Chitra Sarkar

AIIMS Bhopal All India Institute of Medical Sciences, Bhopal, Madhya Pradesh, India

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Publications (318)635 Total impact

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    ABSTRACT: Mutations in H3.3-ATRX-DAXX chromatin remodeling pathway have been reported in pediatric GBMs. H3.3 (H3F3A) mutations may affect transcriptional regulation by altered global histone-methylation. Therefore, we analyzed yet partly understood global histone code (H3K-4/9/27/36) trimethylation pattern in H3F3A-ATRX mutants and wild-type. H3F3A, HIST1H3B, IDH1, ATRX, DAXX and Tp53 mutations were identified by sequencing/immunohistochemistry in 27 pediatric GBMs. Global histone-methylation H3K-4/9/27/36me3 and Polycomb-protein EZH2 expression were evaluated by immunohistochemistry. H3F3A-ATRX mutation was observed in 66.7 % (18/27) of pediatric GBMs. K27M and G34R-H3F3A mutations were found in 37 % (10/27) and 14.8 % (4/27) patients respectively. G34V-H3F3A, HIST1H3B and IDH1 mutations were absent. Notably, commonest global histone-methylation mark lost was H3K27me3 (17/25, 68 %) followed by H3K4me3 (45.5 %, 10/22) and H3K9me3 (18.2 %, 4/22). Global H3K36me3 showed no loss. Most significant observation was loss of one or more histone-trimethylation mark in 80 % (20/25) pediatric GBMs. Notably, simultaneous loss of H3K27me3 and H3K4me3 were present in 7/22 (31.8 %) of pediatric GBMs. Low expression of EZH2 was found in 12/24 (50 %) of cases. However no significant correlation of loss of histone-marks or EZH2 expression with H3F3A-ATRX mutants (loss of at least one histone-marks in 87.5 % (14/16) cases) versus wild-types (loss of at least one histone-marks in 75 % (6/8) cases) was seen. The present study highlights for the first time combinatorial loss of one or more histone-trimethylation marks associated with majority of pediatric GBMs and the finding suggests significant role of histone-code in the molecular biology that underlies pediatric GBMs. Hence therapies for patients with particular combinations of histone modifications present opportunity to design innovative patient-tailored treatment protocols.
    Journal of Neuro-Oncology 12/2014; · 3.12 Impact Factor
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    ABSTRACT: Objective F-18 Fluorodeoxyglucose positron emission tomography (FDG-PET) and ictally subtracted single photon emission tomography (iSPECT) are important for localizing the epileptogenic focus. The following study analyzes the role of inter-concordance between FDG-PET and iSPECT in predicting long-term outcomes after epilepsy surgery. Methods We prospectively evaluated (January 2003-January 2008) patients undergoing surgery for temporal or extratemporal drug refractory epilepsy (DRE) who had at least a 5 years follow up. Patients with MRI and video EEG (vEEG) concordance for the seizure focus underwent iSPECT and FDG-PET. Concordance of the iSPECT and FDG-PET with each other and with the substrate (defined by MRI and vEEG) for temporal and extra-temporal epilepsies was evaluated and correlated with outcomes. Results One hundred twenty-three patients (74 males) were included in the study (mean age at time of surgery: 18.9 ± 10.41 years). The mean age of onset of seizures was 9.87 ± 8.37 years. The most common semiology was complex partial (45%). When both FDG-PET and iSPECT were concordant with each other, this translated into a (Class I Engel at 5 years) outcome of 62% for extra-temporal epilepsies (provided they were also concordant with the lesion, as defined by MRI and vEEG). This percentage was significant (p < 0.01) compared with all other situations (both FDG-PET/iSPECT not concordant to MRI/vEEG, only PET or iSPECT concordant with MRI/vEEG). This correlation was not found for the temporal epilepsies, where the MRI and vEEG were the most important prognostic parameters. In both temporal and extratemporal epilepsies the concordance of the iSPECT/FDG-PET with the MRI/vEEG correlated with a better 5-year outcome (Temporal: 70% vs 25%; Extra-temporal: 62% vs 33%; p < 0.05). Significance: Concordance between non-invasive investigation iSPECT and FDG-PET is an important predictive factor for surgical outcomes in extra-temporal epilepsy.
    Epilepsy Research. 09/2014;
  • Neurology India 09/2014; 62(5):543-5. · 1.04 Impact Factor
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    ABSTRACT: Hypoxia is a critical aspect of the glioma microenvironment and has been associated with poor prognosis and resistance to various therapies. However, the mechanisms responsible for hypoxic survival of glioma cells remain unclear. Recent studies strongly suggest that microRNAs act as critical mediators of the hypoxic response. We thus hypothesized their prominent role in hypoxia resistance in glioblastoma (GBM) and aimed to identify those.
    BMC genomics. 08/2014; 15(1):686.
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    ABSTRACT: Pediatric glioblastoma multiforme (GBM) is rare, and there is a single study, a seminal discovery showing association of histone H3.3 and isocitrate dehydrogenase (IDH)1 mutation with a DNA methylation signature. The present study aims to validate these findings in an independent cohort of pediatric GBM, compare it with adult GBM, and evaluate the involvement of important functionally altered pathways.
    Neuro-Oncology 07/2014; · 6.18 Impact Factor
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    ABSTRACT: Background: Meningiomas are benign central nervous system tumors; however, significant fraction recurs, irrespective of histological grade. Materials and Methods: We performed fluorescence in-situ hybridization for 1p36 and 14q32, and immunohistochemistry for progesterone receptor (PR), p53 and MIB-1 on 84 meningiomas. Results and Conclusion: Sixty-four were convexity tumors (30 grade I, 21 grade II, 13 grade III) and 20 petroclival (grade I; 10 with gross total resection (GTR), 10 with subtotal resection (STR)). Isolated 1p36 deletion was seen in 20% grade I, 28.6% grade II and 30.8% grade III convexity meningiomas, and isolated 14q deletion in one grade III convexity tumor. 1p/14q co-deletion was seen in none of grade I, 28.5% grade II and 30% grade III convexity meningiomas. PR immunoreactivity was less frequent in grade III tumors. Petroclival tumors did not show isolated deletion. However, 1p/14q co-deletion was seen in 20% of petroclival tumors with STR and in none with GTR. Frequency of chromosomal alterations and MIB-1 labeling index both increase with tumor grade. 1p/14q co-deletion is characteristic of grade II/III meningiomas, while PR immunoreactivity inversely correlates with grade, suggesting their use as surrogate markers for grading. Identification of 1p/14q co-deletion in grade I petroclival tumors with STR suggests that unresectable petroclival meningiomas are biologically more aggressive than their grade I convexity counterparts.
    Neurology India 07/2014; 62(4):376-382. · 1.04 Impact Factor
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    ABSTRACT: Meningeal fibromas are rare intracranial tumors that mimic meningiomas radiologically as well as histologically. The authors report 2 cases of meningeal fibroma with detailed clinical, radiological, histopathological, and immunohistochemical features, and discuss the differential diagnosis of this entity. Knowledge of this rare tumor is essential for pathologists to be able distinguish it from more common meningeal tumors, especially in younger patients. This knowledge is also essential for neurosurgeons, as incomplete resection may lead to tumor recurrence, and such patients require close follow-up.
    Journal of Neurosurgery Pediatrics 06/2014; · 1.63 Impact Factor
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    ABSTRACT: Meningeal hemangiopericytomas (HPCs) are aggressive dural-based tumors, for which no prognostic or predictive marker has been identified. Gross total resection is treatment of choice, but not easily achieved; hence, alkylating agents like temozolomide (TMZ) are now being tried. O(6) -methylguanine-DNA methyltransferase (MGMT) promoter methylation has proven prognostic and predictive value in glioblastomas. This study evaluates MGMT promoter methylation in meningeal HPCs to determine its role in HPC oncogenesis and its association with patient outcome. Meningeal HPCs diagnosed between 2002 and 2011 were retrieved and clinicopathological features reviewed. MGMT promoter methylation status was assessed by methylation-specific polymerase chain reaction (MSP) and immunohistochemistry (IHC) for MGMT protein. HPCs accounted for 1.1% of all CNS tumors. Forty cases were analyzed; the majority were adults (mean age = 41.4 years). Seventy percent were primary and 30% were recurrent tumors; 60% were grade II and 40% were grade III. MGMT promoter methylation was identified in 45% of cases, including Grade II (54.2%) and Grade III (31.3%) (P = 0.203). Promoter methylation was significantly (P = 0.035) more frequent in primary (57.1%) than in recurrent (16.7%) tumors. No correlation was noted between MGMT promoter methylation by MSP and MGMT protein expression by IHC, or with progression-free survival. Thus, a significant proportion of HPCs demonstrate MGMT promoter methylation, suggesting possible susceptibility to TMZ. As promoter methylation is more frequent in primary tumors, TMZ may serve as a therapeutic option in residual primary tumors. Epigenetic inactivation of MGMT in HPCs necessitates the assessment of prognostic and predictive value of MGMT promoter methylation in HPCs in larger clinical trials.
    Neuropathology 02/2014; · 1.91 Impact Factor
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    ABSTRACT: Dipeptidyl-peptidase III (DPP III), a cytosolic metallo-aminopeptidase implicated in various physiological and pathological processes. A previous study from our laboratory indicated elevated expression of DPP III in glioblastoma (U87MG) cells. In the present study we investigated the role of IL-6, a pleiotropic cytokine produced by glial tumors in regulation of DPP III expression. Immunohistochemistry, western blotting and qRT-PCR were used for quantitation of DPP III and IL-6 in human glioblastoma cells and tumors. Cell transfections and DPP III promoter reporter assays were performed to study the transcriptional regulation of DPP III by IL-6. Promoter deletion analysis, site directed mutagenesis, Chromatin Immunoprecipitation (ChIP) assays and siRNA technology was employed to elucidate the molecular mechanism of IL-6 mediated regulation of DPP III in glioblastoma cells. Our results for the first time demonstrate a negative correlation(r=0.632, p= 0.01) between DPP III and IL-6 in both human tumors and cultured glioblastoma cells. Treatment of U87MG cells with IL-6 significantly decreased DPP III expression with a concomitant increase in the levels of transcription factor C/EBP-β. Deletion/mutagenesis of C/EBP-β binding motif of DPP III promoter significantly increased its activity and abolished its responsiveness to IL-6. This effect could also be mimicked by C/EBP-β siRNA. In conclusion our study for the first time demonstrates C/EBP-β mediated transcriptional down regulation of DPP III by IL-6. Our results demonstrating negative correlation between IL-6 and DPP III taken together with previously reported prognostic significance of this cytokine in glioblastoma suggests that DPP III may prove useful as a prognostic marker. This article is protected by copyright. All rights reserved.
    FEBS Journal 01/2014; · 4.25 Impact Factor
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    ABSTRACT: Conventional circumferential stabilization for pathologies causing instability of the thoracic spine requires a 2 or even a 3 staged procedure. The authors present their tertiary care center experience of single staged procedure to establish a circumferential fusion through an extended costo-transversectomy approach. The purpose of this study was to demonstrate [1] neural canal decompression [2] removal of the pathology [3] achieve circumferential fusion and [4] correcting the deformity through a single procedure. Prospective, observational. Forty-six patients with pan thoracic column instability due to various pathologies. Neurological condition was evaluated using ASIA and ECOG grading system. Outcome was evaluated with regard to the decompression of neural canal, correction of deformity, and neurological improvement. All patients were evaluated for neural canal compromise, degree of kyphosis preoperatively, early and late postoperatively. All patients had severe spinal canal compromise (mean, 59% + 9%) and loss of vertebral body height (mean, 55% + 10%). A single stage circumferential fusion was performed (4 level pedicle screw fixation along with a ventral cage fixation following a vertebrectomy or corpectomy) through an extended costo-transversectomy approach. The pathologies included: trauma (21), tuberculosis (18), haemangioma (2), aneurysmal bone cyst (1), recurrent haemangioendothelioma (1), solitary metastasis (1) and solitary plasmacytoma (1) and neurofibromatosis (1). 35/46 patients (76%) demonstrated improvement in the performance status. The major complications included pneumonitis (3), pneumothorax (3) and neurological deterioration (3; improved in 2), deep venous thrombosis (2), recurrent hemoptysis (1). No implant failures were noted on last radiology follow up. There were two mortalities; one due to myocardial infarction and another because of respiratory complications. The following study demonstrated that extended costo-trasversectomy approach is a good option for achieving single staged circumferential fusion for correcting unstable thoracic spine due to both traumatic and non-traumatic pathologies.
    The spine journal: official journal of the North American Spine Society 01/2014; · 2.90 Impact Factor
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    ABSTRACT: Primary angiitis of the central nervous system (PACNS) is a rare form of vasculitis of unknown aetiology. Multifaceted clinical manifestations, non-specific MRI findings, a broad range of differential diagnoses and diverse pathological appearances prove to be a diagnostic challenge. However, a prompt diagnosis and aggressive treatment are crucial to avoid permanent damage. Hence, we present the clinico-pathological spectrum of this entity and highlight the limitations of currently available diagnostic modalities. We describe in detail the histopathological findings of eight cases of PACNS diagnosed at the Department of Pathology, AIIMS, over a period of eight years. Eight cases of PACNS were identified during this period. Five cases (62.5%) showed features of granulomatous vasculitis, two (25%) showed lymphocytic vasculitis and one case (12.5%) showed a predominantly necrotizing pattern of vasculitis. Diagnosis of PACNS is a challenge and requires a high index of clinical suspicion. Appropriate work-up to exclude other conditions is mandatory. Brain biopsy is useful in making the diagnosis and ruling out mimicking conditions.
    Folia neuropathologica / Association of Polish Neuropathologists and Medical Research Centre, Polish Academy of Sciences 01/2014; 52(2):187-96. · 1.55 Impact Factor
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    ABSTRACT: Background. Chordomas are slow-growing tumors and most commonly involve the sacrum and clivus. Multiple recurrences are frequent. at Childhood chordomas are rare and often show exceptionally aggressive behavior, resulting in short survival and a high incidence of meta static spread.
    Neuro-Oncology 12/2013; 2013; 0, 1 – 10, doi:10.1093/neuonc/228. · 6.18 Impact Factor
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    ABSTRACT: Background Chordomas are slow-growing tumors and most commonly involve the sacrum and clivus. Multiple recurrences are frequent. Childhood chordomas are rare and often show exceptionally aggressive behavior, resulting in short survival and a high incidence of metastatic spread.Objective This study examined the histologic features and immunohistochemical profile of pediatric chordomas and compared them with their adult counterparts.Methods Nine pediatric and 13 adult cases were included in the study. Childhood chordomas were classified into conventional, atypical, and poorly differentiated types. Immunohistochemistry was performed for cytokeratin, epithelial membrane antigen, vimentin, S100, brachyury, p53, INI1, epidermal growth factor receptor (EGFR), and CD117. Cytogenetic analyses were performed in a subset of tumors for SMARCB1/INI1 locus on 22q chromosome by fluorescent in situ hybridization (FISH) and analysis of the SMARCB1/INI1 gene sequence.ResultsAll tumors showed expression of cytokeratin, epithelial membrane antigen, S100, vimentin, brachyury, and EGFR. Atypical morphology, p53 expression, higher MIB-1 labelling index (LI), and INI1 loss were more frequently seen in pediatric chordomas as compared with adults. None of the tumors showed CD117 expression. No point mutation in the SMARCB1/INI1 gene was noted in the tumors examined; however, 4 pediatric and 1 adult chordoma showed loss of this locus on FISH analysis.ConclusionsA subset of pediatric chordomas with atypical histomorphologic features needs to be identified, as they behave in an aggressive manner and require adjuvant therapy. Pediatric chordomas more frequently show p53 expression, INI1 loss, and higher MIB-1 LI as compared with adults, whereas EGFR expression is common to both.
    Neuro-Oncology 12/2013; · 6.18 Impact Factor
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    ABSTRACT: Ependymomas are relatively rare glial tumours, whose pathogenesis is not well elucidated. They are enigmatic tumours that show site-specific differences in their biological behaviour. Recent studies have hypothesized that ependymoma cancer stem cells (CSC) are derived from radial glia and express stem-cell markers such as nestin, which is associated with a poor prognosis. CSCs reside in 'vascular niches', where endothelial cells and molecular signals like vascular endothelial growth factor (VEGF) play an important role in their survival. Studies analyzing VEGF expression in ependymomas showed that ependymal vascular proliferation is less sensitive to induction by VEGF, questioning the possible beneficial effect of anti-VEGF therapy in ependymomas. We aimed to study nestin and VEGF immunoexpression in ependymomas, correlate them with clinicopathological parameters and reveal a role for VEGF in ependymomas that extends beyond the context of tumour angiogenesis. We analyzed 126 cases of ependymomas of different grades and location for nestin and VEGF immunoexpression. Endothelial cells were labeled with CD34. Vascular patterns and microvascular density was determined. Nestin and VEGF expression in tumour cells were more frequent in supratentorial tumours {89% (33/37) & 65% (24/37) respectively}, and were associated with a significantly poor progression-free survival (PFS). VEGF expression did not reveal any correlation with necrosis or bizarre vascular patterns. Supratentorial location is an independent predictor of a poor PFS. Significant co-expression of nestin and VEGF suggests that latter possibly augments stem cell survival. Thus, anti-VEGF therapy may be a good option in future for nestin immunopositive ependymomas.
    Neuropathology and Applied Neurobiology 11/2013; · 4.84 Impact Factor
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    ABSTRACT: Ependymomas are relatively uncommon tumours of the central nervous system which arise from the ependymal lining of the ventricles and spinal canal. The molecular changes leading to ependymal oncogenesis are not completely understood. We examined chromosome 9q33-34 locus for gain, potential oncogenes at this locus (Notch-1 and Tenascin-C) and Notch pathway target genes (Hes-1, Hey-2 & C-myc) in ependymomas by fluorescent in situ hybridization (FISH) and immunohistochemistry (IHC), respectively, to assess if they have any correlation with clinical characteristics. We analyzed 50 cases of ependymomas by FISH for 9q gain and by IHC for Notch-1 and its target gene proteins (Hes-1, Hey-2 and C-myc) expression. We also performed IHC for Tenascin-C to rule out any correlation with aggressiveness/grade of tumour. FISH study revealed significant chromosome 9q gain in ependymomas of adult onset (age > 18 years) and spinal cord origin. Notch-1 showed significantly more frequent immunohistochemical expression in supratentorial and anaplastic ependymomas. Tenascin-C (TN-C) expression was significant in intracranial, childhood (age ≤ 18 years) and anaplastic ependymomas. Of the three Notch pathway target gene proteins (Hes-1, Hey-2 and C-myc), Hes-1 and C-myc expression showed significant correlation with anaplastic and adult onset ependymomas, respectively. Genetic alterations are independent prognostic markers in ependymomas. A clinicopathological correlation with various molecular signatures may be helpful in the development of new therapeutic targets.
    Journal of Neuro-Oncology 11/2013; · 3.12 Impact Factor
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    ABSTRACT: Thyroid tumours with both papillary and medullary carcinoma features are rare and represent less than 1% of all thyroid malignancies. These tumours have a different clinical presentation and biological behaviour from tumours that have only papillary or medullary carcinoma features. The phenomenon of mixed thyroid tumours can be observed in two settings - a mixed tumour showing dual differentiation, or a collision tumour. For a precise diagnosis of this rare mixed thyroid carcinoma, fine needle aspiration cytology results should be correlated with serum calcitonin and thyroglobulin levels. The diagnosis should also be confirmed using immunocytochemistry. Surgery is the treatment of choice, and the role of postoperative radioiodine is controversial. We herein report the case of a 35-year-old man with a mixed medullary-papillary carcinoma of the thyroid, which presented with C-cell hyperplasia, granulomatous inflammation and metastasis to the cervical lymph nodes. The patient was treated with total thyroidectomy and nodal clearance. This case highlights the need for awareness of coexistent entities as they warrant separate treatments.
    Singapore medical journal 07/2013; 54(7):e146-8. · 0.63 Impact Factor
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    ABSTRACT: Muscular dystrophies are progressive, genetic disorders of muscle degeneration. The current gold standard for diagnosis is muscle biopsy or genetic studies. Muscle biopsy is an invasive procedure and genetic testing facilities are available only in a few centers. Thus, a diagnostic test that is easily available, simpler, and less invasive is desirable. Over the past 2 decades, skin biopsy has been evolving as a suitable option. Two cases of sarcoglycanopathy are described here, which have been correctly diagnosed by skin biopsy. Muscle biopsy has been used as the gold-standard diagnostic method. Skin biopsy can substitute for muscle biopsy as the preliminary diagnostic tool directing appropriate molecular testing. However, these results require validation in studies with an adequate sample size. This holds promise for the future when repeated biopsies will be required for evaluating protein rescue in trials of novel treatment options in these disorders.
    Journal of child neurology 05/2013; · 1.59 Impact Factor
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    ABSTRACT: BACKGROUND: MicroRNAs (miRNAs) are non-uniformly distributed in genomes and ~30% of the miRNAs in the human genome are clustered. In this study we have focused on the imprinted miRNA cluster miR-379/miR-656 on 14q32.31 (hereafter C14) to test their coordinated function. We have analyzed expression profile of >1000 human miRNAs in >1400 samples representing seven different human tissue types obtained from cancer patients along with matched and unmatched controls. RESULTS: We found 68% of the miRNAs in this cluster to be significantly downregulated in glioblastoma multiforme (GBM), 61% downregulated in kidney renal clear cell carcinoma (KIRC), 46% in breast invasive carcinoma (BRCA) and 14% in ovarian serous cystadenocarcinoma (OV). On a genome-wide scale C14 miRNAs accounted for 12-30% of the total downregulated miRNAs in different cancers. Pathway enrichment for the predicted targets of C14 miRNA was significant for cancer pathways, especially Glioma (p< 3.77x10-6, FDR<0.005). The observed downregulation was confirmed in GBM patients by real-time PCR, where 79% of C14 miRNAs (34/43) showed downregulation. In GBM samples, hypermethylation at C14 locus (p<0.003) and downregulation of MEF2, a crucial transcription factor for the cluster was observed which likely contribute to the observed downregulation of the entire miRNA cluster. CONCLUSION: We provide compelling evidence that the entire C14 miRNA cluster is a tumor suppressor locus involved in multiple cancers, especially in GBM, and points toward a general mechanism of coordinated function for clustered miRNAs.Reviewers: Reviewed by: Prof. Gregory J Goodall and Dr. Alexander Max Burroughs.
    Biology Direct 04/2013; 8(1):10. · 2.72 Impact Factor
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    ABSTRACT: Uterus-like mass is an extremely rare choristoma of müllerian origin arising in association with neural tube defects. In this article, we describe the case of a 9-year-old girl with spina bifida, a mass lesion within the conus, and a subcutaneous lipoma in the lumbosacral region. Histopathological examination of the conus lesion revealed a uterus-like structure comprising of endometrial glands and stroma surrounded by fascicles of smooth muscle. This case differs from the few previously described cases in absence of neurological symptoms and early age at diagnosis. Thorough histopathological examination of resected tissue is therefore recommended for the diagnosis of this rare entity, as it may not have a typical presentation in all instances.
    Pediatric Neurosurgery 04/2013; · 0.42 Impact Factor

Publication Stats

2k Citations
635.00 Total Impact Points

Institutions

  • 2005–2014
    • AIIMS Bhopal All India Institute of Medical Sciences
      Bhopal, Madhya Pradesh, India
  • 1987–2014
    • All India Institute of Medical Sciences
      • • Department of Pathology
      • • Department of Biochemistry
      • • Department of Neurosurgery
      • • Department of Neurology
      New Dilli, NCT, India
  • 2004
    • Hôpital La Pitié Salpêtrière (Groupe Hospitalier "La Pitié Salpêtrière - Charles Foix")
      Lutetia Parisorum, Île-de-France, France