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Amol Raheja, Howard Colman, Cheryl A. Palmer and William T. Couldwell

Sunitinib is a multiple tyrosine kinase inhibitor with antiangiogenic, cytostatic, and antimigratory activity for meningiomas. A recent clinical trial of sunitinib for treatment of recurrent Grade II and III meningiomas suggested potential efficacy in this population, but only 2 patients exhibited significant radiographic response with tumor volume reduction. The authors illustrate another such case and discuss a complication related to this dramatic tumor volume reduction in aggressive skull base meningiomas.

The authors describe the case of a 39-year-old woman who had undergone repeat surgical interventions and courses of radiotherapy over the previous 11 years for recurrent cranial and spinal meningiomas. Despite 4 operations over the course of 4 years on her right petroclival meningioma with cavernous sinus and jugular fossa extensions, she had progressive neurological deficits and tumor recurrences. The specimen histology progressed from WHO Grade I initially to Grade II at the time of the third recurrence. The lesion was then irradiated 3 times using stereotactic radiosurgery for further recurrences. More recently, the tumor size increased rapidly on imaging, in association with progressive neurological symptoms arising from brainstem compression and vasogenic edema. Institution of sunitinib therapy yielded a dramatic radiographic response, with marked reduction in the tumor volume and reduction of brainstem vasogenic edema within a few weeks of initiation of treatment. The significant radiographic response of tumor in the clival region was also associated with CSF rhinorrhea from a dural breach created by resolution of the invasive skull base meningioma, which necessitated withholding the sunitinib medication. To address the leak, the authors undertook surgical exploration and transsphenoidal packing using an autologous fat graft and a vascularized pedicled nasoseptal flap. The patient has done well during follow-up of 3 months after packing, with no evidence of recurrent CSF leak, and the medication was subsequently restarted.

Prior clinical data and the dramatic radiographic response in this patient suggest that sunitinib holds promising therapeutic potential in carefully selected patients with recurrent atypical meningiomas where conventional strategies have been exhausted. There is a potential risk of associated CSF rhinorrhea, especially in more invasive skull base lesions showing dramatic radiographic response.

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Amol Raheja, Aleksandra Sowder, Cheryl Palmer, Fausto J. Rodriguez and William T. Couldwell

Epstein-Barr virus (EBV)–associated smooth muscle tumors (SMTs) have recently been associated with primary and secondary immunodeficiencies. They are broadly divided into 3 subgroups: HIV-related, posttransplant, and congenital immunodeficiency. Subsequent to organ transplantation and acquired immunosuppression, a few cases of EBV-associated SMTs have been described in the liver, respiratory tract, and gastrointestinal system. To the authors' knowledge, intracranial involvement after peripheral blood stem cell transplantation has never been reported previously. The authors describe the case of a 65-year-old woman who presented with recent-onset painful ophthalmoplegia. She had a prior history of acute myelogenous leukemia requiring allogenic peripheral blood stem cell transplantation 2 years earlier, but she was in a remission phase. Imaging revealed a T1/T2 isointense, homogeneously enhancing lesion of the left cavernous sinus. A presumptive diagnosis of Tolosa-Hunt syndrome was made, and she was treated with steroids; however, her symptoms progressed quickly and repeat imaging revealed that the lesion was growing. To rule out leukemic deposits, a minimally invasive lateral orbitotomy extradural transcavernous approach was performed for biopsy sampling and debulking of the lesion. The biopsied tumor tissue was found to be infiltrative, grayish, firm, and moderately vascular. The final pathology results indicated an EBV-associated SMT of the cavernous sinus. Subsequently, the patient's steroid treatment was stopped and she had obtained partial symptomatic relief at her last follow-up visit, 3 months after surgery. EBV-associated SMT should be included in the differential diagnosis for intracranial and dural-based central nervous system lesions, especially in immunocompromised patients. Paradoxical response to steroids with worsening of symptoms is a hallmark of EBV-associated SMTs.

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Vijay M. Ravindra, Amol Raheja, Heather Corn, Meghan Driscoll, Corrine Welt, Debra L. Simmons and William T. Couldwell

Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma and comprises approximately 30% of all lymphomas. Patients typically present with a nonpainful mass in the neck, groin, or abdomen associated with constitutional symptoms. In this report, however, the authors describe a rare case of a 61-year-old woman with hyperprolactinemia, hypothyroidism, and acromegaly (elevation of insulin-like growth factor-1 [IGF-1]) with elevated growth hormone–releasing hormone (GHRH) in whom an MRI demonstrated diffuse enlargement of the pituitary gland. Despite medical treatment, the patient had persistent elevation of IGF-1. She underwent a transsphenoidal biopsy, which yielded a diagnosis of DLBCL with an activated B-cell immunophenotype with somatotroph hyperplasia. After stereo-tactic radiation therapy in combination with chemotherapy, she is currently in remission from her lymphoma and has normalized IGF-1 levels without medical therapy, 8 months after her histopathological diagnosis. This is the only reported case of its kind and displays the importance of a broad differential diagnosis, multidisciplinary evaluation, and critical intraoperative decision-making when treating atypical sellar lesions.

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Gmaan Alzhrani, Yair M. Gozal, Ilyas Eli, Walavan Sivakumar, Amol Raheja, Douglas L. Brockmeyer and William T. Couldwell

OBJECTIVE

Surgical treatment of pathological processes involving the ventral craniocervical junction (CCJ) traditionally involves anterior and posterolateral skull base approaches. In cases of bilateral extension, when lesions extend beyond the midline to the contralateral side, a unilateral corridor may result in suboptimal resection. In these cases, the lateral extent of the tumor will prevent extirpation of the lesion via anterior surgical approaches. The authors describe a unilateral operative corridor developed along an extreme lateral trajectory to the anterior aspect of the clival and upper cervical dura, allowing exposure and resection of tumor on the contralateral side. This approach is used when the disease involves the bone structures inherent to stability at the anterior CCJ.

METHODS

To achieve exposure of the ventral CCJ, an extreme lateral transcondylar transodontoid (ELTO) approach was performed with transposition of the ipsilateral vertebral artery, followed by drilling of the C1 anterior arch. Resection of the odontoid process allowed access to the contralateral component of lesions across the midline to the region of the extracranial contralateral vertebral artery, maximizing resection.

RESULTS

Exposure and details of the surgical procedure were derived from anatomical cadavers. At the completion of cadaveric dissection, morphometric measurements of the relevant anatomical landmarks were obtained. Illustrative case examples for approaching ventral CCJ chordomas via the ELTO approach are presented.

CONCLUSIONS

The ELTO approach provides a safe and direct surgical corridor to treat complex lesions at the ventral CCJ with bilateral extension through a single operative corridor. This approach can be combined with other lateral approaches or posterior infratemporal approaches to remove more extensive lesions involving the rostral clivus, jugular foramen, and temporal bone.

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Amol Raheja, Sumit Sinha, Neha Samson, Sanjeev Bhoi, Arulselvi Subramanian, Pushpa Sharma and Bhawani Shankar Sharma

OBJECTIVE

There has been increased interest in the potential importance of biochemical parameters as predictors of outcome in severe traumatic brain injury (sTBI).

METHODS

Of 107 patients with sTBI (age 18–65 years with a Glasgow Coma Scale score of 4–8 presenting within 8 hours after injury) who were randomized for a placebo-controlled Phase II trial of progesterone with or without hypothermia, the authors serially analyzed serum biomarkers (S100-B, glial fibrillary acidic protein [GFAP], neuron-specific enolase [NSE], tumor necrosis factor–α, interleukin-6 [IL-6], estrogen [Eg], and progesterone [Pg]). This analysis was performed using the sandwich enzyme-linked immunosorbent assay technique at admission and 7 days later for 86 patients, irrespective of assigned group. The long-term predictive values of serum biomarkers for dichotomized Glasgow Outcome Scale (GOS) score, functional independence measure, and survival status at 6 and 12 months were analyzed using an adjusted binary logistic regression model and receiver operating characteristic curve.

RESULTS

A favorable GOS score (4–5) at 1 year was predicted by higher admission IL-6 (above 108.36 pg/ml; area under the curve [AUC] 0.69, sensitivity 52%, and specificity 78.6%) and Day 7 Pg levels (above 3.15 ng/ml; AUC 0.79, sensitivity 70%, and specificity 92.9%). An unfavorable GOS score (1–3) at 1 year was predicted by higher Day 7 GFAP levels (above 9.50 ng/ml; AUC 0.82, sensitivity 78.6%, and specificity 82.4%). Survivors at 1 year had significantly higher Day 7 Pg levels (above 3.15 ng/ml; AUC 0.78, sensitivity 66.7%, and specificity 90.9%). Nonsurvivors at 1 year had significantly higher Day 7 GFAP serum levels (above 11.14 ng/ml; AUC 0.81, sensitivity 81.8%, and specificity 88.9%) and Day 7 IL-6 serum levels (above 71.26 pg/ml; AUC 0.87, sensitivity 81.8%, and specificity 87%). In multivariate logistic regression analysis, independent predictors of outcome at 1 year were serum levels of Day 7 Pg (favorable GOS—OR 3.24, CI 1.5–7, p = 0.003; and favorable survival—OR 2, CI 1.2–3.5, p = 0.01); admission IL-6 (favorable GOS—OR 1.04, CI 1.00–1.08, p = 0.04); and Day 7 GFAP (unfavorable GOS—OR 0.79, CI 0.65–0.95, p = 0.01; and unfavorable survival—OR 0.80, CI 0.66–0.96, p = 0.01).

CONCLUSIONS

Serial Pg, GFAP, and IL-6 monitoring could aid in prognosticating outcomes in patients with acute sTBI. A cause and effect relationship or a mere association of these biomarkers to outcome needs to be further studied for better understanding of the pathophysiology of sTBI and for choosing potential therapeutic targets.

Clinical trial registration no.: CTRI/2009/091/000893 (http://www.ctri.nic.in).

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Amol Raheja, Vaishali Suri, Ashish Suri, Chitra Sarkar, Arti Srivastava, Sujata Mohanty, Krishan G. Jain, Meher C. Sharma, Hruda N. Mallick, Pradeep K. Yadav, Mani Kalaivani and Ravindra M. Pandey

Object

Bone marrow–derived stem cells enhance the rate of regeneration of neuronal cells leading to clinical improvement in nerve injury, spinal cord injury, and brain infarction. Recent experiments in the local application of bone marrow–derived mononuclear cells (BM-MNCs) in models of sciatic nerve transection in rats have suggested their beneficial role in nerve regeneration, although the effects of variable doses of stem cells on peripheral nerve regeneration have never been specifically evaluated in the literature. In this paper, the authors evaluated the dose-dependent role of BM-MNCs in peripheral nerve regeneration in a model of sciatic nerve transection in rats.

Methods

The right sciatic nerve of 60 adult female Wistar rats (randomized into 2 test groups and 1 control group, 20 rats in each group) underwent transection under an operating microscope. The cut ends of the nerve were approximated using 2 epineural microsutures. The gap was filled with low-dose (5 million BM-MNCs/100 μl phosphate-buffered saline [PBS]) rat BM-MNCs in one group, high-dose (10 million BM-MNCs/100 μl PBS) rat BM-MNCs in another group, and only PBS in the control group, and the approximated nerve ends were sealed using fibrin glue. Histological assessment was performed after 30 days by using semiquantitative and morphometric analyses and was done to assess axonal regeneration, percentage of myelinated fibers, axonal diameter, fiber diameter, and myelin thickness at distal-most sites (10 mm from site of repair), intermediate distal sites (5 mm distal to the repair site), and site of repair.

Results

The recovery of nerve cell architecture after nerve anastomosis was far better in the high-dose BM-MNC group than in the low-dose BM-MNC and control groups, and it was most evident (p < 0.02 in the majority of the parameters [3 of 4]) at the distal-most site. Overall, the improvement in myelin thickness was most significant with incremental dosage of BM-MNCs, and was evident at the repair, intermediate distal, and distal-most sites (p = 0.001).

Conclusions

This study emphasizes the role of BM-MNCs, which can be isolated easily from bone marrow aspirates, in peripheral nerve injury and highlights their dose-dependent facilitation of nerve regeneration.