Combined effects of botulinum toxin type A and repetitive transcranial magnetic stimulation with intensive motor training immediately after injection in a patient with chronic stroke: A case report.

STUDY DESIGN: Single case report. INTRODUCTION: A previous study clarified that spasticity and motor function were improved by combined treatment with botulinum toxin type A (BTX) injection and 1-Hz repetitive transcranial magnetic stimulation (rTMS) with intensive motor training at 4 weeks after injection. However, it is not clear whether 1-Hz rTMS with intensive motor training immediately after BTX injection also improves spasticity and motor function in stroke patients. PURPOSE OF THE CASE REPORT: The purpose of this case report is to test the short- and long-term effects of BTX injection and rTMS with intensive motor training on the spasticity, motor function, and usefulness of the paretic hand in a stroke patient. METHODS: A 64-year-old male, who suffered from a right cerebral hemorrhage 53 months previously, participated in the present study. BTX was injected into the spastic muscles of the affected upper limb. He then received the new protocol for a total of 24 sessions. The Modified Ashworth Scale (MAS), Fugl-Meyer Assessment (FMA), and Motor Activity Log, consisting of the amount of use and quality of movement scales, were assessed before and immediately after BTX injection, at discharge, and monthly for up to 5 months after discharge. RESULTS: For the short-term effects of the therapy, the MAS scores of the elbow and wrist, FMA score, and quality of movement score improved. For the long-term effects of the therapy, the MAS score of the fingers, FMA score, and amount of use score improved for up to 5 months after discharge. CONCLUSIONS: The present case report showed the improvement of all assessments performed in the short and/or long term and suggest the possibility of shortening the intervention period of combined therapy of BTX and rTMS with intensive motor training.

Effect of intensive motor training with repetitive transcranial magnetic stimulation on upper limb motor function in chronic post-stroke patients with severe upper limb motor impairment.

Background Intensive motor training with low-frequency repetitive transcranial magnetic stimulation (rTMS) has efficacy as a therapeutic method for motor dysfunction of the affected upper limb in patients with mild to moderate stroke. However, it is not clear whether this combination therapy has the same effect in chronic post-stroke patients with severe upper limb motor impairment. Objectives The aim of this study was to test the treatment effects of intensive motor training with low-frequency rTMS in chronic post-stroke patients with severe upper limb motor impairment. Methods A convenience sample of 26 chronic post-stroke patients with severe upper limb motor impairment participated in this study with the non-randomized, non-controlled clinical trial. All subjects were hospitalized to receive intensive motor training with low-frequency rTMS. During 2 weeks in which Sundays were excluded, a total of 24 sessions (2 sessions per day) of the intervention were conducted. The Fugl-Meyer Assessment (FMA) and Wolf Motor Function Test (WMFT) were used to assess motor impairment and function of the affected upper limb, respectively, before and after intervention. Paired t-test was used to analyze the effects of the intervention. Results The FMA total score and WMFT log performance time significantly improved from before to after intervention (FMA: 12.6-18.0; WMFT: 3.6-3.3, p < 0.001). Conclusions The present results suggest that intensive motor training with low-frequency rTMS could improve motor impairment in chronic post-stroke patients with severe upper limb motor impairment and contribute to the expansion of the application range of this combination therapy.

NMES with rTMS for moderate to severe dysfunction after stroke.

BACKGROUND: Motor dysfunction after stroke might be improved by neuromuscular electrical stimulation (NMES) combined with 1 Hz repetitive transcranial magnetic stimulation (rTMS) in patients with moderate and severe motor dysfunction. OBJECTIVE: This preliminary study tested the effect of this treatment combination. METHODS: Fifteen patients (60.5 ± 10.3 years old) participated in the study. All patients had been affected by cerebral artery infarction or hemorrhage and had moderate or severe motor dysfunction in their affected hand. The patients received NMES at paretic wrist extensor muscles combined with rTMS over the unaffected M1 hemisphere twice a day, six days/week over two weeks. All participants underwent the following battery of tests to evaluate the motor function of the affected hand: Upper limb Fugl-Meyer Assessment (UFMA), Wolf Motor Function Test (WMFT), and Box and Block Test (BBT). RESULTS: UFMA, WMFT, and BBT scores improved significantly after the study. CONCLUSIONS: These results suggest that NMES combined with rTMS could be useful for recovery of moderate and severe motor function after stroke.

The incorporation of neuroendoscopy in neurosurgical training programs.

Previously considered the domain of the otolaryngologists, the endoscopy is now a common part of the armamentarium of a neurosurgeon. Neuroendoscopy or endoscope-assisted microsurgery is now being used in almost all routine procedures performed in the neurosurgical operating room. Hands-on training has become essential to learn the basics of neuroendoscopy, even for neurosurgeons well accustomed to the use of microscopes. To decrease the slope of the learning curve of residents during their training and reduce complications of procedures, most neurosurgery training programs around the world have incorporated laboratory or dissection programs in their curricula. Preconference workshops held during annual meetings are also an excellent tool to aid in the transition of surgeons from being a resident under the umbrella of an attending neurosurgeon to being a neurosurgeon able to operate independently and with confidence. In this "tech-savvy era," various cadaver or synthetic models are readily available for endoscopy training in a virtually simulated environment. In accord with the results of a surveys conducted by individual groups and societies, the authors firmly believe that incorporation of endoscopy in the neurosurgical curriculum would add a new dimension to the existing protocol. There is an urgent need for dedicated endoscopy training programs similar to postresidency fellowships in addition to translational research and establishment of dedicated societies to formulate guidelines for such research and monitor its progress.

Stimulation-dependent intraspinal microtubules and synaptic failure in Alzheimer's disease: a review.

There are many microtubules in axons and dendritic shafts, but it has been thought that there were fewer microtubules in spines. Recently, there have been four reports that observed the intraspinal microtubules. Because microtubules originate from the centrosome, these four reports strongly suggest a stimulation-dependent connection between the nucleus and the stimulated postsynaptic membrane by microtubules. In contrast, several pieces of evidence suggest that spine elongation may be caused by the polymerization of intraspinal microtubules. This structural mechanism for spine elongation suggests, conversely, that the synapse loss or spine loss observed in Alzheimer's disease may be caused by the depolymerization of intraspinal microtubules. Based on this evidence, it is suggested that the impairment of intraspinal microtubules may cause spinal structural change and block the translocation of plasticity-related molecules between the stimulated postsynaptic membranes and the nucleus, resulting in the cognitive deficits of Alzheimer's disease.

The effects of high-frequency transcranial magnetic stimulation combined with transcutaneous electrical stimulation in a severe stroke patient.

The case report describes the effects of 5 Hz repetitive transcranial magnetic stimulation (rTMS) combined with transcutaneous electrical stimulation (TES) in a patient with severe stroke. The patient was a 69-year-old male who was affected by a left middle cerebral artery infarction. The patient had no movement in his right hand. To assess the effects, cerebral blood flow and motor function were measured before and after treatment. This treatment delivered rTMS over the affected M1 with TES at the paretic wrist extensor muscles for 10 days. The regional cerebral blood flow (rCBF) in the entire brain was measured by positronemission tomography. To evaluate the motor function, the Fugl-Meyer assessment (FMA) was used. After treatment, the rCBF was increased (except for the stimulated region), and the FMA score was slightly improved. These results suggest the potential therapeutic use of rTMS combined with TES for recovery in severe stroke.

Role of aneurysm projection in "A2" fork orientation for determining the side of surgical approach.

PURPOSE: To determine factors that help decide the side of approach for anterior communicating artery (AComA) aneurysms, based on a prospective study. METHODS: Between January 2004 and January 2006, 93 cases with AComA aneurysms were treated through pterional approach. They were classified as Type I, II (IIa, IIb), III and IV, based on the various projections and size of aneurysm. The principle for the choice of operative side was designed based on the type of aneurysm and the A2 fork orientation (the interrelations between the plane of bilateral A2, AComA, and mid-saggital plane). RESULTS: There were 55 aneurysms of Type I, 10 of Type IIa, 14 of Type IIb, 12 of Type III, and 2 of Type IV. In Types I and IIa, the side posteriorly placed to A2 was chosen for the approach. In Type IIb, the side of the dominant A1 was selected. In Type III, the side anteriorly placed to A2 was chosen. Type IV aneurysms were difficult to handle even if approached from the dominant A1. There were 11 cases treated from the side of non-dominant A1. The overall outcome in the treatment of AComA aneurysms were considered excellent in 90.8% of cases according to the Glasgow Outcome Scale, with complete occlusion of aneurysms and complete patency of parent or perforating arteries. CONCLUSIONS: Applying three-dimensional computed tomography and magnetic resonance angiography, we classified AComA aneurysms as four types and undertook surgical clipping from the chosen side of approach, according to the type of aneurysm and the A2 fork orientation. The selective side of approach on the basis of individual decision-making has led to favourable outcomes.

Dorsal column stimulation in persistent vegetative state.

Objectives. The problem of treating patients in a vegetative state remains grossly unresolved, and spinal cord stimulation (SCS) had seemed promising in some studies, suggesting, to us, further study. Materials and Methods. A prospective uncontrolled and nonrandomized observational study for 20 consecutive years (1986-2005) was performed on the effect of SCS in 214 patients in persistent vegetative state (PVS) that resulted from global anoxia and/or, stroke and/or head injury. After confirming the condition of PVS, a spinal cord stimulator, at the C2-C4 level, was implanted, stimulating according to a protocol of 15-min on/15-min off during daytime only. The results were evaluated using an efficacy scale designed by us for our study, detecting signs of awareness of self and surrounding. Results. Excellent and positive results were obtained in 109 of 201 patients (54%), but better in those patients below the age of 35, those of PVS of traumatic origin and those patients with regional cerebral blood flow over 20 mL/100 g/min. Conclusions. These findings, though inconclusive of actual benefit of SCS for PVS, indicate to us that further evidence-based, randomized controlled trials are needed to confirm efficacy of the treatment and define those who are going to benefit from this treatment method.

Amyloid beta: a putative intra-spinal microtubule-depolymerizer to induce synapse-loss or dentritic spine shortening in Alzheimer's disease.

A loss or shortening of dendritic spines has been described in patients with neurodegenerative disorders such as Alzheimer's disease, but the underlying mechanisms are poorly understood. Recently, there have been four reports of capture of the plus-ends of microtubules in the dendritic spines. One report, based on acute hippocampal slices that were fixed by a microtubule preserving process after LTP-inducing stimulation, showed that microtubules of the dendritic shaft ramified into spines in a manner that was specific to the stimulated postsynaptic membranes. This resulted in enlarged protrusion of the dendritic spines. Other reports using living cultured neurons, showed that growing microtubule plus-ends enter spines and modulate spine morphology. Since microtubules originate from the centrosome, these four reports strongly suggest a stimulation-dependent connection between the nucleus and the stimulated postsynaptic membrane by microtubules. Several pieces of evidence suggest that spine elongation may be caused by microtubule polymerization. Firstly, the entry of plus-ends of microtubules into spines accompanies spine enlargement. Further, microtubule-associated protein-1B is over-expressed in Fragile X syndrome, in which spines are much elongated. Chronic stress causes neurite outgrowth and spine elongation. Polymerization of microtubules caused neurite outgrowth and microtubules-depolymerizing agents neurite retraction, both consistent with the proposition that spine elongation is caused by microtubule polymerization. This structural mechanism for spine elongation suggests, conversely, that synapse loss or spine shortening observed in Alzheimer's disease may be caused by depolymerization of intraspinal microtubules. The fact that a new drug, dimebon, shows promising results against memory disturbance in Alzheimer's patients and can also cause neurite outgrowth in cultured neurons may also support this idea. Amyloid activates GSK-3beta and it causes the abnormal hyperphosphorylation of tau and depolymerization of axonal microtubules, resulting in the impairment of axonal transport. Normal tau is mainly present in the axon, but hyperphosphorylated tau newly distributes to the dendrites and sequesters normal tau, MAP1A/MAP1B and MAP2, and may cause disruption of intraspinal microtubules by losing the microtubule-preserving effect of MAPs. Nevertheless, it may be strongly suspected that amyloid beta may be a putative intra-spinal microtubule-depolymerizer to induce spine shortening, synaptic loss and finally the memory disturbance in Alzheimer's disease.

Redistribution of microtubules in dendrites of hippocampal CA1 neurons after tetanic stimulation during long-term potentiation.

It is now well accepted that the trafficking of AMPA receptors to the postsynaptic plasma membrane plays an essential role in long-term potentiation at the hippocampal Schaffer collateral synapses on CA1 pyramidal cells, but the motor mechanism of trafficking is unknown. We suspected that this trafficking of AMPA receptors during long-term potentiation may be carried out along microtubules by their motors. To ascertain this hypothesis, we light- and electron-microscopically studied the distribution of microtubules in dendrites of CA1 neurons of non-stimulated and stimulated rat hippocampal slices by using very strong tetanic stimulation for inducing long-term potentiation. As a result, we observed the following changes: 1. In immunofluorescence for microtubules and IP3 receptor using ultrathin-cryosections, linear signals of microtubules in main dendritic shafts were changed into fragmented. 2. Many spotty signals of microtubules emerged at the peripheral area of dendrites. Electron-microscopically, there was redistribution of microtubules in dendritic spines and dendritic shafts, and the thickening of post-synaptic density. 3. Many microtubules concentrated to thickened postsynaptic density in spines and new ones emerged, going to spines from dendritic shafts. These results strongly suggest that new tracks of microtubules from cell bodies to the stimulated postsynaptic membranes were produced after tetanic stimulation during long-term potentiation. This newly produced microtubules between stimulated postsynaptic membranes and the cell body must be the most promising candidate of the track for the trafficking of AMPA receptors to the stimulated postsynaptic plasma membrane.

Microtubules to form memory.

Microtunbule-depolymerizing agents cause amnesia. Some signal translocations to the stimulated postsynaptic membrane are essential for inducing LTP in CA1 neurons like AMPA receptors, CaMKII and mRNA. On the other hand, LTP requires protein synthesis and gene expression. This indicates that signals generated at the synapse might be transmitted to the nucleus. Recently, we have reported that LTP-producing stimulation makes new microtubule track between cell body and the stimulated postsynaptic membrane in CA1 neurons. This newly produced microtubule track only to the stimulated postsynaptic membrane might be the route of these bi-directional transportation of signals during LTP formation. This lead us the hypothesis of the "endless memory amplifying circuit" that means gene expression-promoting molecules are translocated from postsynaptic membrane to the cell body and enter into nucleus and activate transcription factors, and gene products, which will probably promote plasticity, may be re-translocated only to the stimulated postsynaptic membrane along microtubules.

Microinjected F-actin into dividing newt eggs moves toward the next cleavage furrow together with Ca2+ stores with inositol 1,4,5-trisphosphate receptor in a microtubule- and microtubule motor-dependent manner.

It has been reported that F-actin is transported to the presumptive cleavage furrow along the cortex during anaphase-cytokinesis, an event termed cortical actin flow in animal cultured cells. The motor source has remained unknown. We reported that Ca2+ stores with IP3 receptor (IP3R) was re-distributed from the polar cortex during metaphase to the presumptive cleavage furrow just before the onset of furrowing, and that Ca2+ stores with IP3R microinjected into dividing newt eggs moved toward the presumptive cleavage furrow during anaphase-cytokinesis in a microtubule-dependent manner, and that Ca2+ store-enriched microsome fractions induced the cleavage furrow as the putative cleavage stimulus. Because the distribution of F-actin and Ca2+ stores with IP3R during metaphase to cytokinesis is similar, we considered that this cortical actin flow may be powered by transportation of Ca2+ stores with IP3R. Purified F-actin labeled with phalloidin-rhodamine was microinjected into the dividing newt eggs and the eggs observed under a confocal microscope. We found that the microinjected F-actin moved linearly toward the next cleavage furrow and that this movement was blocked by nocodazole, microtubule-depolarizing agent and AMP-PNP, a blocking agent of microtubule motors. Co-microinjected rhodamine-labeled F-actin and sacro/endoplasmic reticulum Ca2+-ATPase (SERCA)-GFP-labeled Ca2+ stores with IP3R co-moved and co-accumulated to the next cleavage furrow. These results strongly suggest that Ca2+ stores with IP3R, which is transferred by microtubule-based motility as cleavage stimulus, act as an F-actin translocator.

Neuroendoscope in aneurysm surgeries: past, present and future / Neuroendoscopia em cirurgia de aneurismas: passado, presente e futuro

Even with the use of most sophisticated microscope sometimes the relationship between the aneurysm and the adjacent structures are not clearly defined. The straight line of view by microscope results in inadequate visualization of structures thatlie immediately behind other structures like the neck, branches or perforators of the aneurysm. Hence exposure of these structures may require risky retraction either of the parent artery or the aneurysm itself, which can be overcome by clear anatomical information obtained by the use of endoscope instead of attempting extensive manipulation under the microscope. The endoscope permits close up, wide angled views of regional anatomic features and verification of the optimal clip position. Visual conformation of regional anatomy achieved using the rigid endoscope provides valuable information for subsequent microsurgical procedures and enhances the safety and reliability. Endoscopic-assisted microsurgery is an exceptional aid and using the PIP (picture-in picture) technology, simultaneous observation of microscope and endoscopic images can be viewed through the ocular system of microscope. The advantages of neuroendoscope include the ability to look around corners and behind obstructions. With less brain retraction, smaller operative exposures and better visualization, neuroendoscopy may reduce operative morbidity. However he surgeon should be familiar with this technique and be prepared for the inconveniences and risks during the procedure.

A neuroendoscopia reflete a tendência da neurocirurgia moderna em buscar acessos mínimos., ou seja, acessar e visualizar lesões através de corredores o menor possível e com máxima efetividade ao objetivo, com mínima alteração do tecido norma;. Embora o primeiro procedimento endoscópico intracraniano tenha sido realizado no início do século 20, esta técnica tornou-se popular entre os neurocirurgiões, somente nos anos recentes, após o refinamento dos endoscópios e de seus instrumentos. Mesmo com o uso de microscópios, as vezes as relações entre os aneurismas e as estruturas vizinhas não é claramente definida. A visão reta oferecida pelo microscópio resulta em visualização inadequada de estruturas que se colocam imediatamente atrás, como o colo, ramos ou perfurantes do aneurisma. Assim, a exposição destas estruturas pode requerer retrações de risco para a artéria aferente ou o próprio aneurisma, o que pode ser superado por uma clara informação anatômica obtida com o endoscópio, ao invés de uma eventual manipulação externa com o microscópio. O endoscópio permite “close-up”, amplas e anguladas observações das características anatômicas e verificação do posicionamento ótimo do clipe. A conformação visual da anatomia regional obtida com o uso do endoscópio rígido oferece aliosa informação para subseqüentes e a confiabilidade. Microscopia assistida por endoscopia é um auxílio excepcional, e o uso de tecnologia PIP (quadro a quadro), permite a observação simultânea das imagens no microscópio e no endoscópio, através da ocular do microscópio. As vantagens da neuroendoscopia incluem a habilidade de olhar em volta de ângulos e atrás de obstáculos. Com menos retração cerebral, menores abordagens e melhor visualização, a neuroendoscopia pretende reduzir a morbidade operatória. Para tal, o neurocirurgião deve estar familiarizado com a técnica e preparado para os inconvenientes e riscos do procedimento.

Expression and structure of interleukin 4 receptor (IL-4R) complex in human invasive pituitary adenomas.

Pituitary adenomas are frequently invasive of surrounding tissues, which adversely affects the surgical outcome and the disease-free survival of patients. In the present study, Interleukin 4 receptor (IL-4R) complex has been investigated to figure out whether the three subunits are overexpressed in human invasive pituitary adenomas. Reverse transcription-polymerase chain reaction (RT-PCR) analysis for interleukin 4 receptor alpha (IL-4Ralpha), interleukin 13 receptor alpha1 (IL-13Ralpha1), interleukin 2 receptor gammac (IL-2Rgammac) were performed on total RNA extracted from 10 non-invasive pituitary adenomas, 30 invasive pituitary adenomas, one glioblastoma multiforme, one normal human pituitary tissue sample and one normal human brain tissue sample. Quantitative real-time PCR and in situ immunofluorescence assay were performed in five invasive functioning pituitary adenoma samples and five invasive nonfunctioning pituitary adenoma samples. RT-PCR analysis for IL-4Ralpha, IL-13Ralpha1 and IL-2Rgammac chains were overexpressed in invasive pituitary adenomas. The transcripts for three subunits were not/weakly expressed in normal pituitary tissue and normal brain tissue. The quantitative real-time PCR and in situ immunofluorescence assay confirmed the results of the RT-PCR analysis. Our results indicate that human invasive pituitary adenomas express type III IL-4R complex. These receptors may serve as a novel target for immunotoxin therapy in patients with invasive pituitary adenomas who are not amenable to total surgical resection or for recurrent cases.

Management of complex, surgically intractable intracranial aneurysms: the option for intentional reconstruction of aneurysm neck followed by endovascular coiling.

BACKGROUND: A limited series of patients with aneurysm were reviewed retrospectively to analyze strategies for integrating microsurgical and endovascular techniques in the management of complex, surgically intractable aneurysms. METHODS: Four patients were managed in Fujita Health University with a multimodality approach: intentional reconstruction of the aneurysm neck followed by endovascular coiling. RESULTS: A total of 5 aneurysms were treated, of which 3 were large or giant in size, and 3 were fusiform or multilobulated. Complete angiographic obliteration was confirmed in 4 aneurysms (80%). All patients had a good outcome (Glasgow Outcome Scale score 5; mean follow-up, 64 months). CONCLUSION: As for complex, surgically intractable aneurysms, the intentional reconstruction of the aneurysm neck followed by endovascular coiling should be considered more often.

Decompressive craniectomy and mild hypothermia reduces infarction size and counterregulates Bax and Bcl-2 expression after permanent focal ischemia in rats.

Both mild hypothermia (MH) and decompressive craniectomy (CE) have been shown to have neuroprotective effects in brain ischemia. We investigated a possible effect of MH and a combination of CE and MH (CE + MH) on the changes of infarction size, DNA fragmentation, and immunoreactivities for Bcl-2 and Bax after 24 h of permanent middle cerebral artery occlusion (MCAO) in rats. For the estimation of ischemic brain injury, we calculated the infarct size of the MCA region at 24 h after the MCAO. Terminal deoxynucleotidyl transferase-mediated dUTP-biotin in situ nick labeling (TUNEL) staining was performed for the detection of DNA fragmentation. Immunoreactivities for Bcl-2 and Bax were stained. Infarction size after permanent MCAO was significantly reduced by CE+MH treatment (P < 0.01). Infarction size did not change significantly by application of MH alone (P > 0.05). TUNEL staining was remarkably reduced both in MH-treated animals and in CE + MH-treated animals. Immunoreactivity for Bcl-2 was greatly induced both in MH-treated animals and in CE + MH-treated animals. Induction of immunoreactivity for Bcl-2 was obviously inhibited both in MH-treated animals and in CE + MH-treated animals. It suggests that temporary MH delays infarct evolution and ameliorates neuron apoptosis but does not significantly reduce definite infarction size. CE + MH not only ameliorates neuron apoptosis but also remarkably reduces infarction size.

CT angiography with electrocardiographically gated reconstruction for visualizing pulsation of intracranial aneurysms: identification of aneurysmal protuberance presumably associated with wall thinning.

Electrocardiographically (ECG) gated multisection helical CT images were obtained in 23 patients with ruptured intracranial aneurysms. 4D-CTA (3D CT angiography plus phase data) images were generated by ECG-gated reconstruction. Four patients showed pulsation of an aneurysmal bleb. Clipping was performed in two of these patients, and the rupture site matched the pulsatile bleb seen in 4D-CTA.