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Background: There is an urgent need of neuronal cell models to be applied to high-throughput screening settings while recapitulating physiological and/or pathological events occurring in the Central Nervous System (CNS). Stem cells offer a great opportunity in this direction since their self renewal capacity allows for large scale expansion. Protocols for directed differentiation also promise to generate populations of biochemically homogenous neuronal progenies. NS (Neural Stem) cells are a novel population of stem cells that undergo symmetric cell division in monolayer and chemically defined media, while remaining highly neurogenic., Results: We report the full adaptation of the NS cell systems for their growth and neuronal differentiation to 96- and 384-well microplates. This optimized system has also been exploited in homogeneous and high-content assays., Conclusions: Our results show that these mouse NS cells may be suitable for a series of applications in high-throughput format.

Stereotactic radiosurgery (SR) is increasingly utilized for the treatment of intracranial and extracranial pathology. It is considered an important adjuvant to surgery, chemotherapy or fractionated radiotherapy, and the role of SR as a primary treatment modality continues to be explored. Although SR for spinal lesions is in its infancy, there is a growing body of literature supporting its efficacy. The purpose of this review is to summarize the pertinent literature regarding the use of SR for lesions of the spine and spinal cord. Particular emphasis will be placed on large clinical series of both primary and secondary spine tumors., (2010 S. Karger AG, Basel.)

Objective: Essential tremor (ET), one of the most common neurological disorders, comprises uncontrollable tremor, usually in the upper extremities. Idiopathic normal pressure hydrocephalus (iNPH) features ventricular enlargement in the absence of elevated intracranial pressure; its three cardinal symptoms are gait impairment, incontinence, and dementia. iNPH is among the most common medical problems in the older population. To date, the genetic etiologies of ET and iNPH remain largely elusive., Methods: We previously identified a large kindred in which the affected members developed ET in adolescence or young adulthood and iNPH when elderly, in that case called ETINPH. Employing two different genotyping microarrays and two- or multipoint linkage analysis strategies, genome-wide linkage scans were performed., Results: We mapped the ETINPH locus to chromosome 19q12-13.31. Fine-mapping in this region revealed a maximum two-point lod score of 2.8 at rs2023865 and a maximum multipoint lod score of 17.9 at rs9304878. By haplotype construction, a (conservatively) approximately 17-cM critical region from SNP rs11084582 to SNP rs7258420 was defined. This region contains several neuronal genes that constitute tantalizing etiological candidates for ETINPH., Conclusion: The importance of uncovering the genetic etiology of this disorder is irrefutable, as such a discovery could offer valuable insights into ET, iNPH, and related neurological conditions., (Copyright 2010 S. Karger AG, Basel.)

In this article the authors review the literature for recent studies of radiosurgical treatment for glomus jugulare. These studies demonstrate that radiosurgery results in similar glomus jugulare tumor control and a superior morbidity profile compared with surgical treatment. In addition, patients treated with radiosurgery usually remain stable clinically or improve. Given the indolent nature of these tumors, however, more follow-up is required to ensure that the immediate benefits are lasting. These preliminary reports demonstrate that the use of radiosurgery as a primary treatment for glomus jugulare should be extended to encompass more of the patients who are currently assigned to microsurgical treatment.

Cavernous malformations (CMs) consist of dilated vascular channels that have a characteristic appearance on MRI. CMs are usually found intracranially, although such lesions can also affect the spinal cord. Individuals with CMs can present with epilepsy and focal neurological deficits or acute intracranial hemorrhage. In many cases, however, patients with such lesions are asymptomatic at diagnosis. Furthermore, several natural history studies have documented that a substantial proportion of asymptomatic CMs follow a benign course. Surgical resection is recommended for CMs that require intervention. Radiosurgery has been advocated for many lesions that have not been easily accessible by conventional surgery. The outcomes of radiosurgery and surgery for deep lesions, however, vary widely between studies, rendering treatment recommendations for such CMs difficult to make. In addition to reviewing the literature, this article will discuss the current understanding of lesion pathophysiology and explore the controversial issues in the management of CMs, such as when to use radiosurgery or surgery in deep-seated lesions, the treatment of epilepsy, and the safety of anticoagulation.

Objective: Shunt patency studies are performed to determine whether shunt revision surgery is needed in malfunctioned ventriculoperitoneal shunt. The aim of our study was to develop a simple diagnostic algorithm in the diagnostic workup and identify factors associated with improvement after revision surgery., Methods: A retrospective review of patients with confirmed shunt obstruction who underwent a revision surgery and were followed for 6 to 12 months was performed. A simpler algorithm to identify shunt obstruction was created and compared with the 4-variable algorithm., Results: Of the 63 patients in whom shunt obstruction was suspected, 39 were diagnosed with complete or partial obstruction. Thirty-seven patients underwent shunt revision surgery that included removal of shunt (n = 2), conversion to a ventriculoatrial shunt (n = 8), and relocation of the distal end of the catheter into a different part of the peritoneal cavity (n = 27). Improvements were seen in 63.3% (n = 19) of patients evaluated at 6 months and 63.6% (n = 14) of patients evaluated at 12 months. The positive predictive value of the study was 80%. A simpler 1-variable algorithm using T(1/2) (half-time) could correctly classify 86.9% of patients with shunt obstruction, compared with a 4-variable algorithm that correctly classified 80% of patients., Conclusion: Shunt patency studies are very useful for evaluation of shunt patency. Their results can be interpreted using a single-variable (T(1/2)) algorithm. Patients most likely to respond to a revision surgery are those who had a good response to original placement of a ventriculoperitoneal shunt.

Introduction: Because of the difficulty in distinguishing idiopathic normal pressure hydrocephalus (INPH) from other neurodegenerative conditions unrelated to cerebrospinal fluid (CSF) dynamics, response to CSF shunting remains highly variable. We examined the utility of CSF drainage and CSF pressure (Pcsf) dynamics in predicting response to CSF shunting for patients with INPH., Methods: Fifty-one consecutive INPH patients underwent continuous lumbar Pcsf monitoring for 48 hours followed by 72 hours of slow CSF drainage before ventriculoperitoneal shunting. Response to CSF drainage and B-wave characteristics were assessed via multivariate proportional-hazards regression analysis., Results: Improvement in 1, 2, or all 3 INPH symptoms was observed in 35 (69%), 28 (55%), and 11 (22%) patients, respectively, after CSF shunt implantation by 12 months after surgery. A positive response to CSF drainage was found to be an independent predictor of shunt responsiveness (relative risk, 0.30; 95% confidence interval, 0.09-0.98; P = 0.05). There was no difference in Pcsf wave characteristics between the shunt-responsive and -nonresponsive groups, regardless of whether 1-, 2-, or 3-symptom improvement was used to define response to CSF shunting., Conclusion: In this study of 51 INPH patients who underwent Pcsf monitoring with waveform analysis and CSF drainage followed by shunt surgery, there was no correlation between specific Pcsf wave characteristics and objective symptomatic improvement after shunt placement. Pcsf monitoring with B-wave analysis contributes little to the diagnostic dilemma with INPH patients. Clinical response to continuous CSF drainage over a 72-hour period suggests a high likelihood of shunt responsiveness.

The authors report their experience using preoperative chest radiography and intraoperative ultrasonography for percutaneous positioning of the distal end of the catheter when placing ventriculoatrial (VA) shunts in patients with hydrocephalus. The distal portion of VA shunt catheters were percutaneously placed into the internal jugular vein with the aid of intraoperative ultrasonography in 14 consecutive adults. In all cases, the technique was easy, there were no postoperative complications, and postoperative chest radiography demonstrated good positioning of the distal catheter tip. One patient presented with a shunt infection and needed a shunt replacement. The authors therefore conclude that percutaneous placement of a VA shunt under preoperative radiographic guidance and ultrasonographic monitoring is a safe, effective, and reliable technique that is simple to learn.

Ventriculo-atrial (VA) shunts are often used for CSF diversion in situations involving abdominal pathology that preclude the use of ventriculo-peritoneal shunts. Distal (venous) catheters of VA shunts have historically been inserted using a cut-down on the internal jugular vein (IJV). Less invasive placement of atrial catheters may minimize operative times and attenuate post-operative incisional discomfort. We describe a method for atrial catheter placement using ultrasound guidance to visualize the IJV and facilitate percutaneous venous puncture in 17 adult patients (23 total insertions) undergoing treatment for hydrocephalus or pseudotumor cerebri. The IJV and carotid artery were visualized by ultrasound in 23 (100%) cases. Venous penetration and successful atrial catheter placement was achieved on the first attempt in 23 (100%) cases. Pneumothorax, carotid artery puncture or need for venous cut-down occurred in no cases. The utilization of ultrasound guidance for distal VA shunt catheter insertion may increase comfort with this procedure and ultimately decrease complication rate and operative time.

Epidural abcessess can involve the intercranial or spinal compartments and can result in potentially devastating neurological injuries. Although rare, incidence of spinal epidural abscesses (SEAs) is increasing as predisposing factors such as injected-drug use, chronic immunosuppression, and spinal surgery become more common. Whereas symptoms of SEAs can include fever, back pain, and neurological dysfunction, the presentation of intracranial epidural abscesses (ICEAs) is less well defined. Neuroimaging narrows the potential diagnoses and enables prompt empirical therapy until specific microbiological diagnosis is made. Surgical intervention is an integral part of treatment for epidural abscesses in patients with neurological symptoms or who have not responded to medical management. Prognosis for both SEAs and ICEAs is typically poor because of delayed diagnosis and intervention and is dependent on the neurological status at the time of diagnosis. Increased clinical awareness can greatly improve outcomes by helping to diagnose patients earlier.

Temozolomide (TMZ) and carmustine (BCNU), cancer-drugs usually used in the treatment of gliomas, are DNA-methylating agents producing O6-methylguanine. It has been shown that 06-methylguanine triggers DNA mismatch repair and in turn induce apoptosis and senescence, respectively, over a 4 and 6 days period [Y. Hirose, M.S. Berger, R.O. Pieper, p53 effects both the duration of G2/M arrest and the fate of temozolomide-treated human glioblastoma cells, Cancer Res. 61 (2001) 1957-1963; W. Roos, M. Baumgartner, B. Kaina, Apoptosis triggered by DNA damage O6-methylguanine in human lymphocytes requires DNA replication and is mediated by p53 and Fas/CD95/Apo-1, Oncogene 23 (2004) 359-367]. Here we show that TMZ and BCNU have an earlier effect on nuclear organization and chromatin structure. In particular, we report that TMZ and BCNU induce clustering of pericentromeric heterochromatin regions and increase the amount of heterochromatic proteins MeCP2 and HP1alpha bound to chromatin. These drugs also decrease global levels of histone H3 acetylation and increase levels of histone H3 trimethylated on lysine 9 (H3-triMeK9). These events precede the senescence status. We conclude that TMZ and BCNU efficacy in glioma treatment may implicate a first event characterized by changes in heterochromatin organization and its silencing which is then followed by apoptosis and senescence.

REST/NRSF is a transcription factor that represses transcription of several neuronal genes by binding to a DNA regulatory motif known as Repressor Element 1/Neuron-restrictive silencer element (RE1/NRSE). In Huntington's Disease, an inherited degenerative disease affecting the brain, REST/NRSF enters pathologically into the nucleus of affected cells, leading to the activation of the RE1/NRSE sites and causing decreased transcription of several important neuronal genes. Following this discovery, an effort has begun by some of the authors aimed at identifying compounds capable of antagonizing REST/NRSF silencing activity. Here we will review the underlying basis for focusing pharmaceutical efforts on REST/NRSF-RE1/NRSE system as well as some of the strategies for a rational drug design approach. We will highlight approaches aimed at identifying or designing small molecules able to impact REST/NRSF nuclear translocation, its DNA binding or, more generally, the formation of the REST/NRSF transcriptional complex, in the attempt to restore neuronal gene transcription in pathological conditions of the brain.

Purpose: We describe a computerized (or virtual) model of a stereotactic head frame to enable planning prior to the day of radiosurgery. The location of the virtual frame acts as a guide to frame placement on the day of the procedure., Methods and Materials: The software consists of a triangular mesh representation of the essential frame hardware that can be overlaid with any MR scan of the patient and manipulated in three dimensions. The software calculates regions of the head that will actually be accessible for treatment, subject to the geometric constraints of the Leksell Gamma Knife hardware. DICOM-compliant MR images with virtual fiducial markers overlaid onto the image can then be generated for recognition by the treatment planning system., Results: Retrospective evaluation of the software on 24 previously treated patients shows a mean deviation of the position of the virtual frame from the actual frame position of 1.6 +/- 1.3 mm. Initial clinical use on five patients indicates an average discrepancy of the virtual frame location and the actual frame location of <1 mm. MR images with virtual fiducial markers can be imported into radiosurgical treatment planning software and used to generate an initial treatment plan., Conclusions: The virtual frame provides a tool for prospective determination of lesion accessibility, optimization of the frame placement, and treatment planning before the day of the procedure. This promises to shorten overall treatment times, improve patient comfort, and reduce the need for repeat treatments due to suboptimally placed frames.

Background/objective: Little is known about the long-term clinical course and management of patients with normal pressure hydrocephalus (NPH) treated by cerebrospinal fluid (CSF) shunting., Methods: We retrospectively reviewed records of 55 patients diagnosed with idiopathic NPH (INPH) and treated with CSF shunts, all of whom were followed for more than 3 years after the original shunt surgery. At each annual follow-up visit, the patient was assessed by Folstein Mini Mental State Examination, detailed clinical evaluation of gait and assessment of headache, cognition, gait or urination, as assessed by the patient and relatives., Results: The mean duration of follow-up was 5.9+/-2.5 years. There was an overall sustained improvement among all symptoms. Gait showed the highest maintenance of improvement over baseline (83% at 3 years and 87% at the last analysed follow-up of 7 years), cognition showed intermediary improvement (84% and 86%, respectively), and urinary incontinence showed the least improvement (84% and 80%, respectively). Fifty-three percent of patients required shunt revisions. Indications for revision included shunt malfunction (87%), infection (10%) and change of shunt configuration (3%). Overall, 74% revisions resulted in clinical improvement., Conclusions: Clinical improvement of patients with NPH can be sustained for 5-7 years in some patients with NPH, even if shunt revision surgery is needed multiple times. With earlier diagnosis and treatment of NPH and the increasing lifespan of the ageing population, the need for long-term follow-up after shunt surgery for NPH may be greater than it was in the past. Monitoring, identification and treatment of shunt obstruction is a key management principle.

Objective: To examine effectiveness of standardized occupational therapy and physical therapy assessments in detecting functional changes and predicting clinical improvement in patients with suspected normal pressure hydrocephalus undergoing cerebrospinal fluid drainage., Design: Cohort study., Patients: Eighty-seven patients admitted to an inpatient neurology unit for elective cerebrospinal fluid drainage for suspected normal pressure hydrocephalus., Methods: Before and after a protocol of continuous cerebrospinal fluid drainage via spinal catheter, patients were administered the Functional Independence Measure (FIMTM), Timed Up and Go (TUG), Tinetti Assessment Tool of Gait and Balance, 9-hole peg test, and Cognitive Assessment of Minnesota (CAM). Following cerebrospinal fluid drainage, changes in functional performance were compared for responders to cerebrospinal fluid drainage and non-responders to cerebrospinal fluid drainage., Results: At baseline, CAM was more sensitive than the Mini Mental State Exam in predicting responders. Post-drainage: responders improved on 52% of tests while non-responders improved on only 11%. Assessments that differentiated magnitude of improvement in responders vs non-responders were: TUG (p<0.05), Tinetti total (p<0.001), Tinetti balance (p<0.001), Tinetti gait (p<0.001), FIM toilet transfer (p<0.001), and FIM lower body dressing (p<0.001)., Conclusion: Specific occupational therapy and physical therapy assessments demonstrate sensitivity to change and predictive value with patients with suspected normal pressure hydrocephalus undergoing cerebrospinal fluid drainage.

Objective: Using ribonucleic acid interference on cultured cell lines, we examined the role of Krev interaction trapped 1 (krit1) and integrin cytoplasmic domain-associated protein-1 alpha (icap1alpha) in beta1-integrin-mediated cell proliferation., Methods: Upon depletion of either krit1 or icap1alpha in the HeLa cells, umbilical vein endothelial cells, and microvascular endothelial cells, we examined the cell number and proliferation changes in the cells, followed by the evaluation of beta1-integrin-mediated mitogen-activated protein kinase signal pathway and microscopic study., Results: Depletion of krit1 reduces cell number and decreases endothelial cell proliferation. Examination of beta1-integrin signaling downstream of focal adhesion kinase reveals decreased phosphorylation along the extracellular signal-regulated kinase/mitogen-activated protein kinase pathway. Depletion of icap1alpha, a protein known to interact with krit1, has similar effects, suggesting synergistic function. We also show that krit1 colocalizes with icap1alpha in both the nucleus and the cytoplasm; however, most of icap1alpha is found in the nucleus and most of krit1 is found in the cytoplasm at steady state. On depletion of krit1, icap1alpha decreases in the cytoplasm and is no longer detected in the nucleus., Conclusion: Both krit1 and icap1alpha act concordantly to play a critical role in beta1-integrin-mediated cell proliferation. Our data further suggest that krit1 both stabilizes and shuttles icap1alpha and thus modulates its regulation of beta1-integrin-mediated signal transduction.

This case report presents a patient suffering acute fatal intracranial-intratumoral hemorrhage during a gamma knife treatment session. Acute hemorrhage during a radiosurgery session is extremely rare and a plausible cause for this case is discussed along with a literature review of previously reported incidents. The patient was a 71-year-old male presenting with three large intracranial lesions and an underlying primary renal cell carcinoma malignancy. Because of a severe kyphotic deformity resulting from ankylosing spondylitis, the patient was placed in a moderate Trendelenburg position to allow his head to fit into the gamma knife unit during the radiosurgery session. The two left-sided lesions were to be treated with 20 Gy to the 50% isodose line, and the right-sided lesion with 16 Gy to the 40% isodose line. Anesthesia was available throughout the treatment session to aid with pain control. The gamma knife treatment was aborted because the patient suffered a generalized seizure while in the unit. Immediate head CT of the patient revealed large acute hemorrhages into all three intracranial masses. This proved to be a fatal complication. It is likely that this positioning contributed to the hemorrhage. The clinical history of this patient is provided as well as a review of the literature on acute intracranial hemorrhage associated with radiosurgical therapy.

REST/NRSF is a multifunctional transcription factor that represses or silences many neuron-specific genes in both neural and non-neural cells by recruitment to its cognate RE1/NRSE regulatory sites. An increase in RE1/NRSE genomic binding is found in Huntington's disease (HD), resulting in the repression of REST/NRSF regulated gene transcription, among which BDNF, thus representing one of the possible detrimental effectors in HD. Three 2-aminothiazole derivatives were recently identified as potent modulators of the RE1/NRSE silencing activity through a cell-based gene reporter assay. In this study, the structure-activity relationships (SAR) of a library of commercially available 2-aminoisothiazoles diversely substituted at the amino group or at position 4 has been evaluated. A quantitative structure-activity relationship analysis performed using the Phase strategy yielded highly predictive 3D-QSAR pharmacophore model for in silico drug screening.

In this report, we identified a large five-generation distinctive kindred with essential tremor (ET) presenting during the teen years and the consequent appearance of idiopathic normal pressure hydrocephalus (iNPH) when elderly (>65 years), in an autosomal dominant fashion. Through clinical and genetic analysis, we defined this kindred as a new essential tremor-idiopathic normal pressure hydrocephalus (ETINPH) disorder. One of the most common neurological disorders, ET comprises uncontrollable tremor, most commonly the upper limbs. Molecular genetic studies in hereditary ET have been initiated, but only with negative results so far. iNPH is an adult-onset hydrocephalus characterized by ventricular enlargement in the absence of significant elevations of intracranial pressure. iNPH patients usually have a triad of clinical symptoms: gait impairment, incontinence, and dementia, which is among the most common medical problems in the older population. The genetic etiology of iNPH is totally unknown. We hypothesize that ET is the consequence of the abnormal function of a specific neuronal gene, and that the same gene causes tremor at an early age eventually leading to the development of iNPH later in life. An understanding of the genetic components of this disorder may offer us significant insights into the molecular pathogenesis of ET, iNPH, and other related neurological conditions. In our genetic analysis of this family, array-based comparative genomic hybridization (aCGH) was carried out, and we could not identify any possible copy number changes of the genomic fragment along the whole-genome in ETINPH patient. Candidate gene linkage analysis was also performed, and we excluded this disorder from several established loci associated with tremor. We conclude that the pedigree reported here is a new autosomal dominant genetic disorder ETINPH. The characterization of the gene that causes ETINPH will certainly enhance our understanding of motor diseases in general.

Objective: The response to shunt surgery for idiopathic normal-pressure hydrocephalus (INPH) is variable because INPH is difficult to distinguish from other conditions causing the same symptoms. To date, no clinical picture or diagnostic test can distinguish INPH or predict response to cerebrospinal fluid (CSF) shunt surgery. We reviewed our 10-year experience with INPH to characterize long-term outcome and to identify independent predictors of outcome after shunt surgery., Methods: Patients were classified as having INPH only if they had: 1) ventriculomegaly, 2) two or more INPH clinical features, 3) no risk factor for secondary normal-pressure hydrocephalus, 4) A- or B-waves on CSF pressure monitoring, and 5) clinical improvement during a 3-day CSF drainage trial via a spinal catheter. Independent predictors of outcome were assessed via a multivariate proportional hazards regression analysis., Results: One hundred thirty-two patients underwent 179 shunt surgeries. Forty-four (33%), 79 (60%), and 99 (75%) patients demonstrated objective improvement 3, 6, and 24 months after shunt surgery, respectively. Gait improved first in 88 (93%) patients. Dementia and urinary incontinence were twofold less likely to improve. Radiological evidence of corpus callosum distension, gait impairment as the primary symptom, and shorter duration of INPH symptoms predicted improvement. Duration of symptoms and gait as the primary symptom were independent predictors by multivariate analysis., Conclusion: INPH can be diagnosed accurately with CSF pressure monitoring and CSF drainage via a spinal catheter. CSF shunting is safe and effective for INPH with a long-term shunt response rate of 75%. Independent predictors of improvement are the presence of gait impairment as the dominant symptom and shorter duration of symptoms.

Background: Lumbar decompressive surgery can be complicated by dural tears, infection, nerve root injury, deep venous thrombosis, and epidural hematoma. However, perioperative complications of multilevel laminectomies in patients with achondroplasia rarely are reported. Our objective was to determine the perioperative complication rates associated with laminectomies in patients with achondroplasia., Methods: We reviewed the medical records of the initial laminectomies for all ninety-eight patients with achondroplasia at our institution, which included twenty-eight patients who had had previous spine surgeries at other institutions, and determined the rates of complications in the following categories: neurologic, pulmonary, cardiovascular, and gastrointestinal complications; intraoperative dural tears; infections at the incision site; and mortality., Results: Sixty (61%) of ninety-eight patients had at least one perioperative complication. By category, these included intraoperative dural tears, which occurred in 37% (thirty-six patients); neurologic complications, in 23% (twenty-three patients); infections at the incision site, in 9% (nine patients); deep venous thrombosis, in 3% (three patients); pulmonary complications, in 3% (three patients); and gastrointestinal complications, in 3% (three patients). The only death was caused by a pulmonary embolism., Conclusions: Perioperative complications are common in patients with achondroplasia undergoing multilevel laminectomies, and the perioperative care team should be aware of these complications when caring for these patients.

Objectives: Gait abnormalities are an early clinical symptom in normal pressure hydrocephalus (NPH), and subjective improvement in gait after temporary removal of CSF is often used to decide to perform shunt surgery. We investigated objective measures to compare gait before and after CSF drainage and shunt surgery., Design: Twenty patients and nine controls were studied. Quantitative gait measures were obtained at baseline, after 3 days of controlled CSF drainage, and after shunt surgery. Decision to perform surgery was based on response to drainage, and patients were assigned to shunted or unshunted groups for comparison., Results: There was no improvement after CSF drainage in the unshunted group (n = 4). In the shunted group (n = 15) velocity, double-support time, and cadence improved significantly after drainage, and improved further after shunt surgery. The degree of improvement after drainage significantly correlated to the degree of improvement postshunt for velocity, double-support time, cadence, and stride length., Conclusions: There are significant, quantifiable changes in gait after CSF drainage that correspond to improvement after shunt surgery for patients with NPH. Use of objective gait assessment may improve the process of identifying these candidates when response to CSF removal is used as a supplemental prognostic test for shunt surgery.

Study Design: Retrospective morphometric population study., Objective: To characterize pedicle and spinal canal morphology of the achondroplastic lower thoracic and lumbar vertebrae and to suggest dimensions for improving pedicle screw selection and placement., Summary of Background Data: Although morphometric population studies exist for various races, to our knowledge, no such analysis has been made in achondroplastic patients., Methods: With computer software, we measured pedicle parameters on the computed tomography images of 19 adult achondroplastic patients., Results: Pedicle and chord lengths ranged from 9.5-12.5 mm and 29.5-36.4 mm, respectively. Transverse pedicle diameter increased from T9 (5.5 mm) to L5 (14.2 mm). Sagittal pedicle diameter declined from L1 (11.6 mm) to L5 (7.8 mm). Transverse angulation was greatest at L5 (15.7 degrees ) and smallest at T12 (1.1 degrees ). Pedicles were directed cranially at all levels, ranging from 3.8 degrees -15.6 degrees . Interpedicular distance and cross-sectional area were smallest at L4 (14.9 mm and 119 mm, respectively). Pedicle starting points diverged from T9 (13.6 mm) to L5 (19.2 mm2)., Conclusion: Achondroplastic pedicle morphology differs markedly from those of the normal spine: chord lengths are substantially shorter, pedicles are inclined cranially, pedicle starting points diverge progressively in the lumbar spine, and pedicle shape transitions from vertically to horizontally oriented ellipsoids along the lumbar spine. Consideration of this variation could maximize the effectiveness and safety of pedicle instrumentation.

Increased levels of the repressor element 1/neuron restrictive silencer element (RE1/NRSE) silencing activity promoter, and a consequent reduction in the transcription of many RE1/NRSE-bearing neuronal genes, including brain-derived neurotrophic factor (BDNF), have been demonstrated in Huntington disease (HD) and represent one possible effector of its selective neuronal vulnerability. Restoring the expression levels of neuronal genes in diseased neurons therefore seems to be an attractive therapeutic approach. To this end, we have developed a cell-based reporter assay for monitoring RE1/NRSE silencing activity and validated it by genetically inactivating the RE1/NRSE or pharmacologically stimulating global transcription. In a pilot compound screen, we identified three closely related structural analogues that up-regulate reporter expression at low nanomolar concentrations, and follow-up studies have shown that they efficaciously increase endogenous BDNF levels in HD cells. Moreover, one of the compounds increases the viability of HD cells. Our findings suggest a new avenue for the development of drugs for HD and other neurodegenerative disorders based on the pharmacological up-regulation of the production of the neuronal survival factor BDNF and of other RE1/NRSE-regulated neuronal genes.

Background: Beyond the classic Normal Pressure Hydrocephalus (NPH) triad of gait disturbance, incontinence, and dementia are characteristic signs of motor dysfunction in NPH patients. We used highly sensitive and objective methods to characterize upper limb extrapyramidal signs in a series of NPH subjects compared with controls. Concentrated evaluation of these profound, yet underappreciated movement disorders of NPH before and after techniques of therapeutic intervention may lead to improved diagnosis, insight into pathophysiology, and targeted treatment., Methods: Twenty-two (22) consecutive NPH patients and 17 controls performed an upper limb motor task battery where highly sensitive and objective measures of akinesia/bradykinesia, tone, and tremor were conducted. NPH subjects performed this test battery before and more than 36 h after continuous CSF drainage via a spinal catheter over 72 h and, in those subjects undergoing permanent ventriculo-peritoneal shunt placement, at least 12 weeks later. Control subjects performed the task battery at the same dates as the NPH subjects. Statistical analyses were applied to group populations of NPH and control subjects and repeated measures for within subject performance., Results: Twenty (20) NPH subjects remained in the study following CSF drainage as did 14 controls. NPH subjects demonstrated akinesia/bradykinesia (prolonged reaction and movement times) and increased resting tone compared with controls. Furthermore, the NPH group demonstrated increased difficulty with self-initiated tasks compared with stimulus-initiated tasks. Following CSF drainage, some NPH subjects demonstrated reduced movement times with greater improvement in self- versus stimulus-initiated tasks. Group reaction time was unchanged. Resting tremor present in one NPH subject resolved following shunt placement. Tone measures were consistent for all subjects throughout the study., Conclusion: Clinical motor signs of NPH subjects extend beyond gait deficits and include extrapyramidal manifestations of bradykinesia, akinesia, rigidity, and propensity to perform more poorly when external cues to move are absent. Objective improvement of some but not all of these features was seen following temporary or permanent CSF diversion.

Object: The goal in this study was to determine the percentage of patients with hydrocephalus who were treated with shunt surgery and to assess Medicare expenditures for those with and without shunt surgery., Methods: Retrospective cost analyses were performed using the Standard Analytic Files of paid claims for beneficiaries enrolled in both Parts A (Inpatient) and B (Outpatient) of the Medicare program for 1997 through 2001. The main outcome measures were 5-year total payments and 5-year payments for separate types of service; for example, acute hospital (inpatient and outpatient), skilled nursing facility, home health, and physician/supplier services., Results: Of 1441 patients with hydrocephalus, 25.1% underwent shunt surgery during the study period. The effect of a shunt procedure on 5-year Medicare expenditures is a cost difference of $25,477 (p < 0.0001) less per patient, which is equal to a potential -$184.3 million difference in 5-year Medicare expenditures. The following three factors had a negative association with whether shunt surgery was performed: (1) age 80 to 84 years (odds ratio [OR] 0.619, confidence interval [CI] 0.390-0.984); (2) age 85 years or older (OR 0.201, CI 0.110-0.366); and (3) African-American race (OR 0.506, CI 0.295-0.869). The effect of age on the likelihood of shunt surgery persisted after adjusting for the propensity to die score., Conclusions: Medicare expenditures for patients with hydrocephalus treated with shunt surgery are significantly lower than expenditures for untreated patients. Research to improve the diagnosis and treatment of hydrocephalus has the potential to improve outcomes and reduce health care expenditures further.

Background: The treatment of large and high-grade (Spetzler-Martin III-V) AVMs remains a challenge. There is a paucity of literature addressing the efficacy of radiosurgery in this group. We retrospectively analyze our experience with repeat radiosurgery with such AVMs., Methods: Between 1989 and 2004, 14 patients with large and high-grade AVMs deemed to be nonoperative candidates were treated with repeat radiosurgery. Patients were treated either on a LINAC or gamma knife-based system at 2- to 3-year intervals with targeting of the entire nidus with each treatment. Patients who did not receive their full treatment course or follow-up at the institution were excluded., Results: Mean follow-up was 18 months. The complete obliteration rate was 35.7%, with a mean volume reduction of 53% in the remaining lesions. Twenty percent of grade III and 50% of grade IV lesions experienced cure. Complications included persistent headaches (2 patients). Statistical analysis revealed no difference between obliterated and partially obliterated groups with regard to mean pretreatment volume (24.87 cm(3)), median Spetzler-Martin grade (IV), mean follow-up (30.5 months), total delivered dose (3550 cGy), mean dose per stage (13 Gy), median number of stages (2), or mean interval between treatment stages (40 months)., Conclusion: The present study demonstrates the potential role of repeat radiosurgery in the treatment of this cohort in the context of our short follow-up. The benefits of repeat therapy could be derived from using lower doses per session and repeat targeting of the lesion in an effort to increase response and decrease complication rates.

Ultrasound has been used to aid cannulation of veins of the neck, chest, antecubital fossa, and femoral vein. This investigation compared the traditional method of peripheral intravenous (IV) cannulation of veins of the hands and forearms with ultrasound-guided IV cannulation of these veins. After obtaining institutional review board approval and written informed consent, 35 adult subjects with a history or suspicion of difficult IV cannulation were prospectively enrolled with 16 subjects randomly assigned to the traditional group and 19 to the ultrasound group. Time taken for successful venous cannulation and number of attempts between the groups were compared using a Mann-Whitney U test. The number of subjects in whom IV cannulation was successful on the first attempt was compared between the groups using the Fisher exact test. No significant differences were noted between groups in demographics, time to successful cannulation, number of attempts, and number of subjects in whom IV cannulation was successful on the first attempt. Ultrasound was as efficacious as the traditional method of IV cannulation in this subset of patients. Future investigations should examine the efficacy of the ultrasound-guided technique of IV cannulation of these veins in patients in whom the traditional method failed.

Objective: The presentation and natural history of untreated, symptomatic intramedullary spinal cavernomas at our institution were analyzed. The objective is to provide additional information regarding the natural history of conservatively managed, symptomatic, intramedullary spinal cord cavernous malformations., Methods: The medical records of patients treated in our institution between 1989 and 2002 were reviewed to identify those with intramedullary cavernomas. The medical, radiological, surgical, and pathological records from these patients were retrospectively reviewed and analyzed., Results: Fourteen patients were included in the study. The mean age at presentation was 42 years. Four lesions (29%) were located in the cervical region and 10 lesions (71%) were present in the thoracolumbar spinal cord. All patients were symptomatic at the time of presentation. In this cohort of 14 patients, 10 patients (71%) were conservatively managed. For these patients, the mean duration of symptoms before presentation was 10 months. The mean duration of follow-up from the time of presentation was 80 months. The median McCormick grade for conservatively treated patients at presentation was II. During this period, none of the conservatively managed patients had an acute intramedullary bleed. In nine patients, the McCormick grade at the last follow-up evaluation was the same as or better than their score at presentation. Four patients (29%) were treated surgically. The mean duration of symptoms before presentation was 33 months. The mean duration of follow-up from the time of presentation was 42 months. In two surgical patients, the McCormick grade at the last follow-up evaluation remained unchanged compared with their score at presentation, whereas the McCormick grade improved in one patient and deteriorated in another patient., Conclusion: This cohort of conservatively managed patients with symptomatic, intramedullary spinal cord cavernomas was clinically stable throughout the follow-up period. In this series, patients harboring symptomatic spinal cord cavernous malformation did not have significant, permanent neurological decline during the follow-up period when treated with the conservative approach of observation. This data provides additional information for determining the appropriate treatment strategy for patients with intramedullary spinal cavernomas.

Object: The authors attempted to determine whether continuous intracranial pressure monitoring via the shunt reservoir identifies ventriculoperitoneal (VP) shunt malfunctions that are not identified by radionuclide shunt patency study or shunt tap in adults with hydrocephalus., Methods: During a 2-year period, 26 adults underwent 32 in-hospital continuous intracranial pressure (ICP) monitoring evaluations via needle access of a shunt reservoir. Monitoring was performed for 26.8 +/- 13.8 hours (mean +/- standard deviation). No ICP waveform abnormality was detected in 31% of the evaluations (10 of 32). In contrast, abnormalities were detected in 69% (22 of 32 evaluations), including B waves (nine of 22 evaluations), siphoning (nine of 22 evaluations), and variable ICP (two of 22 evaluations). In 20 (91%) of these 22 evaluations, the ICP abnormality was detected only after continuous ICP monitoring; in the other two evaluations, ICP became abnormal immediately on accessing the shunt reservoir. On the basis of the ICP monitoring results, shunt revision was performed in 66% (21 of 32 evaluations) and medical therapy was administered in 34% (11 of 32 evaluations). Shunt revision led to symptom improvement in 82% (18 of 22 patients) and no change in 18% (four of 22 patients); medical therapy led to improvement in 18% (two of 11 patients), worsening in 18% (two of 11 patients), and no change in 64% (seven of 11 patients; p < 0.05)., Conclusions: Continuous ICP monitoring via the shunt reservoir provides a more accurate assessment of shunt malfunction than transient ICP monitoring with a shunt tap or a radionuclide shunt patency study. It is a safe method for evaluating patients with suspected VP shunt malfunction, provides in vivo assessment of the effect of the shunt system on a patient's ICP, and can lead to more effective shunt revision.

Objective: Long-term anticoagulation is often considered a contraindication to shunt surgery for elderly patients with normal pressure hydrocephalus (NPH). However, no studies have investigated this question., Methods: We evaluated 25 patients who were taking warfarin for NPH between 2001 and 2004 with a protocol of cerebrospinal fluid (CSF) pressure monitoring and controlled CSF drainage via spinal catheter. Warfarin was stopped 5 to 7 days before lumbar puncture or shunt surgery and restarted 3 to 5 days after operation or at the time of discharge from the hospital. Programmable shunts with antisiphon devices set at the high-pressure range were preferentially used and adjusted in small increments., Results: After CSF drainage, 16 patients showed improvement and 15 underwent shunt surgery. Thirteen (87%) out of these 15 patients showed significant improvement in at least one symptom during a mean follow-up period of 8.2 months (range, 1-70 mo) after shunt surgery. There were two bleeding complications. One patient (6.7%) with cirrhosis who developed a subdural hematoma 13 days after operation had the shunt removed; another patient who developed an abdominal subcutaneous hematoma 5 days after operation required surgical evacuation and shunt revision surgery. Otherwise, 14 (93.3%) out of the 15 patients had no subdural hematoma during the follow-up period and there were no thromboembolic complications while the patients were not taking warfarin., Conclusion: Elderly patients on long-term warfarin anticoagulation can be safely evaluated and treated for NPH using a protocol of continuous CSF drainage via spinal catheter for diagnosis, cautious periprocedural management of anticoagulation, and use of programmable shunts with antisiphon devices. The risk of subdural hematoma is not higher than reported series. Long-term anticoagulation with warfarin is not a contraindication per se for shunt surgery in NPH.

Objective: Cerebral cavernous malformations (CCM) are a relatively common autosomal dominant disorder leading to the formation of vascular malformations in the nervous system. Mutations in krit1 and malcavernin, the proteins encoded by the genes at the CCM1 and CCM2 loci, respectively, are responsible for the majority of CCMs. Similar to integrin cytoplasmic domain-associated protein-1alpha, a known krit1 interactor, malcavernin is a phosphotyrosine binding protein. We report here that krit1 also interacts with malcavernin., Methods: We used two-hybrid analysis, in vivo coimmunoprecipitation, and epitope mapping to explore the interaction between krit1 and malcavernin. Immunocytochemistry was used to study the cellular localization of these proteins., Results: We demonstrate that malcavernin independently binds to two of the three NPXY (asparagine, proline, undetermined/variable amino acid, and tyrosine) motifs in krit1. By immunocytochemistry, malcavernin protein is cytoplasmic at steady state, but shuttles between the nucleus and cytoplasm, despite lacking either a nuclear localization signal or a nuclear export signal in its sequence., Conclusion: These data suggest that krit1 interacts with malcavernin through its NPXY motifs and may shuttle it through the nucleus via its nuclear localization signal and nuclear export signals, thereby regulating its cellular function.

Studies of the cognitive outcome after shunt insertion for treatment of Normal Pressure Hydrocephalus have reported widely mixed results. We prospectively studied performance of 60 patients with Normal Pressure Hydrocephalus on a comprehensive battery of neuropsychological tests before and after shunt surgery to determine which cognitive functions improve with shunt insertion. We also administered a subset of cognitive tests before and after temporary controlled drainage of cerebrospinal fluid to determine if change on this brief subset of tests after drainage could predict which patients would show cognitive improvement three to six months after shunt insertion. There was a significant improvement in learning, retention, and delayed recall of verbal memory three to six months after surgery (using paired t-tests). The majority (74%) of patients showed significant improvement (by at least one standard deviation) on at least one of the memory tests. Absence of improvement on verbal memory after temporary drainage of cerebrospinal fluid had a high negative predictive value for improvement on memory tests at 3-6 months after surgery (96%; p=0.0005). Also, the magnitude of improvement from Baseline to Post-Drainage on few specific tests of learning and recall significantly predicted the magnitude of improvement after shunt surgery on the same tests (r2=0.32-0.58; p=0.04-0.001). Results indicate that testing before and after temporary drainage may be useful in predicting which patients are less likely to improve in memory with shunting.

Introduction: Endoscopic third ventriculostomy (ETV) is accepted as an effective treatment for obstructive hydrocephalus (OHC); however, its benefit in patients previously treated with cerebrospinal fluid (CSF) shunting remains unclear. The value of concurrent ETV and ventriculoperitoneal (VP) shunting in patients with frequent shunt failure remains unstudied., Methods: Outcomes were compared between OHC patients receiving ETV as initial CSF diversion treatment (n= 19) versus OHC patients receiving ETV for shunt failure (n= 11) by log-rank analysis and Kaplan-Meier plots of recurrence-free periods. To determine if the performance of ETV with concurrent shunt revision decreased the incidence of catastrophic treatment failure in patients experiencing frequent and emergent shunt failures (n = 8), the time to treatment failure after ETV and shunt revision was compared with the mean duration of their previous CSF shunts., Results: ETV after shunt failure was 2.5-fold more likely to fail [risk ratio (RR): 2.48, p<0.05] versus ETV as initial CSF diversion treatment for OHC. Following ETV as initial CSF diversion treatment, 17 patients (89%) experienced immediate improvement and 65% remained recurrence-free at year 2. Following ETV after shunt failure, 16 patients (71%) experienced immediate improvement, but only 25% remained recurrence-free at year 2. In patients with a history of multiple shunt revisions and complications, concurrent use of ETV and VP shunt did not significantly decrease treatment failure. However, the incidence of catastrophic shunt failure requiring acute intervention decreased (43% versus 17%)., Conclusion: In our experience with ETV for OHC, prior CSF shunting in patients with obstructive hydrocephalus was associated with the decreased time to treatment failure following conversion to ETV. ETV may be less effective for the treatment of OHC in previously shunted patients. ETV combined with concurrent CSF shunting may be an important strategy to prevent catastrophic treatment failure in OHC patients with a history of multiple shunt revisions and complications.

Human hydrocephalus is a common medical condition that is characterized by abnormalities in the flow or resorption of cerebrospinal fluid (CSF), resulting in ventricular dilatation. Human hydrocephalus can be classified into two clinical forms, congenital and acquired. Hydrocephalus is one of the complex and multifactorial neurological disorders.A growing body of evidence indicates that genetic factors play a major role in the pathogenesis of hydrocephalus. An understanding of the genetic components and mechanism of this complex disorder may offer us significant insights into the molecular etiology of impaired brain development and an accumulation of the cerebrospinal fluid in cerebral compartments during the pathogenesis of hydrocephalus. Genetic studies in animal models have started to open the way for understanding the underlying pathology of hydrocephalus. At least 43 mutants/loci linked to hereditary hydrocephalus have been identified in animal models and humans. Up to date, 9 genes associated with hydrocephalus have been identified in animal models. In contrast, only one such gene has been identified in humans. Most of known hydrocephalus gene products are the important cytokines, growth factors or related molecules in the cellular signal pathways during early brain development. The current molecular genetic evidence from animal models indicate that in the early development stage, impaired and abnormal brain development caused by abnormal cellular signaling and functioning, all these cellular and developmental events would eventually lead to the congenital hydrocephalus. Owing to our very primitive knowledge of the genetics and molecular pathogenesis of human hydrocephalus, it is difficult to evaluate whether data gained from animal models can be extrapolated to humans. Initiation of a large population genetics study in humans will certainly provide invaluable information about the molecular and cellular etiology and the developmental mechanisms of human hydrocephalus. This review summarizes the recent findings on this issue among human and animal models, especially with reference to the molecular genetics, pathological, physiological and cellular studies, and identifies future research directions.

Radiosurgery to the right fifth cranial nerve was performed with the Gamma Knife on a 39- year-old patient who presented with classic symptoms of trigeminal neuralgia (TN), but was found on imaging studies to harbour a small intrinsic vascular malformation within the nerve. Based on size and drainage, the arteriovenous malformation (AVM) was Spetzler-Martin Grade III and no previous history of bleeding was reported. The patient had failed a trial of carbamazepine, and no surgical procedures had been performed. A decrease in symptoms was reported by the 6-month follow-up. A review of the literature on microAVM-induced TN is provided as well as a discussion of management.

CARD only protein (Cop) was recently identified as a protein with significant homology with the CARD of caspase-1. We have conducted functional studies on Cop and report on its role as an inhibitor of cell death in a broad range of cell death paradigms. A notable exception in the ability of Cop to inhibit cell death pertains to its inability to inhibit ER stress-mediated cell death. Furthermore, in addition to the known interaction of Cop and caspase-1, we demonstrated a novel interaction of Cop with caspase-4. We propose that Cop's action to prevent TNF-alpha-induced cell death may operate independently of the mitochondrial death pathway. Furthermore, Cop overexpression inhibits Bid cleavage. In summary, Cop inhibition of cell death, at least to a certain extent, results from its interference with the activation of caspase-1 and caspase-4. Understanding the mechanistic details modulating caspase cell death pathways should provide important information for the development of therapies for diseases featuring aberrant caspase activation. Cop, as an inhibitor of an important apical caspase cell death axis, may provide a tool for modulating pathological cell death.

Idiopathic normal pressure hydrocephalus (INPH) is a syndrome that is characterized by gait impairment, cognitive decline and urinary incontinence, and is associated with ventriculomegaly in the absence of elevated cerebrospinal fluid (CSF) pressure. There is significant variation in the clinical presentation and progression of this disorder, and its diagnosis often represents a challenge for neurologists and neurosurgeons. Various supplemental tests, including the CSF tap test, external CSF drainage via spinal catheter, and CSF outflow resistance determination, can improve the accuracy of predicting a response to surgical treatment. CSF shunting provides significant symptom improvement in the majority of appropriately evaluated patients. In 2005, an international study group published evidence-based guidelines for the diagnosis and management of INPH. This review will highlight the clinical presentation, radiographic findings, supplemental prognostic tests, differential diagnosis, surgical treatment and outcomes of INPH.

Background: Several studies have reported that ventriculoperitoneal shunt insertion for treatment of normal-pressure hydrocephalus results in improvement of gait and, less frequently, improvement of cognition. We sought to identify the demographic factors associated with cognitive improvement after shunt insertion to improve assessment of prognosis for cognitive gains with treatment., Review Summary: We report cognitive testing before and after ventriculoperitoneal shunt insertion in 36 patients with normal pressure hydrocephalus, who previously had improvement of any clinical symptom--gait, urinary incontinence, cognition--after a diagnostic trial of continuous cerebrospinal fluid drainage., Conclusions: One third of patients met our definition of good cognitive improvement: improvement by at least 25% on at least half of the cognitive tests administered. There was a significant negative linear relationship between age and probability of good cognitive improvement. Additionally, the degree of cognitive improvement was found to be greater in women than men (P = 0.002). Age was found to be a better predictor of improvement on memory tests, while sex was a better predictor of improvement on non-memory tests after shunt insertion.

The expansion of a polyglutamine tract in the ubiquitously expressed huntingtin protein causes Huntington's disease (HD), a dominantly inherited neurodegenerative disease. We show that the activity of the cholesterol biosynthetic pathway is altered in HD. In particular, the transcription of key genes of the cholesterol biosynthetic pathway is severely affected in vivo in brain tissue from HD mice and in human postmortem striatal and cortical tissue; this molecular dysfunction is biologically relevant because cholesterol biosynthesis is reduced in cultured human HD cells, and total cholesterol mass is significantly decreased in the CNS of HD mice and in brain-derived ST14A cells in which the expression of mutant huntingtin has been turned on. The transcription of the genes of the cholesterol biosynthetic pathway is regulated via the activity of sterol regulatory element-binding proteins (SREBPs), and we found an approximately 50% reduction in the amount of the active nuclear form of SREBP in HD cells and mouse brain tissue. As a consequence, mutant huntingtin reduces the transactivation of an SRE-luciferase construct even under conditions of SREBP overexpression or in the presence of an exogenous N-terminal active form of SREBP. Finally, the addition of exogenous cholesterol to striatal neurons expressing mutant huntingtin prevents their death in a dose-dependent manner. We conclude that the cholesterol biosynthetic pathway is impaired in HD cells, mice, and human subjects, and that the search for HD therapies should also consider cholesterol levels as both a potential target and disease biomarker.

Objective: The response to shunt surgery for idiopathic normal-pressure hydrocephalus (INPH) is variable because INPH is difficult to distinguish from other conditions causing the same symptoms. To date, no clinical picture or diagnostic test can distinguish INPH or predict response to cerebrospinal fluid (CSF) shunt surgery. We reviewed our 10-year experience with INPH to characterize long-term outcome and to identify independent predictors of outcome after shunt surgery., Methods: Patients were classified as having INPH only if they had: 1) ventriculomegaly, 2) two or more INPH clinical features, 3) no risk factor for secondary normal-pressure hydrocephalus, 4) A- or B-waves on CSF pressure monitoring, and 5) clinical improvement during a 3-day CSF drainage trial via a spinal catheter. Independent predictors of outcome were assessed via a multivariate proportional hazards regression analysis., Results: One hundred thirty-two patients underwent 179 shunt surgeries. Forty-four (33%), 79 (60%), and 99 (75%) patients demonstrated objective improvement 3, 6, and 24 months after shunt surgery, respectively. Gait improved first in 88 (93%) patients. Dementia and urinary incontinence were twofold less likely to improve. Radiological evidence of corpus callosum distension, gait impairment as the primary symptom, and shorter duration of INPH symptoms predicted improvement. Duration of symptoms and gait as the primary symptom were independent predictors by multivariate analysis., Conclusion: INPH can be diagnosed accurately with CSF pressure monitoring and CSF drainage via a spinal catheter. CSF shunting is safe and effective for INPH with a long-term shunt response rate of 75%. Independent predictors of improvement are the presence of gait impairment as the dominant symptom and shorter duration of symptoms.

Treatment of neurodegenerative diseases represents a major challenge for the pharmaceutical industry. Key to developing novel and efficacious therapeutics is the discovery of new druggable targets. Toward this aim, the current drug discovery process is strongly relying on the improved understanding of disease mechanisms and on a synergistic approach with chemistry, molecular biology and robotics. In this scenario, we present the case of a newly discovered molecular mechanism that may be of interest for drug discovery programmes in Huntington's disease and other neurodegenerative diseases.

Huntingtin is a protein of 348 kDa that is mutated in Huntington's disease (HD), a dominantly inherited neurodegenerative disorder. Previous data have led us to propose that aspects of the disease arise from both a loss of the neuroprotective function of the wild-type protein, and a toxic activity gained by the mutant protein. In particular, we have shown that wild-type huntingtin stimulates the production of brain-derived neurotrophic factor (BDNF), a pro-survival factor for the striatal neurons that die in the pathology. Wild-type huntingtin controls BDNF gene transcription in cerebral cortex, which is then delivered to its striatal targets. In the disease state, supply of cortical BDNF to the striatum is strongly reduced, possibly leading to striatal vulnerability. Here we show that a reduction in cortical BDNF messenger level correlates with the progression of the disease in a mouse model of HD. In particular, we show that the progressive loss of mRNAs transcribed from BDNF exon II, III and IV follows a different pattern that may reflect different upstream mechanisms impaired by mutation in huntingtin. On this basis, we also discuss the possibility that delivery of BDNF may represent an useful strategy for Huntington's disease treatment.

Huntington's Disease (HD) is a neurodegenerative disorder caused by an abnormally expanded polyglutamine trait in the amino-terminal region of huntingtin. Pathogenic mechanisms involve a gained toxicity of mutant huntingtin and a potentially reduced neuroprotective function of the wild-type allele. Among the molecular abnormalities reported, HD cells are characterized by the presence of aggregates, transcriptional dysregulation, altered mitochondrial membrane potential and aberrant Ca++ handling. In addition, upon exposure to toxic stimuli, increased mitochondrial release of cytochrome C and activation of caspase-9 and caspase-3 are found in HD cells and tissue. Here we report that HTRA2 and Smac/DIABLO, two additional mitochondrial pro-apoptotic factors, are aberrantly released from brain-derived cells expressing mutant huntingtin. This event causes a reduction in levels of the cytosolic IAP1 (Inhibitor of Apoptosis Protein-1) and XIAP (X-linked inhibitor apoptosis) antiapoptotic IAP family members. Reduced IAP levels are also found in post-mortem HD brain tissue. Treatment with ucf101, a serine protease HTRA2 specific inhibitor, counteracts IAPs degradation in HD cells and increases their survival. These results point to the IAPs as potential pharmacological targets in Huntington's Disease.

Objectives: Currently, headache, nausea/vomiting, visual changes, and altered mental status are accepted as indications for the evaluation of hydrocephalus in children; while dementia, gait apraxia, and urinary incontinence remain indications in the elderly. The clinical presentation of hydrocephalus in young and middle-aged adults remains poorly described. Hence, middle-aged patients with mild gait, cognitive, or urinary symptoms unaccompanied by clear exam findings often remain undiagnosed and untreated., Methods: We report the clinical presentation, treatment, and outcomes of 46 adults (ages 16-55 years) presenting with congenital, acquired, or idiopathic hydrocephalus with imaging-documented ventriculomegaly and elevated CSF pressure., Results: Primary symptoms were related to gait (70%), cognition (70%), urinary urgency (48%), and headaches (56%). Eighty-four percent complained of impaired job performance. The exam findings were subtle or absent (no gait apraxia, minor gait changes in 42.9%, mildly abnormal Mini Mental State exams in only 14.3%, and incontinence in only 3.6%). Twenty-nine patients underwent ventriculoperitoneal (VP) shunting, and 11 endoscopic third ventriculostomy, of whom six subsequently required a VP shunt. Symptomatic improvement was observed in 93% of patients 16+/- 11 months after shunting (56% complete resolution, 37% partial resolution). Patients had been followed for their symptoms an average of 6 years (range, 1-30) prior to diagnosis., Discussion: We propose that there exists a clinically distinct syndrome of hydrocephalus in young and middle-aged adults (SHYMA) that comprises hydrocephalus of all etiologies. SHYMA is characterized by complaints of impaired gait, cognition, bladder control, and headaches, with a discrepancy between the prominence of symptoms and the subtlety of clinical signs. Despite the subtlety of clinical signs, CSF diversion treatment is effective at resolving symptomatology.

Background: The risks associated with implanting a cerebrospinal fluid (CSF) shunt in immunocompromised patients with ongoing CSF infection have historically discouraged surgeons from implanting CSF shunts in patients with HIV and cryptococcal meningitis. However, this patient population often requires frequent lumbar punctures to manage elevated intracranial pressure (ICP) secondary to cryptococcal infection. To date, only 7 cases of ventriculoperitoneal (VP) shunting for the treatment of intracranial hypertension in patients with HIV-associated cryptococcal meningitis have been reported. Few of these reports have included outcomes more than 3 months postsurgery. It remains unclear if VP shunts are an effective long-term treatment of intracranial hypertension in this patient population., Case Descriptions: Two patients with HIV/AIDS (CD4 counts of 8 and 81 cells/mm(3)) presented with altered mental status, visual changes, florid cryptococcal meningitis, and elevated ICP (>500 mm CSF) without evidence of hydrocephalus on computed tomography scan. Both patients experienced rapid reversal of symptoms with external lumbar CSF drainage, and remained lumbar drain-dependent after 2 weeks of amphotericin B and flucytosine therapy. Despite evidence of unresolved cryptococcal meningitis, each patient underwent implantation of a VP shunt without complication and was discharged on lifetime fluconazole therapy. They remained asymptomatic at 12 and 16 months after surgery without evidence of shunt infection or malfunction., Conclusion: Patients with intracranial hypertension and HIV-associated cryptococcal meningitis who cannot tolerate cessation of external lumbar CSF drainage or frequent lumbar punctures may be considered for VP shunt placement despite severe immunosuppression and persistent CSF cryptococcal infection.

Objective and Importance: "Silent" somatotrophinomas are very rare, typically large pituitary adenomas that present with mild or no acromegalic features despite positive immunostaining for growth hormone and autonomous (nonglucose-suppressible) growth hormone secretion. Because of this, they may be amenable to treatment with somatostatin analogues., Clinical Presentation: We report a giant somatotrophinoma (7 cm in maximal diameter) in a young woman with 6 years of amenorrhea who had no clinical features of acromegaly despite frankly elevated serum insulin-like growth factor 1 level at the time of diagnosis. Immunohistochemistry revealed focal strong positive staining for growth hormone in only 10% of the surgical specimen. Mutations in exons 8 or 9 of GNAS1, which are present in 40% of somatotrophinomas, were absent in the surgical specimen. The patient's clinical, biochemical, and radiological presentation is described and is compared with previously reported cases of silent somatotrophinomas., Intervention: Because of the size and visual symptomatology, partial resection was performed via a transcranial approach. External adjuvant beam radiotherapy was used. As insulin-like growth factor 1 levels remained elevated, treatment with somatostatin analogue is being pursued., Conclusion: This case represents one of the largest somatotrophinomas described to date, and it demonstrates that serum insulin-like growth factor 1 should be measured even in the absence of acromegalic features in patients presenting with apparently nonsecreting macroadenomas. In addition to surgery and radiotherapy, somatostatin analogues may play an important role in controlling tumor growth.