Postoperative epidural hematoma contributes to delayed upper cord tethering after decompression of Chiari malformation type I.

Symptomatic arachnoiditis after posterior fossa surgical procedures such as decompression of Chiari malformation is a possible complication. Clinical presentation is generally insidious and delayed by months or years. It causes disturbances in the normal flow of cerebrospinal fluid and enlargement of a syrinx cavity in the upper spinal cord. Surgical de-tethering has favorable results with progressive collapse of the syrinx and relief of the associated symptoms. Case Description: A 30-year-old male with Chiari malformation type I was treated by performing posterior fossa bone decompression, dura opening and closure with a suturable bovine pericardium dural graft. Postoperative period was uneventful until the fifth day in which the patient suffered intense headache and progressive loose of consciousness caused by an acute posterior fossa epidural hematoma. It was quickly removed with complete clinical recovering. One year later, the patient experienced progressive worsened of his symptoms. Upper spinal cord tethering was diagnosed and a new surgery for debridement was required. Conclusions: The epidural hematoma compressing the dural graft against the neural structures contributes to the upper spinal cord tethering and represents a nondescribed cause of postoperative fibrosis, adhesion formation, and subsequent recurrent hindbrain compression.

Focal dermal hypoplasia (goltz-gorlin syndrome): A new case with a novel variant in the PORCN gene (c.1250T>C:p.F417S) and unusual spinal anomaly.

Focal dermal hypoplasia (FDH; Goltz-Gorlin syndrome; OMIM 305600) is a disorder that features involvement of the skin, skeletal system, and eyes. It is caused by loss-of-function mutations in the PORCN gene. We report a young girl with FDH, microphthalmos associated with colobomatous orbital cyst, dural ectasia and cystic malformation of the spinal cord, and a de novo variant in PORCN. This association has not been previously reported, and based on these observations the phenotypic spectrum of FDH might be broader than previously appreciated. It would be prudent to alter the suggested surveillance for this rare disorder. © 2013 Wiley Periodicals, Inc.

Nontraumatic spinal epidural hematoma during pregnancy: diagnosis and management concerns.

OBJECTIVE: Nontraumatic spinal epidural hematoma (SEH) during pregnancy is rare. Therefore, appropriate management of this occurrence is not well defined. The aim of this study was to extensively review the literature on this subject, to propose some novel treatment guidelines. METHODS: Electronic databases, manual reviews and conference proceedings up to December 2011 were systematically reviewed. Articles were deemed eligible for inclusion in this study if they dealt with nontraumatic SEH during pregnancy. Search protocols and data were independently assessed by two authors. RESULTS: In all, 23 case reports were found to be appropriate for review. The mean patient age was 28 years and gestational age was 33.2 weeks. Thirteen cases presented with acute interscapular pain. The clinical picture consisted of paraplegia, which occurred approximately 63 h after pain onset. Spinal cord decompression was performed within an average time of 20 h after neurological deficit onset. Fifteen patients had cesarean deliveries, even when the gestational age was less than 36 weeks. CONCLUSION: This review failed to identify articles, other than case reports, which could assist in the formation of new guidelines to treat SEH in pregnancy. However, we believe that SEH may be managed neurosurgically, without requiring prior, premature, cesarean section.

Recovery of paraplegia after type B dissection due to spinal collateral recruitment.

Acute paraplegia could be a symptom of aortic dissection due to sudden compromise of arterial spinal cord blood supply. Complete spontaneous neurologic recovery is possible and was observed in the present case 3 hours after symptom onset. Spontaneous spinal cord reperfusion after acute type B dissection was probably due to two main mechanisms. Reperfusion of false lumen and collateral vascular network recruitment, recently confirmed by anatomic animal studies, serve as potential explanations. Favorable evolution of acute paraplegia after aortic dissection exists, but prognosis is uncertain, probably due to individual variable anatomic distribution of spinal cord blood supply.

The c-Jun N-terminal kinase 1 (JNK1) in spinal astrocytes is required for the maintenance of bilateral mechanical allodynia under a persistent inflammatory pain condition.

Peripheral inflammation induces persistent central sensitization characterized by mechanical allodynia and heat hyperalgesia that are mediated by distinct mechanisms. Compared to well-demonstrated mechanisms of heat hyperalgesia, mechanisms underlying the development of mechanical allodynia and contralateral pain are incompletely known. In this study, we investigated the distinct role of spinal JNK in heat hyperalgesia, mechanical allodynia, and contralateral pain in an inflammatory pain model. Intraplantar injection of complete Freund's adjuvant (CFA) induced bilateral mechanical allodynia but unilateral heat hyperalgesia. CFA also induced a bilateral activation (phosphorylation) of JNK in the spinal cord, and the phospho JNK1 (pJNK1) levels were much higher than that of pJNK2. Notably, both pJNK and JNK1 were expressed in GFAP-positive astrocytes. Intrathecal infusion of a selective peptide inhibitor of JNK, D-JNKI-1, starting before inflammation via an osmotic pump, reduced CFA-induced mechanical allodynia in the maintenance phase but had no effect on CFA-induced heat hyperalgesia. A bolus intrathecal injection of D-JNKI-1 or SP600126, a small molecule inhibitor of JNK also reversed mechanical allodynia bilaterally. In contrast, peripheral (intraplantar) administration of D-JNKI-1 reduced the induction of CFA-induced heat hyperalgesia but did not change mechanical allodynia. Finally, CFA-induced bilateral mechanical allodynia was attenuated in mice lacking JNK1 but not JNK2. Taken together, our data suggest that spinal JNK, in particular JNK1 plays an important role in the maintenance of persistent inflammatory pain. Our findings also reveal a unique role of JNK1 and astrocyte network in regulating tactile allodynia and contralateral pain.

Preoperative assessment of neurovesical function in children with anorectal malformation: association with vertebral and spinal malformations.

PURPOSE: We preoperatively assessed neurovesical function and spinal cord function in children with anorectal malformations. In cases of neurovesical dysfunction we looked for an association with vertebral malformation or myelodysplasia. MATERIALS AND METHODS: We prospectively evaluated 80 children with anorectal malformations via preoperative urodynamics and magnetic resonance imaging of the spine. Bladder compliance and volume, detrusor activity and vesicosphincteric synergy during voiding allowed urodynamic evaluation. Results were reported according to Wingspread and Krickenbeck classifications of anorectal malformations. RESULTS: Urodynamic findings were pathological in 14 children (18%). Pathological evaluations did not seem related to type of fistula or level of anorectal malformation. Vertebral anomalies were seen in 34 patients (43%) and myelodysplasia in 16 (20%). Neither vertebral anomaly nor myelodysplasia seemed associated with type of fistula or severity of anorectal malformation. Of 14 children with pathological urodynamics no vertebral anomaly or myelodysplasia was found in 7. Of 66 children with normal urodynamics 40 presented with vertebral or spinal malformation. CONCLUSIONS: Lower urinary tract dysfunction is common in patients with anorectal malformations. Normal spine or spinal cord does not exclude neurovesical dysfunction. Myelodysplasia or vertebral anomaly does not determine lower urinary tract dysfunction. Thus, we recommend preoperative urodynamic assessment of the bladder and magnetic resonance imaging of the spine in children with anorectal malformations.

The BH4 domain of Bcl-X(L) rescues astrocyte degeneration in amyotrophic lateral sclerosis by modulating intracellular calcium signals.

Collective evidence indicates that motor neuron degeneration in amyotrophic lateral sclerosis (ALS) is non-cell-autonomous and requires the interaction with the neighboring astrocytes. Recently, we reported that a subpopulation of spinal cord astrocytes degenerates in the microenvironment of motor neurons in the hSOD1(G93A) mouse model of ALS. Mechanistic studies in vitro identified a role for the excitatory amino acid glutamate in the gliodegenerative process via the activation of its inositol 1,4,5-triphosphate (IP(3))-generating metabotropic receptor 5 (mGluR5). Since non-physiological formation of IP(3) can prompt IP(3) receptor (IP(3)R)-mediated Ca(2+) release from the intracellular stores and trigger various forms of cell death, here we investigated the intracellular Ca(2+) signaling that occurs downstream of mGluR5 in hSOD1(G93A)-expressing astrocytes. Contrary to wild-type cells, stimulation of mGluR5 causes aberrant and persistent elevations of intracellular Ca(2+) concentrations ([Ca(2+)](i)) in the absence of spontaneous oscillations. The interaction of IP(3)Rs with the anti-apoptotic protein Bcl-X(L) was previously described to prevent cell death by modulating intracellular Ca(2+) signals. In mutant SOD1-expressing astrocytes, we found that the sole BH4 domain of Bcl-X(L), fused to the protein transduction domain of the HIV-1 TAT protein (TAT-BH4), is sufficient to restore sustained Ca(2+) oscillations and cell death resistance. Furthermore, chronic treatment of hSOD1(G93A) mice with the TAT-BH4 peptide reduces focal degeneration of astrocytes, slightly delays the onset of the disease and improves both motor performance and animal lifespan. Our results point at TAT-BH4 as a novel glioprotective agent with a therapeutic potential for ALS.

Delayed priming promotes CNS regeneration post-rhizotomy in Neurocan and Brevican-deficient mice.

A wealth of literature has provided evidence that reactive tissue at the site of CNS injury is rich in chondroitin sulfate proteoglycans which may contribute to the non-permissive nature of the CNS. We have recently demonstrated using a murine model of human brachial plexus injury that the chondroitin sulfate proteoglycans Neurocan and Brevican are differentially expressed by two subsets of astrocytes in the spinal cord dorsal root entry zone (DREZ) following dorsal root lesion (Beggah et al., Neuroscience 133: 749-762, 2005). However, direct evidence for a growth-inhibitory role of these proteoglycans in vivo is still lacking. We therefore performed dorsal root lesion (rhizotomy) in mice deficient in both Neurocan and Brevican. Rhizotomy in these animals resulted in no significant increase in the number of sensory fibres regenerating through the DREZ compared to genetically matched controls. Likewise, a conditioning peripheral nerve lesion prior to rhizotomy, which increases the intrinsic growth capacity of sensory neurons, enhanced growth to the same extent in transgenic and control mice, indicating that absence of these proteoglycans alone is not sufficient to further promote entry into the spinal cord. In contrast, when priming of the median nerve was performed at a clinically relevant time, i.e. 7 weeks post-rhizotomy, the growth of a subpopulation of sensory axons across the DREZ was facilitated in Neurocan/Brevican-deficient, but not in control animals. This demonstrates for the first time that (i) Neurocan and/or Brevican contribute to the non-permissive environment of the DREZ several weeks after lesion and that (ii) delayed stimulation of the growth program of sensory neurons can facilitate regeneration across the DREZ provided its growth-inhibitory properties are attenuated. Post-injury enhancement of the intrinsic growth capacity of sensory neurons combined with removal of inhibitory chondroitin sulfate proteoglycans may therefore help to restore sensory function and thus attenuate the chronic pain resulting from human brachial plexus injury.

Are myotonic dystrophy and peripheral neuropathy associated? : morphological, morphometric and electrophysiological analysis in DM1 transgenic mice

Abstract: Myotonic dystrophy (DM1), also known as Steinert disease, is an inherited autosomal dominant disease. It is characterized by myotonia, muscular weakness and atrophy, but DM1 may have manifestations in other organs such as eyes, heart, gonads, gastrointestinal and respiratory tracts, as well as brain. In 1992, it was demonstrated that this complex disease results from the expansion of CTG repeats in the 3' untranslated region of the DM protein kinase (DMPK) gene on chromosome 19. The size of the inherited expansion is critically linked to the severity of the disease and the age of onset. Although several electrophysiological and histological studies have been carried out to verify the possible involvement of peripheral nerve abnormality with DM1, the results have not been univocal. Therefore, at present the possible association between peripheral neuropatliy and DM1 remains debated. Recently, transgenic mice have been generated, that carry the human genomic DM1 region with 300 CTG repeats, and display the human DMl phenotype. The generation of these DM1 transgenic mice provides a useful tool to investigate the type and incidence of structural abnormalities in the peripheral nervous system associated with DM1 disease. By using the DM1 transgenic mice, we investigated the presence/absence of the three major peripheral neuropathies: axonal degeneration, axonal demyelination and neuronopathy. The morphological and morphometric analysis of sciatic, sural and phrenic nerves demonstrated the absence of axonal degeneration or demyelination. The morphometric analysis also ruled out any loss in the numbers of sensory or motor neurons in lumbar dorsal root ganglia and lumbar spinal cord enlargement respectively. Moreover, the éxamination of serial hind limb muscle sections from DMl mice showed a normal intramuscular axonal arborization as well as the absence of changes in the number and structure of endplates. Finally, the electrophysiological tests performed in DM1 transgenic mice showed that the compound muscle axon potentials (CMAPs) elicited in the hind limb digits in response to a stimulation of the sciatic nerve with anear-nerve electrode were similar to thosé obtained in wild type mice. On the basis of all our results, we hypothesized that 300 CTG repeats are not sufficient to induce disorder in the peripheral nervous system of this DM1 transgenic mouse model. Résumé La dystrophie myotonique (DM1), connue aussi sous le nom de maladie de Steinert, est une maladie héréditaire autosornale dominante. Elle est caractérisée par une myotonie, une faiblesse et une atrophie musculaires, mais peut aussi se manifester dans d'autres organes tels que les yeux, les voies digestive et respiratoire, ou le cerveau. En 1992, il a été montré que cette maladie complexe résultait de l'expansion d'une répétition de CTG dans une partie non traduite en 3' du gène codant pour la protéine kinase DM (DMPK), sur le chromosome 19. La taille de l'expansion héritée est étroitement liée à la sévérité et l'âge d'apparition de DM1. Bien que plusieurs études électrophysiologiques et histologiques aient été menées, pour juger d'une implication possible d'anomalies au niveau du système nerveux périphérique dans la DM1, les résultats n'ont jusqu'ici pas été univoques. Aujourd'hui, la question d'une neuropathie associée avec la DM1 reste donc controversée. Des souris transgéniques ont été élaborées, qui portent la séquence DM1 du génome humain avec 300 répétitions CTG et expriment le phénotype des patients DM1: Ces souris transgéniques DMl procurent un outil précieux pour l'étude du type et de l'incidence d'éventuelles anomalies du système nerveux périphérique dans la DM1. En utilisant ces souris transgéniques DM1, nous avons étudié la présence ou l'absence des trois principaux types de neuropathies périphériques: la dégénération axonale, la démyélinisation axonale et la neuronopathie. Les études morphologiques et morphométrique des nerfs sciatiques, suraux et phréniques ont montré l'absence de dégénération axonale ou de démyélinisation. L'analyse du nombre de cellules neuronales n'a pas dévoilé de diminution des nombres de neurones sensitifs dans les ganglions des racines dorsales lombaires ou de neurones moteurs dans la moëlle épinière lombaire des souris transgéniques DMl. De plus, l'examen de coupes sériées de muscle des membres postérieurs de souris DM1 a montré une arborisation axonale intramusculaire normale, de même que l'absence d'irrégularité dans le nombre ou la structure des plaques motrices. Enfin, les tests électrophysiologiques effectués sur les souris DMl ont montré que les potentiels d'action de la composante musculaire (CMAPs) évoqués dans les doigts des membres postérieurs, en réponse à une stimulation du nerf sciatique à l'aide d'une électrode paranerveuse, étaient identiques à ceux observées chez les souris sauvages. Sur la base de l'ensemble de ces résultats, nous avons émis l'hypothèse que 300 répétitions CTG ne sont pas suffisantes pour induire d'altérations dans le système nerveux périphérique du modèle de souris transgéniques DM 1.

Improvement of rehabilitation possibilities with the MotionMaker (TM)

"MotionMaker (TM)" is a stationary programmable test and training system for the lower limbs developed at the 'Ecole Polytechnique Federale de Lausanne' with the 'Fondation Suisse pour les Cybertheses'.. The system is composed of two robotic orthoses comprising motors and sensors, and a control unit managing the trans-cutaneous electrical muscle stimulation with real-time regulation. The control of the Functional Electrical Stimulation (FES) induced muscle force necessary to mimic natural exercise is ensured by the control unit which receives a continuous input from the position and force sensors mounted on the robot. First results with control subjects showed the feasibility of creating movements by such closed-loop controlled FES induced muscle contractions. To make exercising with the MotionMaker (TM) safe for clinical trials with Spinal Cord Injured (SCI) volunteers, several original safety features have been introduced. The MotionMaker (TM) is able to identify and manage the occurrence of spasms. Fatigue can also be detected and overfatigue during exercise prevented.

Peripheral Nerve Neuropathy is Associated with a Glial Reaction in the Gracile Nucleus Associated with a regulation of the GABA transporter GAT-1

Allodynia (pain in response to normally non painful stimulation) and paresthesia (erroneous sensory experience) are two debilitating symptoms of neuropathic pain. These stem, at least partly, from profound changes in the non-nociceptive sensory pathway that comprises large myelinated neuronal afferents terminating in the gracile and cuneate nuclei. Further than neuronal changes, well admitted evidence indicates that glial cells (especially in the spinal cord) are key actors in neuropathic pain, in particular the possible alteration in astrocytic capacity to reuptake neurotransmitters (glutamate and GABA). Yet, the possibility of such a changed astrocytic scavenging capacity remains unexplored in the dorsal column pathway. The present study was therefore undertaken to assess whether peripheral nerve injury (spared nerve injury model, SNI) could trigger a glial reaction, and especially changes in glutamate and GABA transporters, in the gracile nucleus. SNI surgery was performed on male Sprague-Dawley rats. Seven days after surgery, rats were used for immunofluorescence (fixation and brain slicing), western-blot (fresh brain freezing and protein extraction) or GABA reuptake on synaptosomes. We found that SNI results in a profound glial reaction in the ipsilateral gracile nucleus. This reaction was characterized by an enhanced immunolabelling for microglial marker Iba1 as well as astrocytic protein GFAP (further confirmed by western-blot, p <0.05, n = 7). These changes were not observed in sham animals. Immunofluorescence and western-blot analysis shows that the GABA transporter GAT-1 is upregulated in the ipsilateral gracile nucleus (p <0.001; n = 7), with no detectable change in GAT-3 or glutamate transporters EAAT-1 and EAAT-2. Double immunoflurescence shows that GAT-1 and GFAP colocalize within the same cells. Furthermore, the upregulation of GFAP and GAT-1 were shown to occur all along the rostrocaudal axis of the gracile nucleus. Finally, synaptosomes from ipsilateral gracile nucleus show an increased capacity to reuptake GABA. Together, the data presented herein show that glial cells in the gracile nucleus react to neuropathic lesion, in particular through an upregulation of the GABA transporter GAT-1. Hence, this study points to role of an increased GABA transport in the dorsal column nuclei in neuropathic pain, calling attention to GAT-1 as a putative future pharmacological target to treat allodynia and paresthesia.

Wnt-3a and Wnt-3 differently stimulate proliferation and neurogenesis of spinal neural precursors and promote neurite outgrowth by canonical signaling

Wnt factors regulate neural stem cell development and neuronal connectivity. Here we investigated whether Wnt-3a and Wnt-3, expressed in the developing spinal cord, regulate proliferation and the neuronal differentiation of spinal cord neural precursors (SCNP). Wnt-3a promoted a sustained increase of SCNP proliferation, whereas Wnt-3 enhanced SCNP proliferation transiently and increased neurogenesis through β-catenin signaling. Consistent with this, Wnt-3a and Wnt-3 differently regulate the expression of Cyclin-dependent kinase inhibitors. Furthermore, Wnt-3a and Wnt-3 stimulated neurite outgrowth in SCNP-derived neurons through ß-catenin and TCF4-dependent transcription. GSK-3ß inhibitors mimicked Wnt signaling and promoted neurite outgrowth in established cultures. We conclude that Wnt-3a and Wnt-3 signal through the canonical Wnt/β-catenin pathway to regulate different aspects of SCNP development. These findings may be of therapeutic interest for the treatment of neurodegenerative diseases and nerve injury.

Metabolic gene expression changes in astrocytes in Multiple Sclerosis cerebral cortex are indicative of immune-mediated signaling.

Emerging as an important correlate of neurological dysfunction in Multiple Sclerosis (MS), extended focal and diffuse gray matter abnormalities have been found and linked to clinical manifestations such as seizures, fatigue and cognitive dysfunction. To investigate possible underlying mechanisms we analyzed the molecular alterations in histopathological normal appearing cortical gray matter (NAGM) in MS. By performing a differential gene expression analysis of NAGM of control and MS cases we identified reduced transcription of astrocyte specific genes involved in the astrocyte-neuron lactate shuttle (ANLS) and the glutamate-glutamine cycle (GGC). Additional quantitative immunohistochemical analysis demonstrating a CX43 loss in MS NAGM confirmed a crucial involvement of astrocytes and emphasizes their importance in MS pathogenesis. Concurrently, a Toll-like/IL-1β signaling expression signature was detected in MS NAGM, indicating that immune-related signaling might be responsible for the downregulation of ANLS and GGC gene expression in MS NAGM. Indeed, challenging astrocytes with immune stimuli such as IL-1β and LPS reduced their ANLS and GGC gene expression in vitro. The detected upregulation of IL1B in MS NAGM suggests inflammasome priming. For this reason, astrocyte cultures were treated with ATP and ATP/LPS as for inflammasome activation. This treatment led to a reduction of ANLS and GGC gene expression in a comparable manner. To investigate potential sources for ANLS and GGC downregulation in MS NAGM, we first performed an adjuvant-driven stimulation of the peripheral immune system in C57Bl/6 mice in vivo. This led to similar gene expression changes in spinal cord demonstrating that peripheral immune signals might be one source for astrocytic gene expression changes in the brain. IL1B upregulation in MS NAGM itself points to a possible endogenous signaling process leading to ANLS and GGC downregulation. This is supported by our findings that, among others, MS NAGM astrocytes express inflammasome components and that astrocytes are capable to release Il-1β in-vitro. Altogether, our data suggests that immune signaling of immune- and/or central nervous system origin drives alterations in astrocytic ANLS and GGC gene regulation in the MS NAGM. Such a mechanism might underlie cortical brain dysfunctions frequently encountered in MS patients.

Continuing Medical Education Self-Assessment Questions Vol. 50, No. 2 - April 2014. Focal vibration in neurorehabilitation.

During the last decade, many studies have been carried out to understand the effects of focal vibratory stimuli at various levels of the central nervous system and to study pathophysiological mechanisms of neurological disorders as well as the therapeutic effects of focal vibration in neurorehabilitation. This review aimed to describe the effects of focal vibratory stimuli in neurorehabilitation including the neurological diseases or disorders like stroke, spinal cord injury, multiple sclerosis, Parkinson's' disease and dystonia. In conclusion, focal vibration stimulation is well tolerated, effective and easy to use, and it could be used to reduce spasticity, to promote motor activity and motor learning within a functional activity, even in gait training, independent from etiology of neurological pathology. Further studies are needed in the future well- designed trials with bigger sample size to determine the most effective frequency, amplitude and duration of vibration application in the neurorehabilitation.