Amol Raheja

Serum biomarkers as predictors of long-term outcome in severe traumatic brain injury: analysis from a randomized placebo-controlled Phase II clinical trial

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 ).

Dose-dependent facilitation of peripheral nerve regeneration by bone marrow–derived mononuclear cells: a randomized controlled study

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.

Middle Fossa Approach for Vestibular Schwannoma: Good Hearing and Facial Nerve Outcomes with Low Morbidity

OBJECTIVE The middle fossa approach (MFA) is not used as frequently as the traditional translabyrinthine and retrosigmoid approaches for accessing vestibular schwannomas (VSs). Here, MFA was used to remove primarily intracanalicular tumors in patients in whom hearing preservation is a goal of surgery. METHODS A retrospective chart review was performed to identify consecutive adult patients who underwent MFA for VS. Demographic profile, perioperative complications, pre- and postoperative hearing, and facial nerve outcomes were analyzed with linear regression analysis to identify factors predicting hearing outcome. RESULTS Among 78 identified patients (mean age, 49 years; 53% female; mean tumor size, 7.5 mm), 78% had functional hearing preoperatively (American Academy of Otolaryngology-Head and Neck Surgery class A/B). Follow-up audiologic data were available for 60 patients overall (mean follow-up, 15.1 months). The hearing preservation rate was 75.5% (37/49) at last known follow-up for patients with functional hearing preoperatively. Other than preoperative hearing status (P < 0.001), none of the factors assessed, including demographic profile, size of tumor, and fundal fluid cap, predicted hearing preservation (P > 0.05). Good functional preservation of the facial nerve (House-Brackmann class I/II) was achieved in 90% of patients. The only operative complications were 3 wound infections (3.8%). CONCLUSIONS Preliminary results from this single-center retrospective study of patients undergoing MFA for resection of VS showed that good hearing preservation and facial nerve outcomes could be achieved with few complications. These results suggest that resection via the MFA is a rational alternative to watchful waiting or stereotactic radiosurgery.

Decompressive craniectomy in traumatic brain injury: A single-center, multivariate analysis of 1,236 patients at a tertiary care hospital in India

OBJECT To evaluate the outcome of patients undergoing a decompressive craniectomy (DC) in traumatic brain injury (TBI) and the factors predicting outcome. MATERIALS AND METHODS A total of 1,236 patients with TBI operated with a DC from January 2008 to December 2013 at a tertiary care hospital were included in the study. The data from the hospital computerized database was retrospectively analyzed and 324 (45%) patients were followed-up for a mean duration of 25.3 months (range 3-42 months) among the cohort of 720 alive patients. The institutes ethical committee clearance was obtained before the start of the study. RESULTS There were 81% males with a median age [interquartile range (IQR)] of 32 (23-45) years. The mortality rate and median (IQR) Glasgow outcome score (GOS) at discharge in patients presenting with minor, moderate, and severe head injury were 18%, 5 (4-5); 28%, 4 (1-5); and 47.4%, 2 (1-4), respectively. An overall favorable outcome (GOS 4 and 5) at discharge was observed in 46.5% patients and in 39% patients who presented with severe TBI. Only 7.5% patients were in a persistent vegetative state (PVS), while 78% had an overall favorable outcome at the last follow-up of surviving patients (P < 0.001). On multivariate analysis, the factors predictive of a favorable GOS at discharge were: a younger age (odds ratio (OR) 1.03, confidence interval (CI) = 1.02-1.04; P < 0.001), no pupillary abnormalities at admission (OR 2.28, CI = 1.72-3.02; P < 0.001), absence of preoperative hypotension (OR 1.91, CI = 1.08-3.38; P = 0.02), an isolated TBI (OR 1.42, CI = 1.08-1.86; P = 0.01), absence of a preoperative infarct (OR 3.68, CI = 1.74-7.81; P = 0.001), presence of a minor head injury (OR 6.33, CI = 4.07-9.86; P < 0.001), performing a duraplasty (OR 1.86, CI = 1.20-2.87; P = 0.005) rather than a slit durotomy (OR 3.95, CI = 1.67-9.35; P = 0.002), and, avoidance of a contralateral DC (OR 3.58, CI = 1.90-6.73; P < 0.001). CONCLUSIONS The severity of head injury, performing a duraplasty rather than a slit durotomy, avoidance of a contralateral DC, and the presence of preoperative hypotension, infarct, and/or pupillary asymmetry have the highest odds of predicting the short term GOS at the time of discharge, after a DC in patients with TBI. Although DC carries a high risk of mortality, the probability of the survivors having a favorable outcome is significantly more as compared to those who remain in a PVS.

Primary Intracranial Epidermoid Carcinoma with Diffuse Leptomeningeal Carcinomatosis: Report of Two Cases.

BACKGROUND Malignant degeneration of epidermoid cyst (EC) with accompanying leptomeningeal carcinomatosis (LC) at presentation is extremely rare. We add two cases to the literature, including the first case of primary brainstem involvement with simultaneous diffuse LC, and discuss clinical and radiological cues to differentiate benign and malignant epidermoid tumors for early diagnosis. CASE DESCRIPTION The first patient in this report was a 54-year-old woman with recurrent aseptic meningitis and hydrocephalus. Imaging revealed a prepontine and parapontine extra-axial EC with an intra-axial brainstem ring-enhancing cystic lesion, diffuse leptomeningeal enhancement, and intradural extramedullary nodular deposits throughout the spine. Surgical decompression of the cysts confirmed the diagnosis of invasive primary squamous cell carcinoma of the brainstem and benign epidermoid tumor of the cerebellopontine cistern. The second patient was a 37-year-old woman with extensive left-sided cranial neuropathies. Imaging revealed prepontine and parapontine enhancing and nonenhancing deposits along multiple cranial nerves and diffuse leptomeningeal nodular enhancement in the thoracolumbar spine. A biopsy confirmed the diagnosis of infiltrative, poorly differentiated carcinoma adjacent to a benign EC. Both patients underwent systemic screening to rule out metastatic disease. CONCLUSIONS These cases illustrate that a high index of clinical suspicion is necessary for early diagnosis of disseminated disease in cases of recurrent episodes of aseptic meningitis. In cases of primary benign EC, aggressive resection should be attempted to reduce the risk of malignant degeneration. A separate biopsy specimen from the enhancing portion of the tumor is used to rule out an underlying coexisting malignancy. Multimodal management carries the best prognosis for primary intracranial squamous cell carcinoma with LC.

Initial experience of using high field strength intraoperative MRI for neurosurgical procedures.

We report our initial experience to optimize neurosurgical procedures using high field strength intraoperative magnetic resonance imaging (IOMRI) in 300 consecutive patients as high field strength IOMRI rapidly becomes the standard of care for neurosurgical procedures. Three sequential groups (groups A, B, C; n=100 each) were compared with respect to time management, complications and technical difficulties to assess improvement in these parameters with experience. We observed a reduction in the number of technical difficulties (p<0.001), time to induction (p<0.001) and total anesthesia time (p=0.007) in sequential groups. IOMRI was performed for neuronavigation guidance (n=252) and intraoperative validation of extent of resection (EOR; n=67). Performing IOMRI increased the EOR over and beyond the primary surgical attempt in 20.5% (29/141) and 18% (11/61) of patients undergoing glioma and pituitary surgery, respectively. Overall, EOR improved in 59.7% of patients undergoing IOMRI (40/67). Intraoperative tractography and real time navigation using re-uploaded IOMRI images (accounting for brain shift) helps in intraoperative planning to reduce complications. IOMRI is an asset to neurosurgeons, helping to augment the EOR, especially in glioma and pituitary surgery, with no significant increase in morbidity to the patient.

Dramatic radiographic response resulting in cerebrospinal fluid rhinorrhea associated with sunitinib therapy in recurrent atypical meningioma: case report

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.

Clinical Outcomes with Transcranial Resection of the Tuberculum Sellae Meningioma

BACKGROUND The tuberculum sellae is a relatively common location for meningiomas. We assessed our experience with the use of transcranial resection, which, although criticized for its more invasive nature compared with endonasal approaches, may be the ideal approach in selected patients with tuberculum sellae meningiomas (TSMs). METHODS We retrospectively reviewed the charts of patients with TSMs treated by frontotemporal or bifrontal open cranial resection. Clinical, radiographic, and surgical variables were analyzed. RESULTS Forty-nine patients with a TSM treated by frontotemporal or bifrontal open cranial resection were identified. The mean patient age was 53.2 ± 14.0 years, and the mean duration of follow-up was 42.3 ± 45.4 months. The mean tumor volume was 12.4 ± 18.0 cm3. Optic canal invasion was seen in 46.9% of the patients, and 91.8% presented with visual deficits. Gross total resection (GTR) was achieved in 42 patients (85.7%), and near-total resection was performed in 7 patients (14.3%). Postoperatively, visual outcomes improved in 17 patients (34.7%), remained stable in 22 (44.9%), were intact in 6 (12.2%), and worsened in 1 (2.0%). Good outcome (Glasgow Outcome Scale [GOS] ≥4) was achieved by 46 of 49 patients (93%) at discharge and by 39 of 41 patients (95.1%) at 6 months. A total of 16 manageable and self-limiting complications occurred in 16 patients. CONCLUSIONS In most patients undergoing a frontotemporal approach, a GTR/Simpson grade I resection with manageable and self-limiting surgical complications, a good 6-month GOS in most patients, and improved to stable vision were seen at follow-up. Various treatment approaches can be considered for TSM resection, but the ability to decompress the optic canal and achieve a GTR makes the frontotemporal approach attractive in many cases.

Sellar Wegener Granulomatosis Masquerading as Cabergoline-Resistant Prolactinoma.

BACKGROUND Pituitary manifestation of Wegener granulomatosis (WG) is extremely rare. When there is pituitary involvement, the granulomatous inflammatory lesions involving the pituitary gland may appear several months to years after the primary diagnosis. CASE DESCRIPTION We present a case of a 32-year-old woman who presented with galactorrhea, amenorrhea, and elevated serum prolactin levels. Imaging demonstrated a sellar lesion with characteristics of a pituitary macroadenoma. Treatment with cabergoline was initiated, but the tumor continued to grow during a 6-month period. Subsequent surgical exploration revealed a chronic inflammatory lesion; the patient subsequently was diagnosed with WG based on laboratory evaluation and further systemic manifestations. She had a favorable clinical and radiologic response with immunosuppressive doses of glucocorticoids and rituximab. CONCLUSIONS This case appears to be the first reported of a patient with unknown WG in whom the diagnosis was established after she presented with a sellar lesion mimicking a prolactin-secreting pituitary adenoma on initial presentation requiring surgical resection. The only endocrine abnormality discovered was moderate hyperprolactinemia. Sellar lesions with only moderate elevations in serum prolactin, particularly those that are refractory to medical management with a dopamine agonist, should prompt further investigation to confirm the diagnosis. WG should be part of the differential diagnosis of inflammatory lesions in the sella, the identification of which can facilitate early diagnosis and treatment of this systemic disease for optimal outcome.

Primary spinal extraosseous cervical chondroma in an adult.

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