Raj Murali

High-dose intraarterial verapamil in the treatment of cerebral vasospasm after aneurysmal subarachnoid hemorrhage

OBJECT Because oral calcium channel blockers appear to reduce the severity of cerebral vasospasm after aneurysmal subarachnoid hemorrhage (SAH), interest in their application intraarterially has emerged for cases in which noninvasive means of alleviating vasospasm are unsuccessful. Studies to date have been limited to the administration of low intraarterial doses because of concerns about hemodynamic stability and changes in intracranial pressure. These doses, although effective in cases of milder vasospasm, were inadequate in severe cases. The authors present a series of 10 patients with cerebral vasospasm who underwent 12 procedures in which they received > or = 20 mg of intraarterial verapamil per procedure. METHODS A retrospective review was undertaken of all patients who underwent endovascular treatment for cerebral vasospasm due to aneurysmal SAH by the senior author between February 2005 and October 2006. Ten patients were identified who had undergone a total of 12 procedures during which > or =20 mg of intraarterial verapamil had been administered. From angiography reports, anesthesia records, and nursing records, we obtained pre- and postverapamil mean arterial blood pressures (MABPs), heart rates, intracranial pressures (ICPs) (when available), and visible changes in the degree of vasospasm. RESULTS No statistically significant changes in MABP, heart rate, or ICP were observed after administration of > or = 20 mg of intraarterial verapamil, and the degree of improvement in vasospasm was statistically significant based on our grading system. No correlation was found between the change in hemodynamic parameters and the total dose of verapamil. CONCLUSIONS This study indicates that high-dose intraarterial verapamil may be used to treat cerebral vasospasm without compromising hemodynamic stability or increasing ICP.

Glioblastoma: Molecular Pathways, Stem Cells and Therapeutic Targets

Glioblastoma (GBM), a WHO-defined Grade IV astrocytoma, is the most common and aggressive CNS malignancy. Despite current treatment modalities, the survival time remains dismal. The main cause of mortality in patients with this disease is reoccurrence of the malignancy, which is attributed to treatment-resistant cancer stem cells within and surrounding the primary tumor. Inclusion of novel therapies, such as immuno- and DNA-based therapy, may provide better means of treating GBM. Furthermore, manipulation of recently discovered non-coding microRNAs, some of which regulate tumor growth through the development and maintenance of GBM stem cells, could provide new prospective therapies. Studies conducted by The Cancer Genome Atlas (TCGA) also demonstrate the role of molecular pathways, specifically the activated PI3K/AKT/mTOR pathway, in GBM tumorigenesis. Inhibition of the aforementioned pathway may provide a more direct and targeted method to GBM treatment. The combination of these treatment modalities may provide an innovative therapeutic approach for the management of GBM.

Aeromonas Meningitis Complicating Medicinal Leech Therapy

Medicinal leeches have an important and expanding role in medicine, but infection can complicate their use. We describe a unique case of Aeromonas meningitis associated with the use of leech therapy to salvage a skin flap after central nervous system surgery.

Arachnoid cyst of the cerebellopontine angle manifesting as contralateral trigeminal neuralgia: case report.

A case of an arachnoid cyst in the cerebellopontine angle manifesting as contralateral trigeminal neuralgia is presented. Decompression and excision of the lesion resulted in total relief of symptoms. The possible causes of contralateral trigeminal neuralgia are briefly reviewed, and the surgical treatment of this entity is discussed.

Human Mesenchymal Stem Cells Modulate Inflammatory Cytokines after Spinal Cord Injury in Rat

Transplantation of mesenchymal stem cells (MSC) improves functional recovery in experimental models of spinal cord injury (SCI); however, the mechanisms underlying this effect are not completely understood. We investigated the effect of intrathecal implantation of human MSC on functional recovery, astrogliosis and levels of inflammatory cytokines in rats using balloon-induced spinal cord compression lesions. Transplanted cells did not survive at the lesion site of the spinal cord; however, functional recovery was enhanced in the MSC-treated group as was confirmed by the Basso, Beattie, and Bresnahan (BBB) and the flat beam test. Morphometric analysis showed a significantly higher amount of remaining white matter in the cranial part of the lesioned spinal cords. Immunohistochemical analysis of the lesions indicated the rearrangement of the glial scar in MSC-treated animals. Real-time PCR analysis revealed an increased expression of Irf5, Mrc1, Fgf2, Gap43 and Gfap. Transplantation of MSCs into a lesioned spinal cord reduced TNFα, IL-4, IL-1β, IL-2, IL-6 and IL-12 and increased the levels of MIP-1α and RANTES when compared to saline-treated controls. Intrathecal implantation of MSCs reduces the inflammatory reaction and apoptosis, improves functional recovery and modulates glial scar formation after SCI, regardless of cell survival. Therefore, repeated applications may prolong the beneficial effects induced by MSC application.

Distinct signaling mechanisms of mTORC1 and mTORC2 in glioblastoma multiforme: a tale of two complexes.

Mechanistic target of rapamycin (mTOR) is a serine-threonine kinase that functions via two multiprotein complexes, namely mTORC1 and mTORC2, each characterized by different binding partners that confer separate functions. mTORC1 function is tightly regulated by PI3-K/Akt and is sensitive to rapamycin. mTORC2 is sensitive to growth factors, not nutrients, and is associated with rapamycin-insensitivity. mTORC1 regulates protein synthesis and cell growth through downstream molecules: 4E-BP1 (also called EIF4E-BP1) and S6K. Also, mTORC2 is thought to modulate growth factor signaling by phosphorylating the C-terminal hydrophobic motif of some AGC kinases such as Akt and SGK. Recent evidence has suggested that mTORC2 may play an important role in maintenance of normal as well as cancer cells by virtue of its association with ribosomes, which may be involved in metabolic regulation of the cell. Rapamycin (sirolimus) and its analogs known as rapalogues, such as RAD001 (everolimus) and CCI-779 (temsirolimus), suppress mTOR activity through an allosteric mechanism that acts at a distance from the ATP-catalytic binding site, and are considered incomplete inhibitors. Moreover, these compounds suppress mTORC1-mediated S6K activation, thereby blocking a negative feedback loop, leading to activation of mitogenic pathways promoting cell survival and growth. Consequently, mTOR is a suitable target of therapy in cancer treatments. However, neither of these complexes is fully inhibited by the allosteric inhibitor rapamycin or its analogs. In recent years, new pharmacologic agents have been developed which can inhibit these complexes via ATP-binding mechanism, or dual inhibition of the canonical PI3-K/Akt/mTOR signaling pathway. These compounds include WYE-354, KU-003679, PI-103, Torin1, and Torin2, which can target both complexes or serve as a dual inhibitor for PI3-K/mTOR. This investigation describes the mechanism of action of pharmacological agents that effectively target mTORC1 and mTORC2 resulting in suppression of growth, proliferation, and migration of tumor and cancer stem cells.

Percutaneous Balloon Compression for the Treatment of Recurrent Trigeminal Neuralgia: Long-Term Outcome in 29 Patients

Objective: To analyze the long-term clinical outcomes and complication rates associated with percutaneous balloon compression (PBC) of the trigeminal ganglion in patients with recurrent trigeminal neuralgia (TN) who were treated surgically with procedures other than PBC. Methods: In this retrospective study, the authors reviewed the results of 29 patients who underwent 41 PBC procedures for recurrent TN between 1998 and 2006. Results: The overall mean length of follow-up was 49 months (range 1–101). Pain relief was immediate in 24 (83%) patients. There was no pain relief in 5 patients (17%). 2 patients were lost to follow-up. 12 (54.5%) of 22 patients remained pain-free during a mean follow-up period of 65 months (range 40–101). The other 10 patients (45.5%) who had immediate pain relief experienced recurrent pain, with a mean time to recurrence of 7.3 months (17 days to 38 months). PBC was repeated in 11 patients, and was performed a third time in 2 patients. Morbidities included minor dysesthesia (2 patients), masseter weakness (2 patients), corneal anesthesia (1 patient), anesthesia dolorosa (1 patient), and subarachnoid hemorrhage (1 patient with history of multiple myeloma). Conclusion: PBC is a useful treatment for patients with recurrent TN who have already been treated surgically. Long-term relief of pain in this subset of TN patients is achieved nearly half of the time with side-effect profiles similar to those reported in published data.

Hyponatremia and cerebrovascular spasm in aneurysmal subarachnoid hemorrhage

Background: Hyponatremia develops in approximately a third of patients with aneurysmal subarachnoid hemorrhage (SAH). Studies have been conflicting about the association between hyponatremia and cerebrovascular spasm (CVS). Aims: To investigate whether hyponatremia can signal the onset of CVS. Settings and Design: Retrospective chart review of all patients with SAH treated at a tertiary-care university hospital from January to May 2002. Materials and Methods: 106 patients were included in the study. Serum sodium levels were recorded from days 1 to 14 of hospitalization. Hyponatremia was defined as serum sodium level 4 meq/l from the admission sodium level. The presence of CVS was determined by transcranial doppler sonography. Patients were assigned to one of four groups based on the presence or absence of CVS and hyponatremia. Statistical Analysis: Students t-test was used for comparison of means. A logistical regression model was constructed and odds ratios (OR) were calculated. Results: 41 patients developed hyponatremia and 44 developed CVS. Among the 41 with hyponatremia, 22 (54%) had evidence of CVS, whereas among the 65 patients without hyponatremia, 22 (34%) had evidence of CVS ( P =0.023). Among those with hyponatremia, the mean sodium drop was 7.9 meq/L in those with CVS compared to 7.0 meq/L in those without CVS ( P = 0.068). More than half of those with hyponatremia and CVS (13/22) developed hyponatremia at least a day before CVS was diagnosed. Conclusion: In patients with SAH, hyponatremia is associated with a significantly greater risk of developing CVS and may precede CVS by at least one day.

Chordoma of the Cervical Spine

Eight cases of chordoma limited to the cervical spine are presented. The radiological features are analyzed. Although there is no single diagnostic feature, the combination of osteosclerosis and lysis, multiple vertebral involvement, and the presence of a pre- or paracervical mass is strongly suggestive of a chordoma. Although none of our patients can be considered cured, we recommend an anterior cervical approach with radical removal of the tumor and interbody fusion followed by immobilization in a halo vest and postoperative radiation therapy. The biological behavior of the tumor is extremely variable, and multiple operations for symptomatic recurrences may be helpful.

Stem Cell Therapy and Curcumin Synergistically Enhance Recovery from Spinal Cord Injury

Acute traumatic spinal cord injury (SCI) is marked by the enhanced production of local cytokines and pro-inflammatory substances that induce gliosis and prevent reinnervation. The transplantation of stem cells is a promising treatment strategy for SCI. In order to facilitate functional recovery, we employed stem cell therapy alone or in combination with curcumin, a naturally-occurring anti-inflammatory component of turmeric (Curcuma longa), which potently inhibits NF-κB. Spinal cord contusion following laminectomy (T9–10) was performed using a weight drop apparatus (10 g over a 12.5 or 25 mm distance, representing moderate or severe SCI, respectively) in Sprague-Dawley rats. Neural stem cells (NSC) were isolated from subventricular zone (SVZ) and transplanted at the site of injury with or without curcumin treatment. Functional recovery was assessed by BBB score and body weight gain measured up to 6 weeks following SCI. At the conclusion of the study, the mass of soleus muscle was correlated with BBB score and body weight. Stem cell therapy improved recovery from moderate SCI, however, it had a limited effect on recovery after severe SCI. Curcumin stimulated NSC proliferation in vitro, and in combination with stem cell therapy, induced profound recovery from severe SCI as evidenced by improved functional locomotor recovery, increased body weight, and soleus muscle mass. These findings demonstrate that curcumin in conjunction with stem cell therapy synergistically improves recovery from severe SCI. Furthermore, our results indicate that the effect of curcumin extends beyond its known anti-inflammatory properties to the regulation of stem cell proliferation.