Ashish Suri

Effect of intramedullary signal changes on the surgical outcome of patients with cervical spondylotic myelopathy.

BACKGROUND CONTEXT Intramedullary signal intensity changes on magnetic resonance imaging (MRI) in cervical spondylotic myelopathy are thought to be indicative of the prognosis. However, the prognostic significance of signal intensity changes remains controversial. PURPOSE To determine the radiographic and clinical factors that correlate with the prognosis after surgery in patients with cervical spondylotic myelopathy and to investigate the factors affecting the outcome of intramedullary signal changes on MRI. STUDY DESIGN A prospective study evaluating clinical parameters and MRI in consecutive patients operated on for cervical spondylotic myelopathy. PATIENT SAMPLE A total of 146 consecutive patients with cervical spondylotic myelopathy operated on during a 2-year period (September 1999 to September 2001) formed the study group. OUTCOME MEASURES Age, duration of symptoms, number of cervical prolapsed intervertebral discs, surgical approach, preoperative signal changes, residual compression and postoperative outcome of signal changes; clinical outcome (motor, sensory, autonomic and disability improvement). METHODS The participants in this study underwent anterior cervical discectomy/corpectomy or laminectomy/laminoplasty for cervical spondylotic myelopathy. Clinical features and MRI findings were studied in detail and compared with postoperative clinical and radiological status. The spinal cord signal intensity changes were evaluated before and after surgery. The multifactorial effect of such variables as age, duration of symptoms, number of prolapsed intervertebral discs, surgical approach (anterior/posterior), preoperative cord changes on T1- and T2-weighted sequences and persistence/regression of cord changes on clinical outcome (motor/sensory/autonomic/disability improvement) was studied using stepwise logistic regression. The highlight of the study is the analysis of the factors affecting regression of cord changes and their effect on postoperative outcome. RESULTS Preoperative intramedullary signal changes were present in 121 of 146 patients (82.9%); of these 121 patients, T1- and T2-weighted images were present in 81, and T2-weighted images were present in 40 (no patient had isolated T1 change). Postoperative MRI could be obtained in 44 of 121 patients (36.4%) with preoperative intramedullary signal changes; 14 had regression of cord changes. There was no significant difference in the clinical presentation of patients with and without cord changes. There was a significant correlation between the surgical outcome of patients and their age, duration of symptoms, number of cervical prolapsed intervertebral discs, surgical approach, preoperative signal changes, residual compression and postoperative outcome of signal changes. The patients with no intramedullary signal changes and signal changes only on T2-weighted images had a better outcome than patients with signal changes on both T1- and T2-weighted images. The patients with regression of intramedullary signal changes had significantly better outcome. There was no significant correlation between regression of signal changes and other factors. However, chronicity of disease, multiplicity of discs and postoperative residual compression relatively affect persistence of intramedullary signal changes. CONCLUSIONS The presence of intramedullary signal changes on T1- as well as T2-weighted sequences on MRI in patients with cervical spondylotic myelopathy indicates a poor prognosis. However, the T2 signal intensity changes reflect a broad spectrum of spinal cord reparative potentials. Predictors of surgical outcomes are preoperative signal intensity change patterns of the spinal cord and their postoperative persistence/regression on radiological evaluations, age at the time of surgery, multiplicity of involvement and chronicity of the disease and surgical approach (anterior/posterior).

Pediatric glioblastomas: A histopathological and molecular genetic study

Glioblastoma multiforme (GBM) occurs rarely in children. Relatively few studies have been performed on molecular properties of pediatric GBMs. Our objective in this study was to evaluate the genetic alterations in pediatric GBM (age < or = 18 years) with special reference to p53, p16, and p27 protein expression, alterations of the epidermal growth factor receptor (EGFR), and deletion of the phosphate and tensin homolog gene (PTEN). Thirty cases of childhood GBMs reported between January 2002 and June 2007 were selected, and slides stained with hematoxylin and eosin were reviewed. Immunohistochemical staining was performed for EGFR, p53, p16, and p27, and tumor proliferation was assessed by calculating the MIB-1 labeling index (LI). Fluorescence in situ hybridization analysis was performed to evaluate for EGFR amplification and PTEN deletion. Histopathological features and MIB-1 LI were similar to adult GBMs. p53 protein expression was observed in 63%. Although EGFR protein overexpression was noted in 23% of cases, corresponding amplification of the EGFR gene was rare (5.5%). Deletion of the PTEN gene was also equally rare (5.5%). One case showed polysomy (chromosomal gains) of chromosomes 7 and 10. Loss of p16 and p27 immunoexpression was observed in 68% and 54% of cases, respectively. In pediatric de novo/primary GBMs, deletion of PTEN and EGFR amplification are rare, while p53 alterations are more frequent compared to primary adult GBMs. Frequency of loss of p16 and p27 immunoexpression is similar to their adult counterparts. This suggests that pediatric malignant gliomas are distinctly different from adult GBMs, highlighting the need for identification of molecular targets that may be adopted for future novel therapeutic strategies.

Anterior Encephaloceles: A Study of 92 Cases

Anterior encephalocele is a rare condition, and only a few large series have been published in the literature. Surprisingly, the incidence is much higher in Southeast Asian countries, including some parts of India. While the reported incidence in the West is between 1:35,000 and 1:40,000 live births, it is as high as 1:5,000 live births in Thailand. We present a series comprising 92 cases of anterior encephaloceles treated over a 30-year period (1971–2000). Frontoethmoidal encephaloceles are the commonest type, followed by the nasopharyngeal and orbital type. Among the frontoethmoidal encephaloceles, nasoethmoid is the commonest type, and these patients present with swelling over the bridge of the nose with significant hypertelorism and orbital deformities. The nasopharyngeal type remains occult and presents with nasal obstruction or CSF rhinorrhea. Rarely, the patient may present with meningitis. Since 1978, computed tomography (CT) scans have regularly been performed in our patients. CT scans delineate the skull defect and associated brain anomalies. There was associated hydrocephalus present in 12 patients and agenesis of the corpus callosum in 5 patients. In all patients, one-stage repair of the encephalocele and correction of bony anomalies by appropriate osteotomy was undertaken. Since 1988, in cases of frontoethmoidal encephalocele with significant hypertelorism, medial advancement of the medial half of the orbits on either sides was carried out, instead of a classical Tessier’s operation. Postoperative morbidity included CSF leak in 20 patients, wound infection in 2 and chest infection in 3. There were 3 deaths in our study. The overall cosmetic outcome was good.

Surgical management of giant intracranial aneurysms.

OBJECTIVES The natural history of giant intracranial aneurysms is generally morbid. Mortality and morbidity associated with giant aneurysms is also higher than for smaller aneurysms. This study was carried out to assess the demographic profile, presenting features, complications, and outcome after surgical treatment of giant intracranial aneurysms. PATIENTS AND METHODS A retrospective review of the medical records of all patients with giant intracranial aneurysms treated in the Department of Neurosurgery, Neurosciences Centre, All India Institute of Medical Sciences, New Delhi, from January 1995 through June 2007 was performed. The demographic profiles, presenting features, radiological findings, surgical treatments, and outcomes were assessed. RESULTS A total of 1412 patients harboring 1675 aneurysms were treated. Out of these, 222 patients had 229 (13.7%) giant aneurysms, and of those, 181 aneurysms in 177 patients were managed surgically while 48 were treated with endovascular therapy. In the patients treated with surgery, common clinical presentations included subarachnoid hemorrhage (SAH) in 110 (62%) cases followed by mass effect in 57 (32%) cases. In patients who presented with SAH, the Hunt and Hess SAH grading was: grade I in 43 (39%), grade II in 40 (36%), grade III in 23 (21%), grade IV in two (2%), and grade V in 2 (2%) patients. One hundred and seven aneurysms (in 103 patients) were treated using direct surgical clipping. Forty-six patients with good collateral circulation were treated by gradual occlusion and ligation of the internal carotid artery (ICA) in the neck with a Silverstone clamp. Another nine patients with good collateral circulation, but persisting symptoms after ICA ligation, required trapping for obliteration of the aneurysm. Eleven patients with poor collateral circulation required extracranial-intracranial (EC-IC) bypass before proximal ICA ligation. A post-operative digital subtraction angiography (DSA) was performed in 118 patients and revealed well-obliterated aneurysm in 106 patients. The total treatment mortality rate was 9%. In the last 5 years, 117 patients were operated on with four operative deaths. Overall, the outcome was excellent in 131 (74.0%), good in 22 (12.4%), and poor in eight (4.5%) cases. CONCLUSIONS It is concluded that 14% of all intracranial aneurysms are giant. The most common clinical presentation is SAH followed by features of an intracranial mass lesion. The cavernous ICA is the most common portion of the ICA affected. Direct surgical clipping is a safe and effective method of treatment and should be considered the first line of treatment whenever possible. With proper case selection, optimal radiological evaluation, and appropriate surgical strategy, it is possible to achieve a favorable outcome in almost 90% of the cases.

Effect of bone marrow-derived mononuclear cells on nerve regeneration in the transection model of the rat sciatic nerve

Bone marrow-derived stem cells enhance the rate of regeneration and clinical improvement in nerve injury, spinal cord injury and brain infarction. Recent experiments in rat spinal cord demyelination showed that remyelination was specific to intravenous delivery of the bone marrow-derived mononuclear cell (BM-MNC) fraction, although the specific role of this fraction in peripheral nerve regeneration has not been examined. Therefore we evaluated the role of BM-MNCs in peripheral nerve regeneration in the rat sciatic nerve transection model. After anesthesia, the right sciatic nerve of 20 adult-male Wistar rats was transected under an operating microscope. In the test group, the cut ends of the nerve were approximated with two epineural microsutures, the gap was filled with rat BM-MNCs and the approximated nerve ends were covered with fibrin glue. In the control group, the transected nerve ends were repaired with two epineural microsutures and fibrin sealant only. Histological assessment of the nerve was performed 30 days and 60 days after the operation and regenerative changes were compared between the two groups. The recovery after nerve anastamosis was far better in the test group at both 30 days and 60 days. There was a statistically significant difference in axonal regeneration, remyelination and myelin thickness at sites 5mm and 10mm from the site of repair of the nerve. Schwann cell proliferation and degenerative changes were more prevalent in the controls. This study demonstrates that local delivery of BM-MNCs (which can be isolated easily from bone marrow aspirates) into injured peripheral nerve increases the rate and degree of nerve regeneration. The present study highlights the role of BM-MNCs in peripheral nerve regeneration.

Comparative study of IDH1 mutations in gliomas by immunohistochemistry and DNA sequencing

BACKGROUND Mutations involving isocitrate dehydrogenase 1 (IDH 1) occur in a high proportion of diffuse gliomas, with implications on diagnosis and prognosis. About 90% involve exon 4 at codon 132, replacing amino acid arginine with histidine (R132H). Rarer ones include R132C, R132S, R132G, R132L, R132V, and R132P. Most authors have used DNA-based methods to assess IDH1 status. Preliminary studies comparing imunohistochemistry (IHC) with IDH1-R132H mutation-specific antibodies have shown concordance with DNA sequencing and no cross-reactivity with wild-type IDH1 or other mutant proteins. The present study compares results of IHC with DNA sequencing in diffuse gliomas. MATERIALS AND METHODS Fifty diffuse gliomas with frozen tissue samples for DNA sequencing and adequate tissue in paraffin blocks for IHC using IDH1-R132H specific antibody were assessed for IDH1 mutations. RESULTS Concordance of findings between IHC and DNA sequencing was noted in 88% (44/50) cases. All 6 cases with discrepancy were immunopositive with DIA-H09 antibody. While in 3 of these 6 cases, DNA sequencing failed to reveal any mutations, R132L (arginine replaced by leucine) mutation was found in the rest 3 cases. Interestingly, of the immunopositive cases, 46.6% (14/30) showed immunostaining in only a fraction of tumor cells. CONCLUSIONS IHC is an easy and quick method of detecting IDH1-R132H mutations, but there may be some discrepancies between IHC and DNA sequencing. Although there were no false-negative cases, cross-reactivity with IDH1-R132L was seen in 3, a finding not reported thus far. Because of more universal availability of IHC over genetic testing, cross-reactivity and staining heterogeneity may have bearing over its use in detecting IDH1-R132H mutation in gliomas.

A clinicopathological and molecular analysis of glioblastoma multiforme with long-term survival.

The median survival time of patients with glioblastoma multiforme (GBM) is 12 months, and only 3-5% of patients survive longer than 3 years. We performed histomorphological and detailed molecular analyses of seven long-term survivors of GBM to identify any prognostic factors that potentially contribute to survival. Morphology and immunohistochemistry for p53, phosphatase and tensin homologue (PTEN) and epidermal growth factor receptor (EGFR) protein expression were investigated. EGFR amplification and 1p/19q deletion were assessed by fluorescent in situ hybridization. The O6-methylguanine-DNA methyltransferase (MGMT) gene methylation status was evaluated by performing methylation-specific polymerase chain reaction assays. All tumors were classical GBMs and no significant oligodendroglial differentiation was noted. The majority showed EGFR amplification (4/7), PTEN protein expression (6/7) and MGMT promoter methylation (5/6). Immunopositivity for p53 was noted in three of seven patients. Deletion of chromosome 1p/19q, either isolated or combined, was not identified in any of the se patients. All patients were treated by gross total resection followed by radiotherapy; six patients received additional temozolomide treatment. A relatively young age of onset (48 years), with a high MGMT promoter methylation and PTEN protein expression were favorable factors for long-term survival. The presence of EGFR amplification indicates that more than a single factor determines survival in GBM.

Primary neurocytoma of the spinal cord: a case report and review of literature

SummaryMost central neurocytomas (CN) and spinal neurocytomas (SN) have a bland well-differentiated histologic picture and uneventful clinical course. However, rare examples showing histologic atypia, recurrence and even CSF dissemination have been reported. Herein we report a case of recurrent spinal neurocytoma in a 24-year-old male who presented with a 2-month history of weakness and numbness of the left upper and lower limbs, and was previously operated at the same site 10 months ago. MRI revealed a contrast enhancing intramedullary mass involving C5-T1 region. Radiologic and operative impression at both surgeries was that of a glioma, possibly anaplastic. Histologic and immunohistochemical features in both resections were those of an atypical neurocytoma. The tumor showed rare mitoses, focal mild vascular proliferation in both specimens, and necrosis in the initial specimen. MIB1 labeling indices were 9 and 10%, respectively. Based on the analysis of this case and limited data from the literature, it is hypothesized that SN shows a histopathologic picture, immunoprofile and biologic behavior very similar to CN. However, the presence of histologic atypia and increased MIB1 index in SN appear to more closely correlate with tumor recurrence and a worse overall outcome, in part due to their location in the critical region of cervical spinal cord. Therefore, we hypothesize that SN with atypia requires a close clinical follow up. As in CN, radiation therapy is perhaps best reserved for atypical, progressive and recurrent SN.

O6-Methylguanine DNA Methyltransferase Gene Promoter Methylation Status in Gliomas and Its Correlation With Other Molecular Alterations: First Indian Report With Review of Challenges for Use in Customized Treatment

BACKGROUND: O6-methylguanine methyltransferase (MGMT) promoter methylation in adult glioblastomas (glioblastoma multiforme) is considered a promising molecular alteration, predictive of better response to temozolomide therapy and longer overall survival. OBJECTIVE: To look at the frequency of MGMT methylation in glial tumors of all grades and types, and correlate this alteration with loss of heterozygosity 1p/19q, TP53 gene mutations, epidermal growth factor receptor (EGFR) amplification, and isocitrate dehydrogenase 1 (IDH1) mutations. METHODS: One hundred two gliomas of various grades and subtypes were assessed by methylation-specific polymerase chain reaction for MGMT promoter methylation status. The results were correlated with 1p/19q status, EGFR amplification, TP53, and IDH1 mutations. RESULTS: There was an inverse correlation of MGMT promoter methylation frequency with tumor grade, observed in 79.4%, 70.8%, and 56.8% of grade II, grade III, and grade IV gliomas, respectively. The difference was statistically significant in grade II vs IV tumors (P = .036). The majority of cases with 1p/19q loss of heterozygosity also showed MGMT methylation, although the association was not significant. There was no significant correlation of MGMT status with IDH1 mutation. In astrocytic tumors, there was no correlation of MGMT methylation with TP53 mutation or EGFR amplification. CONCLUSION: MGMT promoter methylation was observed in a considerable proportion of all grades and subtypes of gliomas, with no significant correlation with other known genetic alterations. On extensive literature review, in both low- and high-grade gliomas, wide variability of data on the frequency of MGMT methylation and its association with other molecular alterations from various centers was noted, mostly owing to technical causes. This raises questions regarding the capacity of this test for use as an objective and reproducible marker for customized treatment in individual cases.

Characterization of molecular genetic alterations in GBMs highlights a distinctive molecular profile in young adults.

To evaluate age-related differences in histopathologic and molecular profile of glioblastomas (GBMs) at various age groups, with special reference to TP53 mutation, epidermal growth factor receptor (EGFR) amplification, EGFR vIII mutant, PTEN deletion, and IDH1 mutation. Agewise GBM incidence was calculated over a period of 5 years (2005 to 2009). Seventy-five GBMs were selected for molecular analysis. Majority of cases were in the age group of 41 to 60 years, and mean age was 43.6 years. Histology of all 75 cases selected for molecular profiling was identical. Primary adult GBMs showed EGFR amplification and PTEN deletion in majority (37.3% and 54.9%, respectively). TP53 and IDH1 mutations were rare (11.8% cases each). In secondary GBMs, TP53 (66.7%) and IDH1 mutations (44.4%) were most frequent. PTEN deletion was seen in 33.3% and none had EGFR amplification. Pediatric GBMs (<18 y) harbored frequent TP53 mutations (46.7%) and PTEN deletion in 40%. IDH1 mutations and EGFR amplification were absent. The molecular profile of primary GBMs in young adults (19 to 40 y) was distinctly different from that of adults older than 40 years. TP53 mutation was present in 20% cases. The frequency of EGFR amplification (13.3%) and PTEN deletion (33.3%) was significantly low (P=0.028 and 0.046, respectively). IDH1 mutation, which is rare in primary adult GBMs, was present in 40% of cases. Molecular heterogeneity exists within GBMs of different age cohorts. The molecular profile of GBMs in young adults is distinctly different. Thus, there is a strong need for further studies in various age groups to provide guidelines for therapeutic targeting.