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   Table of Contents - Current issue
Coverpage
May 2022
Volume 65 | Issue 5
Special issue 1
Page Nos. 1-337

Online since Wednesday, May 11, 2022

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EDITORIAL  

From Editor's Desk p. 1
Ranjan Agrawal
DOI:10.4103/0377-4929.345062  
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SECTION A: NEOPLASMS OF CNS - EDITORIAL Top

The Evolving World Health Organization (WHO) classification of tumors of the central nervous system (CNS): Challenges and opportunities Highly accessed article p. 2
Chitra Sarkar, Megha Uppin, Anita Mahadevan
DOI:10.4103/0377-4929.345063  
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SECTION A: NEOPLASMS OF CNS - REVIEW ARTICLES Top

World Health Organization Classification of Tumors of the Central Nervous System 5th Edition (WHO CNS5): What's new? Highly accessed article p. 5
Swati Mahajan, Vaishali Suri, Saumya Sahu, Mehar C Sharma, Chitra Sarkar
DOI:10.4103/ijpm.ijpm_48_22  
The latest fifth edition of the World Health Organization classification of central nervous system tumors (WHO CNS5) has been built on the prior WHO 2016 classification as well as recommendations put forward by seven updates of the Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy (cIMPACT). Various new tumor types and subtypes have been recognized which are of clinical significance. Tumor groups have been restructured and the nomenclature of some tumor types has also been revised. The use of terms 'entity' and 'variant' have been replaced by 'type' and 'subtype'. Significant changes have been introduced in the grading of tumors viz. use of Arabic numerals, grading within individual tumor types and combined histological and molecular grading. The terms 'Not otherwise specified' and 'Not elsewhere classified' can now be used for all tumor types. WHO CNS5 also for the first time endorses the use of DNA methylation profiling for the diagnosis of some tumor types/subtypes. Finally, the importance of combining histology with molecular parameters is emphasized for the “layered reporting” and “integrated diagnosis”, which will provide valuable diagnostic, prognostic, and predictive information, as well as for some entities, suggest targeted therapies.
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A review of adult-type diffuse gliomas in the WHO CNS5 classification with special reference to Astrocytoma, IDH-mutant and Oligodendroglioma, IDH-mutant and 1p/19q codeleted p. 14
Vani Santosh, Shilpa Rao
DOI:10.4103/ijpm.ijpm_34_22  
The fifth edition of the World Health Organization (WHO) Classification of Tumors of the Central Nervous System (WHO CNS5) features several changes in the classification, diagnostic criteria, nomenclature, and grading of diffuse gliomas. Adult-type diffuse gliomas are genetically defined and include astrocytoma, isocitrate dehydrogenase (IDH)-mutant, oligodendroglioma, IDH-mutant and 1p/19q codeleted, and glioblastoma, IDH-wildtype. This review briefly discusses two tumor types: astrocytoma, IDH-mutant, and oligodendroglioma, IDH-mutant and 1p/19q codeleted, with emphasis on relevant changes in their classification and defining molecular genetic alterations. A simplified approach to the diagnosis of these tumors is provided.
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Glioblastoma: Changing concepts in the WHO CNS5 classification p. 24
Jie Chen, Pengcheng Han, Sonika Dahiya
DOI:10.4103/ijpm.ijpm_1109_21  
Glioblastoma is the most common malignant central nervous system (CNS) tumor in adults. Acute common clinical symptoms include headache, seizure, behavior changes, focal neurological deficits, and signs of increased intracranial pressure. The classic MRI finding of glioblastoma is an irregularly shaped, rim-enhancing or ring-enhancing lesion with a central dark area of necrosis. This constellation of features correlates with microscopic findings of tumor necrosis and microvascular proliferation. Besides these common features, several well-recognized histological subtypes include giant cell glioblastoma, granular cell glioblastoma, gliosarcoma, glioblastoma with a primitive neuronal component, small cell glioblastoma, and epithelioid glioblastoma. While glioblastoma was historically classified as isocitrate dehydrogenase (IDH)-wildtype and IDH-mutant groups, the Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy (cIMPACT-NOW) and the fifth edition of the WHO Classification of Tumors of the Central Nervous System clearly updated the nomenclature to reflect glioblastoma to be compatible with wildtype IDH status only. Therefore, glioblastoma is now defined as “a diffuse, astrocytic glioma that is IDH-wildtype and H3-wildtype and has one or more of the following histological or genetic features: microvascular proliferation, necrosis, Telomerase reverse transcriptase promoter mutation, Epidermal growth factor receptor gene amplification, +7/−10 chromosome copy-number changes (CNS WHO grade 4).”
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Circumscribed astrocytic gliomas: Contribution of molecular analyses to histopathology diagnosis in the WHO CNS5 classification p. 33
Yazgı Köy, Tarik Tihan
DOI:10.4103/ijpm.ijpm_1019_21  
The newest revision of the WHO classification of tumors of the central nervous system, also known as WHO 5th edition, introduces substantial changes, especially within the glial tumor category and separates adult-type and pediatric-type glial tumors into different categories for the first time. In addition, another category of glial tumors, “Circumscribed Astrocytic Gliomas” were also created. This group includes pilocytic astrocytoma, pleomorphic xanthoastrocytoma, subependymal giant cell astrocytoma, chordoid glioma, astroblastoma, and the highly nebulous novel entity high-grade astrocytoma with piloid features. We present a brief and critical review of the pathological and molecular characteristics of these often well-demarcated tumors that can occur in adults as well as in the pediatric population.
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Pediatric-type diffuse low grade gliomas: Histomolecular profile and practical approach to their integrated diagnosis according to the WHO CNS5 classification p. 42
Suvendu Purkait, Swati Mahajan, Mehar C Sharma, Chitra Sarkar, Vaishali Suri
DOI:10.4103/ijpm.ijpm_1043_21  
Low-grade gliomas are the most common primary central nervous system (CNS) neoplasms in the pediatric age group. The majority of these tumors are circumscribed, while diffuse low-grade gliomas are relatively rare. The pediatric type diffuse low-grade gliomas (pDLGG) have a distinctly different biological behavior, molecular profile, and clinical outcome as compared to their adult counterpart. In the 5th edition of World Health Organization (WHO) CNS classification, pDLGGs are subclassified into four distinct histomolecular entities, namely, (i) diffuse astrocytoma, MYB- or MYBL1-altered, (ii) angiocentric glioma, (iii) polymorphous low-grade neuroepithelial tumor of the young (PLNTY), and (iv) diffuse low-grade glioma, MAPK pathway-altered. Although the molecular profile, to a great extent, aligns with the morphological features, it is not specific. Many of the molecular alterations described in pDLGG have therapeutic implications with the availability of newer targeted therapies. A wide range of testing platforms are available for routine assessment of these molecular alterations in clinical laboratories, though WHO does not recommend any particular method.
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Paediatric type diffuse high grade gliomas in the WHO CNS5 classification: What the pathologist needs to know? p. 50
Shruti Rao, Ayushi Sahay, Sridhar Epari
DOI:10.4103/ijpm.ijpm_1202_21  
Pediatric-type of diffuse high-grade gliomas (HGG) are classified as a distinct group in the current fifth edition of WHO classification. This group of high-grade tumors is no more called as glioblastoma (GBM), which has been reserved for adult isocitrate dehydrogenase (IDH)-wild type HGG. These tumors are uncommon as compared to embryonal tumors and low-grade gliomas (LGG). Pediatric-type of diffuse HGG biologically differs from their adult counterparts in that they are therapeutically less sensitive to alkylating chemotherapies. They comprise a heterogeneous group of molecularly defined tumors – predominantly histone gene altered, less common receptor tyrosine kinase (RTK)-mediated, and syndrome-associated. This review provides an overview of these uncommon tumors and discusses the diagnostic approach of this heterogeneous group of tumors.
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Glioneuronal and neuronal tumors: A review with special reference to the new types in the WHO CNS5 classification p. 59
Takashi Komori
DOI:10.4103/ijpm.ijpm_1061_21  
Glioneuronal and neuronal tumors (GNTs) are slow-growing lower-grade neuroepithelial tumors with mature neuronal and, less consistently, glial differentiation. Their identification has relied solely on histological proof of neuronal differentiation, which was considered to represent the well-differentiated nature of GNTs. However, after discovering the genetic alterations in GNTs, particularly those in the MAP-kinase pathway, it became evident that histological diagnoses are not always concurrent with genetic alterations and vice versa. Furthermore, since several inhibitors mediating the MAP-kinase pathway are available, at least for clinical trials, molecular-based classification is now warranted. Thus, the upcoming WHO Classification of Central Nervous System Tumors, 5th edition (WHO5CNS) applied DNA methylation profiling to segregate low-grade neuroepithelial tumors. This review gives an overview of the pathological features of GNTs with particular reference to the newly listed tumor types in WHO5CNS. The knowledge and awareness of each tumor type are essential to make a correct diagnosis and avoid unnecessary radical resection and chemoradiotherapy, as GNTs are relatively indolent and have a prolonged clinical course. In addition, being distinctive in location, age group, and histology, the integration of clinicopathological information will help identify relevant tumor types of GNTs without genetic testing, even in resource-limited settings.
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Overview of recent advances in the classification of ependymomas in WHO CNS5 classification: Simplified approach to their integrated diagnosis p. 68
Rakesh K Gupta, Agrima Sharma, Mehar C Sharma
DOI:10.4103/ijpm.ijpm_1212_21  
Ependymomas can arise along the entire neuraxis; however, they possess site-specific unique molecular alterations and a methylome pattern which is directly related with the prognostic outcomes. Since 2016, when the updated fourth edition of World Health Organization (WHO) classification of tumors of the central nervous system was published, it has been emphasized to classify ependymomas by anatomic site and molecular signatures associated genetic alterations so that classification of the disease reflects its underlying biology. In continuation, the fifth edition of the WHO classification of CNS tumors introduces major changes, including site-specific molecular profiles as the basis of classifying ependymomas. Furthermore, an integrated tier system of reporting is recommended for better clinical correlation and predicting outcomes. WHO grading can still be included in a specific tier, along with molecular markers.
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Embryonal tumors in the WHO CNS5 classification: A Review p. 73
Francesca Gianno, Evelina Miele, Manila Antonelli, Felice Giangaspero
DOI:10.4103/ijpm.ijpm_1049_21  
Embryonal tumors are a heterogenous group of neoplasms mostly defined by recurrent genetic driver events. They have been, previously, broadly classified as either medulloblastoma or supratentorial primitive neuroectodermal tumors (PNETs). However, the application of DNA methylation/gene expression profiling in large series of neoplasms histologically defined as PNET, revealed tumors, which showed genetic events associated with glial tumors. These findings led to the definitive removal of the term “PNET” in the 2016 World Health Organization (WHO) classification of CNS tumors. Moreover, further studies on a large scale of methylation profiling have allowed the identification of new molecular-defined entities and have largely influenced the 5th edition of the WHO classification of CNS tumors (WHO CNS5) for both medulloblastomas and other CNS embryonal tumors. The importance of molecular characteristics in CNS embryonal tumors is well represented by the identification of different molecular groups and subgroups in medulloblastoma. So, in the CNS5, the emerged group 3 and group 4 belong to the classification, and the four molecular and morphologic types are now combined into a unique section. Among other embryonal tumors, two new recognized entities are introduced in CNS5: CNS neuroblastoma, FOXR2-activated, and CNS tumor with BCOR internal tandem duplication (ITD). Embryonal tumor with multilayered rosettes (ETMR), already present in the previous classification now has a revised nomenclature as a result of the new DICER1 alteration, additional to the formerly known C19MC. Regarding atypical teratoid/rhabdoid tumor (AT/RT), three molecular subgroups are recognized in CNS5. The combination of histopathological and molecular features reflects the complexity of all these tumors and gives critical information in terms of prognosis and therapy. This encourages the use of a layered diagnostic report with the integrated diagnosis at the top, succeeded by layers including the histological, molecular, and other essential details.
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Meningiomas transition from traditional histological grading to molecular profiling in WHO CNS5: A Review p. 83
Abhijit Goyal-Honavar, Ranjani Jayachandran, Geeta Chacko
DOI:10.4103/ijpm.ijpm_1085_21  
Despite being the most common primary intracranial tumor, meningiomas are classified largely based on histological features. The current system of grading has been shown to be unsatisfactory due to its poor reproducibility as well as the considerable variability within grades. With the increasing availability of genomic and epigenomic profiling, several markers have been suggested to correlate with the location, histological subtype, and clinical behavior of meningiomas. These developments have enabled the development of targeted therapy, as well as individualized use of currently available adjuvant methods. These include copy number alterations (CNAs), specific genetic abnormalities (germline and sporadic), and genome-wide methylation profiles. In this review, we recapitulate the changes in the classification of meningiomas thus far, discuss the various histological subtypes recognized, and present the available literature on the genetic and epigenetic profiles of meningiomas. The recognition and further study of these markers have the potential to usher in an era of personalized therapy in the management of meningiomas, vastly improving outcomes as has been observed in the case of several other tumors.
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Miscellaneous newly recognized types of CNS tumors in the WHO CNS5 classification (other than gliomas, glioneuronal and embryonal tumors) p. 94
Debajyoti Chatterjee, Kirti Gupta
DOI:10.4103/ijpm.ijpm_1038_21  
In this review, we describe salient features of a few of the newer entities recognized in the fifth edition of World Health Organization (WHO) classification of central nervous system (CNS) tumors. While most of these have been offshoots of the deoxyribonucleic acid (DNA) methylation profiling of CNS tumors with distinct profiling such as desmoplastic myxoid tumor (DMT) of the pineal region, SMARCB1-mutant, these also demonstrate subtle, distinct morphological features, which should be carefully searched for to diagnose them.
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Evaluating neurosurgical biopsies for CNS tumor diagnoses: An algorithmic and pattern based approach p. 99
M Adelita Vizcaino, Aditya Raghunathan
DOI:10.4103/ijpm.ijpm_1081_21  
The 2016 and 2021 World Health Organization (WHO) Classifications of Tumors of the Central Nervous System (CNS) reflect the importance of integrating molecular analysis into CNS tumor diagnosis and classification, adding to the complexity of any surgical neuropathology practice. On the other hand, our evolving understanding of genomic alterations across the spectrum of CNS tumors highlights the importance of utilizing traditional histological and immunohistochemical approaches to first establish as accurate a diagnosis as possible. Such an approach is also essential to recognizing the most appropriate ancillary test(s) needed for accurate classification and grading of CNS tumors. Here, we present an algorithmic approach to be considered while evaluating surgical neuropathology biopsies, which includes a recognition of main histological patterns, and incorporates clinical and radiologic features, to assist with accurate diagnosis and optimal selection of subsequent ancillary testing.
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Liquid biopsy in CNS tumors: Current status & future perspectives p. 111
Nuzhat Husain, Adil Husain, Sridhar Mishra, Pallavi Srivastava
DOI:10.4103/ijpm.ijpm_1058_21  
Precise classification of central nervous system (CNS) malignancies is vital for the treatment and prognostication. Identification of noninvasive markers can be of importance to guide treatment decisions and in monitoring treatment response. CNS tumors are classified based on morphology with an essential complement of molecular changes, including mutations, amplifications, and methylation. Neuroimaging is the mainstay for initial diagnosis and monitoring tumor response with obvious limitations of imprecise tumor typing and no information on diagnostic, predictive and prognostic markers. Liquid biopsy has evolved as a diagnostic tool in body fluids and is being investigated as a surrogate for tissue biopsy in managing primary and metastatic brain tumors. Liquid biopsy refers to analyzing biological fluids such as peripheral blood, urine, pleural effusion, ascites, and cerebrospinal fluid (CSF); however, peripheral blood remains the primary source of fluid biopsy. The analytes include cell-free DNA (cfDNA) circulating tumor cells (CTCs), circulating micro RNAs (miRNAs), circulating proteins and extracellular vesicles (EVs). Analysis of these components is actively used for early cancer detection, auxiliary staging, prognosis assessment, detection of minimal residual disease (MRD), and monitoring drug resistance in various solid tumors. In recent years, liquid biopsy has been studied in CNS tumors, and analysis of CTCs and cfDNA have become relevant research topics. In the current review, we have explained the clinical potential of liquid biopsy in CNS tumors to assist in diagnosing and predicting prognosis and response to treatment.
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SECTION B: NON NEOPLASTIC DISORDERS OF CNS - EDITORIAL Top

Non-neoplastic disorders of the nervous system: Emerging from the shadows p. 122
Anita Mahadevan, Megha Uppin, Chitra Sarkar
DOI:10.4103/0377-4929.345064  
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SECTION B: NON NEOPLASTIC DISORDERS OF CNS - REVIEW ARTICLES Top

Granulomatous diseases of the central nervous system: Approach to diagnosis p. 125
Sundaram Challa
DOI:10.4103/ijpm.ijpm_1067_21  
Diagnosis of central nervous system (CNS) granulomas is challenging. The etiology may be infectious or non-infectious. The infectious causes are due to mycobacteria, fungi, parasites and rarely bacteria. The non-infectious causes include autoimmune diseases, diseases of uncertain etiology like sarcoidosis, those associated with neoplasms and reparative processes. Histologic evaluation of type of granuloma as necrotizing, non-necrotizing, fibrotic/calcific or foreign-body type, site of CNS involvement (leptomeninges/dura, brain/spinal cord) and identification of etiologic agent on histochemistry/culture/molecular methods resolves the diagnosis in a many a patient. Correlation with clinical and imaging features, risk factors and route of spread, geographical location and travel history are important. However, diagnosis may remain unresolved despite the application of all available techniques, highlighting the need for better diagnostic techniques.
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Non-granulomatous inflammatory lesions of CNS: Approach to diagnosis p. 135
BN Nandeesh, Shilpa Rao, Anita Mahadevan
DOI:10.4103/ijpm.ijpm_114_22  
Infections constitute an important and common category of diseases, particularly in less developed countries. Infections present with a broad spectrum of clinical and radiologic features dictated by the cell and tissue tropism and host response elicited, posing a considerable diagnostic challenge. Early diagnosis and treatment are crucial in preventing mortality and morbidity. Recourse is often made to biopsy for ascertaining the diagnosis, and hence the pathologist plays a vital role in patient management. Therefore, knowledge of the histopathologic changes is necessary to recognize the histological changes and guide the diagnostic workup and management. Each microbial agent elicits a distinctive pattern of inflammatory tissue response, which can serve as a clue to the etiological agent. Based on the causative organism, microbial, and host factors, the inflammatory response may be acute or chronic, necrotic or non-necrotic. The inflammation can be of varied patterns – lymphohistiocytic, granulomatous, inflammatory demyelinating, fibrosing, or showing minimal inflammation. The pattern of necrosis also differs based on the causative organism. Typically, pyogenic bacteria are associated with suppurative inflammation, tuberculosis with caseous granulomatous, and fungi with suppurative granulomatous inflammation. Viral infections are associated with lymphohistiocytic non-necrotizing inflammation and, based on cell tropism, can cause demyelination (e.g., JCV) and/or viral inclusions. Parasitic infections (protozoal or metazoal) display a broad spectrum of inflammatory changes that overlap with other types of infections. This review briefly describes pathological patterns and associated pathogens and provides an algorithmic approach based on pattern recognition that may be useful for the practicing pathologist.
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Neuropathology of COVID-19 p. 146
Li-Chun Lin, Bailey Hollis, Marco M Hefti
DOI:10.4103/ijpm.ijpm_1103_21  
The COVID-19 pandemic has placed global health care systems under unprecedented strain but has, at the same time, provided a unique opportunity for pathologists to turn autopsy findings into directly actionable insights into patient care. The current data on the neuropathology of COVID-19 remains preliminary and is limited by the lack of suitable controls, but certain tentative conclusions can be drawn. SARS-CoV-2 can infect multiple cell types in the central nervous system and does so in a subset of patients, although the clinical significance of direct infections remains in the central nervous system (CNS) and the peripheral nervous system (PNS) infections remains unclear. The best-described neuropathological manifestations of COVID-19 in the brain are variable patterns of neuroinflammation and vascular injury, although again, it remains unclear to what degree these findings are specifically due to COVID-19. There is also intriguing preliminary data to suggest a complex relationship between COVID-19 and neurodegeneration, with certain alleles that increase AD risk also increasing the risk of severe COVID-19, and conversely, the possibility that COVID-19 may increase the risk of neurodegenerative disease. The neuropathology of so-called “long-COVID” and the potential effects of COVID-19, or critical illness in general, on neurodegenerative disease remains unclear. There is thus an urgent need for long-term cohort studies of COVID-19 survivors, including brain donation, particularly in elderly patients, with careful recruitment of controls with similar non-COVID inflammatory illnesses.
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Role of imaging in CNS infections Highly accessed article p. 153
GG Sharath Kumar, Chaitra Parameshwara Adiga, Prakash P Iyer, Lakshmikanth N Goolahally
DOI:10.4103/ijpm.ijpm_1162_21  
Neuroinfections are seen in both adults and children. These can result in serious morbidity and if left untreated and/or associated with comorbidities can be life threatening. Cross-sectional imaging like computed tomography (CT) and magnetic resonance imaging (MRI) are advised by the clinicians for the diagnosing, confirmation of the diagnosis, assess any complications of the infection, and also for follow up. Though CT is the initial imaging investigation commonly asked by the clinician, due to its lesser soft tissue resolution, early brain changes may not be seen on CT. MRI has better soft tissue resolution with no ionizing radiation to the patient and helps in detecting the early signs of infection. Appropriate MRI, not only helps the radiologist to reduce the number of possibilities of the causative organism but also differentiates tumors from infection. However, CT is useful to assess the bony changes and also easily available and affordable cross-sectional imaging modality worldwide. The review summarizes the approach of the radiologist to central nervous system (CNS) infections and their typical imaging characteristic features.
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Non invasive tests for diagnosis of parasitic infections of CNS p. 164
RS Jayshree, Anita Mahadevan
DOI:10.4103/ijpm.ijpm_1123_21  
Central nervous system (CNS) infections are among the most devastating diseases with high mortality and morbidity. In the pre-human immunodeficiency virus (HIV) era, the occurrence of CNS infections was very infrequent. However, in the past four decades or so, with a global increase in the immunocompromised population, the incidence of opportunistic infections of the CNS has changed. This includes a global increase in the incidence of parasitic infections such as Toxoplasma gondii. Infections such as neurocysticercosis and cerebral malaria are quite prevalent in developing countries. Early diagnosis of these infections is crucial for instituting accurate therapy and preventing mortality and morbidity. Despite advances in neuroimaging techniques, laboratory diagnosis remains the mainstay for confirmation of diagnosis. We present an update on the noninvasive tests available for laboratory diagnosis of parasitic infections of the CNS.
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Pathology of surgically remediable epilepsy: How to evaluate p. 176
Rajalakshmi Poyuran
DOI:10.4103/ijpm.ijpm_1026_21  
Epilepsy surgery is a well-established treatment modality in selected cases of medically refractory epilepsy. Advances in neuroimaging technology has greatly facilitated detection of lesions that are surgically amenable. Hippocampal sclerosis is the most common pathology encountered among specimens from epilepsy-related surgeries. Other common pathologies are malformations of cortical development including focal cortical dysplasia, neoplasms, vascular malformations, inflammatory conditions including Rasmussen encephalitis and glial scars. Proper handling of surgical specimens is necessary for microscopic evaluation. Accurate interpretation and classification of lesions will help define clinically relevant etiologies. In this review, neuropathological aspects of the common etiologies underlying drug-resistant epilepsies are discussed.
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Focal cortical dysplasia: Updates p. 189
Jorge Pinheiro, Mrinalini Honavar
DOI:10.4103/ijpm.ijpm_1226_21  
Focal cortical dysplasias (FCDs) represent the third most frequent cause of drug-resistant focal epilepsy in adults (after hippocampal sclerosis and tumours) submitted to surgery, and the most common in the pediatric age group. The International League Against Epilepsy (ILAE) classification of focal cortical dysplasia is still a reference and consists of a three-tiered system: FCD type I refers to isolated abnormalities in cortical layering; FCD type II refers to cases with abnormalities in cortical architecture and dysmorphic neurons with or without balloon cells; and FCD type III refers to abnormalities in cortical layering associated with other lesions. Recent studies have demonstrated that somatic mutations occurring post-zygotically during embryonal development and leading to mosaicism, underlie most brain malformations. The molecular pathogenesis of FCD type II is associated with activation of the mTOR pathway. Pathogenic variants in this pathway are recognized in up to 63% of cases and may occur both through single activating variants in activators of the mTOR signaling pathway or double-hit inactivating variants in repressors of the signaling pathway. The newly described mild malformation of cortical development with oligodendroglial hyperplasia in epilepsy, has been found to show recurrent pathogenic variants in SLC35A2 with mosaicism. The present review describes the lesions of FCD and discusses the molecular pathogenesis and proposal for a revised classification.
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Role of the pathologist in the diagnosis of autoimmune encephalitis p. 198
Shilpa Rao, M Netravathi, Anita Mahadevan
DOI:10.4103/ijpm.ijpm_41_22  
Autoimmune encephalitis is a group of non-infectious immune-mediated inflammatory disorders manifesting with epilepsy and encephalitis syndromes that are associated with autoantibodies in the serum and/or cerebrospinal fluid (CSF). Pathogenic autoantibodies have been discovered against intracellular onconeural antigens, surface neuronal, or synaptic antigens with distinctive pathogenesis that underlie differences in response to immunotherapy. The onconeural antigens incite cytotoxic T-cell-mediated neuronal destruction, whereas surface antigens trigger direct damage by autoantibodies via complement mediated pathways, and hence respond well to immunomodulatory therapy, in contrast to poor response in the former. Neuroimaging, electroencephalogram, and CSF findings being non-specific, detection of autoantibodies is essential for a confirmatory diagnosis. Detection methods available include tissue-based assay, cell-based assays, immunoblot, cell culture, flow cytometry, and enzyme-linked immunosorbent assays. In this review, we discuss the various testing modalities available for onconeural and cell surface antibodies, their sensitivity and specificity and the emerging role of the pathologist in the diagnosis of autoimmune encephalitis. Early diagnosis is crucial for instituting treatment and preventing morbidity and mortality.
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Perinatal and Fetal Autopsies in Neuropathology: How I do it p. 207
Ram Narayan Das, Bappa Mandal, Mou Das, Kaushik Sil, Suchandra Mukherjee, Uttara Chatterjee
DOI:10.4103/ijpm.ijpm_977_21  
Fetal and perinatal autopsies are useful to identify the accurate cause of death and in the process recognize disorders which may require counselling for future pregnancies. Abnormalities of the CNS are an important cause of fetal loss and perinatal deaths. Most of these are structural abnormalities of the CNS, however a smaller portion show changes pertaining to prematurity, infections and even congenital tumors. In this review we evaluate CNS abnormalities of the fetus and the newborn as detected in autopsy series. We also describe our experience in a tertiary care hospital with a specialized neonatology unit over the last 8 years and discuss some of the newer methods like virtual autopsy.
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Brain banking in India: Relevance in current day practice p. 218
SK Shankar, Anita Mahadevan
DOI:10.4103/ijpm.ijpm_113_22  
Biobanks are set to become the norm. The explosion of new and powerful technologies like genomics and other multiomics has catapulted research from individual laboratories to multi-institutional and international partners. Today, with increasing life span, and the rising incidence of brain diseases, Brain Banks have become an invaluable source for unravelling the pathogenesis of several brain disorders, and develop effective therapies. The article briefly reviews the evolution of brain banking, rise of global networks, with a brief overview of steps involved from donor recruitment, protocols of processing, storage, annotation, and tissue distribution. The ethics of biobanking is one of the most controversial issues in bioethics, the key issues being consent, confidentiality, and commercialisation. Regulatory authorities in different countries and in India, the Indian Council of Medical Research has taken a lead to formulate new ethical guidelines for research involving human participants protecting rights, and well-being of research participants. Although brain banks have been established in the 1960s, in India, the first Brain Bank was established in 1995 at the National Institute of Mental Health and Neurosciences, Bengaluru. Now a network with two more Brain banks is being established in the country. The challenges and benefits of establishing the first Brain Bank as a National Research Facility in India is shared. For optimising available resources and promote brain banking, it is essential for medical professionals, and the public to perceive the crucial advantage in conversion of biological waste into invaluable resources for neuroscience. This will be the greatest “gift of hope” that we can offer for the future generations to overcome hitherto untreatable disorders such as dementias.
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Artificial intelligence in neuropathology: Current status and future perspectives p. 226
Vikas Vazhayil
DOI:10.4103/ijpm.ijpm_115_22  
Machine learning and artificial intelligence (AI) have become a part of our daily routine. There are very few of us who are not influenced by this technology. There are a lot of misconceptions about the scope, utility, and fallacies of AI. Digital neuropathology is an evolving area of research. The importance of digital image processing stems from the rapid gains in computer vision and image processing that have happened in the past decade thanks to advancements in deep learning (DL). The article attempts to present to the audience a simple presentation of the technology and attempts to provide a context-based understanding of the DL process for image processing. Also highlighted are current challenges and the roadblocks in adopting the technology in routine neuropathology.
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SECTION C: NEUROMUSCULAR DISORDERS - EDITORIAL Top

Current status of neuromuscular pathology: An overview with special reference to Indian Scenario p. 230
Megha Uppin, Anita Mahadevan, Chitra Sarkar
DOI:10.4103/0377-4929.345065  
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SECTION C: NEUROMUSCULAR DISORDERS - REVIEW ARTICLES Top

Basic requirements to establish a neuromuscular laboratory p. 233
Bevinahalli N Nandeesh, Gayathri Narayanappa, TC Yasha
DOI:10.4103/ijpm.ijpm_7_22  
Histopathological analysis of muscle biopsy is a prerequisite in the evaluation of neuromuscular disorders, particularly inflammatory myopathies, metabolic myopathies, congenital myopathies, muscular dystrophies and differentiating myopathies and neurogenic disorders with overlapping clinically features. It not only provides useful information that helps in the diagnosis but also treatment and management. Fundamental skills and basic knowledge regarding handling, processing and analyzing a muscle biopsy are required in any specialized or a general pathology lab supporting neuromuscular clinical services. Care during transport of the muscle biopsy, sample receipt in the laboratory and grossing is very important. Standard operating procedure should be followed for the preanalytical steps (freezing and cryomicrotomy), routine and special staining (enzyme and non enzymatic) and immunohistochemistry. A well organized neuromuscular laboratory with good quality management system is necessary for the practice of myopathology. This article gives an overview of establishing such a laboratory.
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Evolving classification and role of muscle biopsy in diagnosis of inflammatory myopathies p. 241
Meenakshi Swain, Megha Uppin
DOI:10.4103/ijpm.ijpm_1033_21  
Idiopathic inflammatory myopathy (IIM) is a broad term that includes dermatomyositis, polymyositis, overlap myositis, sporadic inclusion body myositis, and immune-mediated necrotizing myopathy. The understanding of the pathogenesis of IIM is ever-evolving with regular updates in the classification schema. With the recognition of autoantibodies and their detection, the diagnostic algorithms are changing in favor of non-invasive diagnoses. However, muscle biopsy has immensely contributed to our understanding of the pathogenesis of inflammatory myopathies, and the pathologic features of different subtypes are well established. The biopsy also aids in distinguishing myopathies with overlapping clinical features, particularly dystrophies, which can show inflammation on biopsy in some cases. In this article, the various classification schemes of the IIM are reviewed. Also, the pathogenesis and pathology of each type of IIM have been highlighted. This article emphasizes the role of muscle biopsy in the diagnosis of inflammatory myopathies.
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Current approach to diagnosis of inflammatory myopathies: Clinical features and myositis antibody profiles p. 252
Vineeta Shobha, Liza Rajasekhar
DOI:10.4103/ijpm.ijpm_1082_21  
Diagnosis of inflammatory myositis has been made easier with the availability of commercial assays for myositis-specific and myositis-associated antibodies. Clinico-serological association studies have permitted a better definition of clinical subsets. Myositis-specific auto-antibodies are highly specific and non-overlapping, whereas myositis-associated antibodies are those seen also in other connective tissue disorders such as systemic lupus erythematosus, primary Sjogren's syndrome, and idiopathic pulmonary auto-immune fibrosis. Their value is pronounced when clinical features are subtle or non-specific or when the muscle is not the primary organ involved. Overall, the muscle-specific and myositis-associated antibodies have changed the landscape in terms of diagnostic utility, prognostication, and the approach to organ-specific evaluation and management of idiopathic inflammatory myopathies (IIMs).
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Genetics and muscle pathology in the diagnosis of muscular dystrophies: An update p. 259
Deepti Narasimhaiah, Megha S Uppin, Prajnya Ranganath
DOI:10.4103/ijpm.ijpm_1074_21  
Muscular dystrophies are a clinically and genetically heterogeneous group of disorders involving the skeletal muscles. They have a progressive clinical course and are characterized by muscle fiber degeneration. Congenital muscular dystrophies (CMD) include dystroglycanopathies, merosin-deficient CMD, collagen VI-deficient CMD, SELENON-related rigid spine muscular dystrophy, and LMNA-related CMD. Childhood and adult-onset muscular dystrophies include dystrophinopathies, limb-girdle muscular dystrophies, Emery-Dreifuss muscular dystrophy, facioscapulohumeral muscular dystrophy, and myotonic dystrophy. Traditionally, muscle biopsy and histopathology along with special pathology techniques such as immunohistochemistry or immunoblotting were used for the diagnosis of muscular dystrophies. However, recent advances in molecular genetic testing, especially the next-generation sequencing technology, have revolutionized the diagnosis of muscular dystrophies. Identification of the underlying genetic basis helps in appropriate management and prognostication of the affected individual and genetic counseling of the family. In addition, identification of the exact disease-causing mutations is necessary for accurate prenatal genetic testing and carrier testing, to prevent recurrence in the family. Mutation identification is also essential for initiating mutation-specific therapies (which have been developed recently, especially for Duchenne muscular dystrophy) and for enrolment of patients into ongoing therapeutic clinical trials. The 'genetic testing first' approach has now become the norm in most centers. Nonetheless, muscle biopsy-based testing still has an important role to play, especially for cases where genetic testing is negative or inconclusive for the etiology.
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Congenital myopathies: The current status p. 271
Hans H Goebel, Carsten Dittmayer, Werner Stenzel
DOI:10.4103/ijpm.ijpm_1031_21  
Within the history of neuromuscular diseases (NMD), congenital myopathies (CM) represent a relatively new category introduced in the mid-nineteen hundreds upon advent and subsequent application of enzyme histochemistry and electron microscopy by establishing the three major CM, central core disease, nemaline myopathy, and centronuclear myopathy which later pluralized each when the molecular era began at the end of last century. Quickly, during the following 5 decades, many new CM entities were described, based on muscle biopsies and their CM-characteristic myopathology, the former a prerequisite to recognizing an individual CM, the latter of the nosological hallmark of the individual CM. When the molecular era ushered in immunohistochemistry the spectrum and nosography of CM altered in that some CM became allelic to other cohorts of NMD, e.g., congenital muscular dystrophies, other muscular dystrophies, distal myopathies based on different or identical mutations in the same gene. The nosological spectrum of a defective gene also enlarged by recognizing several entities with mutations in the same gene, and same or similar nosological conditions originated from mutations in different genes. Lately, however, CM were reported which lacked any individual myopathological hallmarks, but were clearly based on molecular defects, a fair number of them being newly identified ones. Few CM still remain without any molecular clarification. This nosographic development rendered the original definition of such new CM questionable and brought uncertainty to their classification and nomenclature.
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Approach to the diagnosis of metabolic myopathies p. 277
Madhu Nagappa, Gayathri Narayanappa
DOI:10.4103/ijpm.ijpm_1088_21  
Metabolic myopathies are a diverse group of genetic disorders that result in impaired energy production. They are individually rare and several have received the 'orphan disorder' status. However, collectively they constitute a relatively common group of disorders that affect not only the skeletal muscle but also the heart, liver, and brain among others. Mitochondrial disorders, with a frequency of 1/8000 population, are the commonest cause of metabolic myopathies. Three main groups that cause metabolic myopathy are glycogen storage disorders (GSD), fatty acid oxidation defects (FAOD), and mitochondrial myopathies. Clinically, patients present with varied ages at onset and neuromuscular features. While newborns and infants typically present with hypotonia and multisystem involvement chiefly affecting the liver, heart, kidney, and brain, patients with onset later in life present with exercise intolerance with or without progressive muscle weakness and myoglobinuria. In general, GSDs result in high-intensity exercise intolerance while, FAODs, and mitochondrial myopathies predominantly manifest during endurance-type activity, fasting, or metabolically stressful conditions. Evaluation of these patients comprises a meticulous clinical examination and a battery of investigations which includes- exercise stress testing, metabolic and biochemical screening, electrophysiological studies, neuro-imaging, muscle biopsy, and molecular genetics. Accurate and early detection of metabolic myopathies allows timely counseling to prevent metabolic crises and helps in therapeutic interventions. This review summarizes the clinical features, diagnostic tests, pathological features, treatment and presents an algorithm to diagnose these three main groups of disorders.
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Electron microscopy in the diagnosis of skeletal muscle disorders: Its utility and limitations p. 291
Rashmi Santhoshkumar, Gayathri Narayanappa
DOI:10.4103/ijpm.ijpm_1113_21  
Electron microscopy (EM) has a substantial role in the diagnosis of skeletal muscle disorders. The ultrastructural changes can be observed in muscle fibers and other components of the muscle tissue. EM serves as a confirmatory tool where the diagnosis is already established by enzyme histochemistry staining. Although it is indispensable in the diagnosis of rare forms of congenital myopathies not appreciated by light microscope, such as cylindrical spiral myopathy, zebra body myopathy, fingerprint body myopathy, and intranuclear rod myopathy, in cases not subjected to histochemical staining, it is required for definitive diagnosis in certain groups of muscle disorders, which includes congenital myopathies, metabolic myopathies in particular mitochondrial myopathies and glycogenosis, and in vacuolar myopathies. It does not have diagnostic implications in muscular dystrophies and neurogenic disorders. In the recent past, despite the availability of advanced diagnostic techniques, electron microscopy continues to play a vital role in the diagnosis of skeletal muscle disorders. This review gives an account of ultrastructural features of skeletal muscle disorders, the role of EM in the diagnosis, and its limitations.
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Laboratory perspectives for Leprosy: Diagnostic, prognostic and predictive tools p. 300
Kiran Preet Malhotra, Nuzhat Husain
DOI:10.4103/ijpm.ijpm_1083_21  
The diagnosis of leprosy poses several challenges. The bacillary load, serology, and tissue response are determined by the host immune status, which make individual tests unsuitable across the spectrum. The sensitivity of tests for identifying paucibacillary cases remains limited, on the other hand, many tests lack specificity in differentiating contacts from diseased cases. Nonetheless, a plethora of laboratory tests have been added to the armamentarium of the clinicians dealing with leprosy. In the current review, we critically analyze the tests available for diagnosis, prognostication, and prediction of treatment response in leprosy. We discuss in brief the conventional tests available and detail the newer serologic and molecular tests added over the past few years with an attempt to suggest the pros and cons of each, and the tests best fit for each clinical scenario. Slit skin smears and skin or nerve biopsies are primarily performed to exclude clinical mimics, confirm a diagnosis, and immunologically subtype the case. Antibody titres of phenolic glycolipid-1 and its synthetic variants can be measured in serum and saliva and provide noninvasive means to detect leprosy with good specificity. Conventional, quantitative, real-time, and other variants of PCR can detect M. leprae DNA and have been used to effect in blood, tissue, and urine samples. T helper I and II cytokine signatures can be used to differentiate the subtypes of leprosy. Newer machine learning algorithms use combinations of these tests to predict the development of leprosy in contacts. Tests to detect treatment response, antimicrobial drug resistance, and predict the onset of reactions in leprosy can be used to advantage. We compare the characteristics of these tests and suggest an algorithm for leprosy diagnosis optimally utilizing them in various clinical settings.
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Recent advances in the diagnosis of immune mediated demyelinating neuropathies p. 310
Shilpa Rao, Madhu Nagappa, Anita Mahadevan
DOI:10.4103/ijpm.ijpm_50_22  
Inflammatory neuropathies are a group of acquired neuropathies which could be due to autoimmune, infectious, paraneoplastic, or paraproteinemic etiology. The etiological diagnosis of inflammatory neuropathy is not simple, and often requires combination of clinical, electrophysiological, and histopathological findings to arrive at a precise diagnosis which is important for management of the disorder. Whereas there are comprehensive and sensitive panel of serological tests available for diagnosis of the infectious, paraneoplastic, paraproteinemic neuropathies, the diagnosis of immune-mediated demyelinating neuropathies remain a considerable challenge as there is both clinical and pathological overlap. Newer non-invasive methodologies such as high-resolution ultrasound, magnetic resonance imaging (MRI), and importantly, serological testing for antibodies are emerging, and it is essential for the practicing pathologist to be up-to-date with emerging modalities. In this review, we focus on the approach to diagnosis of immune-mediated demyelinating neuropathies.
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Hereditary neuropathies: Genetics and utility of nerve biopsy p. 318
TC Yasha, Shivani Sharma, N Gayathri, NB Nandeesh
DOI:10.4103/ijpm.ijpm_146_22  
Peripheral neuropathy is one of the most common neurological conditions of the nervous system. Hereditary neuropathies (HNs) form an important group with varying degrees of severity, causing a significant disease burden. Accurate diagnosis is essential for management, counseling, and preventing unnecessary extended workups for acquired etiologies and inappropriate treatment. Several hereditary neuropathies have characteristic or diagnostic histologic findings; however, in the era of molecular diagnostics, the role of nerve biopsy in the diagnosis of hereditary neuropathy has reduced significantly. Nevertheless, in sporadic cases, cases without a clear family history, clinical mimics, cases with rare mutations, and genetic variants of unknown significance, a nerve biopsy can confirm the diagnosis, provide an unexpected diagnosis, or direct a targeted molecular testing. HN may be non-syndromic, affecting predominantly the peripheral nervous system or syndromic where it is a part of more widespread neurological or multisystem involvement. This review summarizes the microscopic pathological features in a nerve biopsy in some of the more commonly encountered inherited peripheral neuropathies highlighting their utility in selected cases.
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Role of skin punch biopsy in diagnosis of small fiber neuropathy-A review for the neuropathologist p. 329
Deepti Narasimhaiah, Anita Mahadevan
DOI:10.4103/ijpm.ijpm_92_22  
Over the last three decades, skin punch biopsy has become the gold standard for diagnosis of small fiber neuropathies, including autonomic neuropathies commonly seen in diabetics, patients with HIV, and children with hereditary sensory autonomic neuropathies and toxin-induced neuropathy. Clinical, biochemical, electrophysiological tests are inconclusive, making it difficult to diagnose and initiate treatment. A skin punch biopsy is easy to perform in the outpatient clinic, is highly sensitive, and provides an objective diagnosis. Importantly, it helps avoid performing invasive nerve biopsy in patients with small fiber neuropathy, thereby preventing complications such as non-healing of the biopsy site, which is common in these patients. Secondly, the greatest advantage of skin punch biopsies is that they can be repeated any number of times, unlike a nerve biopsy, and are useful to evaluate disease progression and therapeutic response. More recently, its use has been expanded to the diagnosis of large fiber neuropathies, inherited demyelinating neuropathies, etc., obviating the need for a nerve biopsy. The European Federation of Neurological Societies has published guidelines for evaluation to ensure uniformity with regard to the site of biopsy, processing, and quantification. The evaluation of the skin biopsy involves morphometric assessment of the intraepidermal nerve fiber density using PGP 9.5 immunostained sections by bright-field microscopy. This review focuses on the practical aspects of skin punch biopsy and its utility for the practicing pathologist.
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REVIEWERS Top

Reviewers p. 337
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