participants were assigned to either ultra-low-field strength iMRI-guided surgery (0.15 Tesla) or to conventional neuronavigation-guided surgery (cNN). Primary endpoint was residual tumor volume (RTV) percentage. Secondary endpoints were clinical performance, health-related quality of life (HRQOL) and survival. Results: Median RTV in the cNN group is 6.5% with an interquartile range of 2.5-14.75%. Median RTV in the iMRI group is 13% with an interquartile range of 3.75-27.75%. A Mann-Whitney test showed no statistically significant difference between these groups (P =0.28). Median survival in the cNN group is 472 days, with an interquartile range of 244-619 days. Median survival in the iMRI group is 396 days, with an interquartile range of 191-599 days (P =0.81). Clinical performance did not differ either. For HRQOL only descriptive statistics were applied due to a limited sample size. Conclusion: This interim analysis of a randomized trial on iMRI-guided glioblastoma resection compared with cNN-guided glioblastoma resection does not show an advantage with respect to extent of resection, clinical performance, and survival for the iMRI group. Ultra-low-field strength iMRI does not seem to be cost-effective compared with cNN, although the lack of a valid endpoint for neurosurgical studies evaluating extent of glioblastoma resection is a limitation of our study and previous volumetry-based studies on this topic.

Correlation of postmortem 9.4 tesla magnetic resonance imaging and immunohistopathology of the human thoracic spinal cord 7 months after traumatic cervical spine injury.

OBJECTIVE:To correlate high-resolution magnetic resonance imaging (MRI) with immunohistopathology in the injured human spinal cord. METHODS:Postmortem MRI scans at a field strength of 9.4 T, as well as standard histology and immunohistochemistry, were performed on an excised specimen of human high thoracic spinal cord, obtained 7 months after the initial trauma, several segments below a severe spinal cord lesion (C5). RESULTS:A precise correlation is described between MRI and immunohistochemistry of the long white matter tracts undergoing Wallerian degeneration and of an extension of the cervical lesion into the high thoracic cord. CONCLUSION:MRI, the only imaging technique that currently provides useful information on the spinal cord parenchyma after trauma, is rapidly evolving. High-field scanners of up to 9.4 T are being clinically tested. The present postmortem investigation of an isolated spinal cord specimen demonstrates the precise correlation that can be achieved between imaging and pathology. In future investigations, this type of technique can lead to a more precise description of spinal cord injuries and their consequences in remote tissue. Translation into the clinical setting will improve diagnosis and follow-up of spinal cord injured patients.

Acquired tonsillar herniation and syringomyelia after pleural effusion aspiration: case report.

OBJECTIVE We present a case of brachial plexus avulsion and reconstructive surgery with cerebrospinal fluid leak between the cervical subarachnoid space and the pleural cavity responsible for tonsillar herniation and syringomyelia. CLINICAL PRESENTATION A 17-year-old man presented with headaches when he was positioned upright, simultaneously with a persistent right pleural effusion for about 4 months after reconstructive surgery for a right brachial plexus avulsion. In addition, the headaches had worsened considerably after two aspirations of the pleural effusion. Magnetic resonance imaging (MRI) demonstrated signs of chronic intracranial hypotension and tonsillar herniation with a presyrinx cavity from vertebral level C1 to C7. None of those abnormalities were seen on the MRI scan obtained a few days after the initial trauma 7 months previously. Plexus brachial MRI confirmed the presence of a cerebrospinal fluid leak between the avulsed root of C8 and the pulmonary apex. INTERVENTION The leak was treated by surgical closure of the dural tear of the C8 root. Postoperatively, the patients headaches immediately resolved, and MRI 4 months later showed resolution of cerebellar tonsil herniation and regression of the syrinx. CONCLUSION Resolution of acquired tonsillar herniation and syringomyelia can be achieved by closure of the dural tear responsible of the cerebrospinal fluid leak.

Spinal cord injury and its treatment: current management and experimental perspectives

Clinical management of spinal cord injury (SCI) has significantly improved its general prognosis. However, to date, traumatic paraplegia and tetraplegia remain incurable, despite massive research efforts. Current management focuses on surgical stabilisation of the spine, intensive neurological rehabilitation, and the prevention and treatment of acute and chronic complications. Prevention remains the most efficient strategy and should be the main focus of public health efforts. Nevertheless, major advances in the understanding of the pathophysiological mechanisms of SCI open promising new therapeutic perspectives. Even if complete recovery remains elusive due to the complexity of spinal cord repair, a strategy combining different approaches may result in some degree of neurological improvement after SCI. Even slight neurological recovery can have high impact on the daily functioning of severely handicapped patients and, thus, result in significant improvements in quality of life.The main investigated strategies are: [1] initial neuroprotection, in order to decrease secondary injury to the spinal cord parenchyma after the initial insult; [2] spinal cord repair, in order to bridge the lesion site and reestablish the connection between the supraspinal centres and the deafferented cord segment below the lesion; and [3] re-training and enhancing plasticity of the central nervous system circuitry that was preserved or rebuilt after the injury.Now and in the future, treatment strategies that have both a convincing rationale and seen their efficacy confirmed reproducibly in the experimental setting must carefully be brought from bench to bedside. In order to obtain clinically significant results, their introduction into clinical research must be guided by scientific rigour, and their coordination must be rationally structured in a long-term perspective.