Parisi, Joseph E.

Abstract Neuromyelitis optica is an autoimmune inflammatory disorder targeting aquaporin-4 water channels in CNS astrocytes. Histopathological descriptions of astrocytic lesions reported in neuromyelitis optica so far have emphasized a characteristic loss of aquaporin-4, with deposition of IgG and complement and lysis of astrocytes, but sublytic reactions have been underappreciated. We performed a multi-modality study of 23 neuromyelitis optica autopsy cases (clinically and/or pathologically confirmed; 337 tissue blocks). By evaluating astrocytic morphology, immunohistochemistry and AQP4 RNA transcripts, and their associations with demyelinating activity, we documented a spectrum of astrocytopathy in addition to complement deposition, microglial reaction, granulocyte infiltration and regenerating activity. Within advanced demyelinating lesions, and in periplaque areas, there was remarkable hypertrophic astrogliosis, more subtle than astrocytic lysis. A degenerative component was suggested by ‘dystrophic’ morphology, cytoplasmic vacuolation, Rosenthal fibres and associated stress protein markers. The abundance of AQP4 mRNA transcripts in sublytic reactive astrocytes devoid of aquaporin-4 protein supported in vivo restoration following IgG-induced aquaporin-4 endocytosis/degradation. Astrocytic alterations extending beyond demyelinating lesions speak to astrocytopathy being an early and primary event in the evolving neuromyelitis optica lesion. Focal astrocytopathy observed without aquaporin-4 loss or lytic complement component deposition verifies that astrocytic reactions in neuromyelitis optica are not solely dependent on IgG-mediated aquaporin-4 loss or lysis by complement or by IgG-dependent leucocyte mediators. We conclude that neuromyelitis optica reflects a global astrocytopathy, initiated by binding of IgG to aquaporin-4 and not simply definable by demyelination and astrocytic lysis. The spectrum of astrocytic morphological changes in neuromyelitis optica attests to the complexity of factors influencing the range of astrocytic physiological responses to a targeted attack by aquaporin-4-specific IgG. Sublytic astrocytic reactions are no doubt an important determinant of the lesion’s evolution and potential for repair. Pharmacological manipulation of the astrocytic stress response may offer new avenues for therapeutic intervention.

ObjectiveHistology reveals that early active multiple sclerosis lesions can be classified into 3 main interindividually heterogeneous but intraindividually stable immunopathological patterns of active demyelination (patterns I–III). In patterns I and II, a T‐cell‐ and macrophage‐associated demyelination is suggested, with pattern II only showing signs of a humoral immune response. Pattern III is characterized by inflammatory lesions with an oligodendrocyte degeneration. Patterns suggest pathogenic heterogeneity, and we postulated that they have distinct magnetic resonance imaging (MRI) correlates that may serve as biomarkers.MethodsWe evaluated in an international collaborative retrospective cohort study the MRI lesion characteristics of 789 conventional prebiopsy and follow‐up MRIs in relation to their histopathologically classified immunopathological patterns (n = 161 subjects) and lesion edge features (n = 112).ResultsA strong association of a ringlike enhancement and a hypointense T2‐weighted (T2w) rim with patterns I and II, but not pattern III, was observed. Only a fraction of pattern III patients showed a ringlike enhancement, and this was always atypical. Ringlike enhancement and T2w rims colocalized, and ringlike enhancement showed a strong association with macrophage rims as shown by histology. A strong concordance of MRI lesion characteristics, meaning that different lesions showed the same features, was found when comparing biopsied and nonbiopsied lesions at a given time point, indicating lesion homogeneity within individual patients.InterpretationWe provide robust evidence that MRI characteristics reflect specific morphological features of multiple sclerosis immunopatterns and that ringlike enhancement and T2w hypointense rims might serve as a valuable noninvasive biomarker to differentiate pathological patterns of demyelination. ANN NEUROL 2021;90:440–454

Abstract Context. —The World Health Organization (WHO) recently published its 4th edition of the classification of tumors of the central nervous system, incorporating a substantial number of important changes to the previous version (WHO 2000). The new WHO classification introduces 7 changes in the grading of central nervous system neoplasms, ranging in significance from minor to major, in categories of anaplastic oligoastrocytomas, meningiomas, choroid plexus tumors, pineal parenchymal tumors, ganglioglioma, cerebellar liponeurocytoma, and hemangiopericytomas. The 4th edition also introduces 10 newly codified entities, variants, and patterns, as well as 1 new genetic syndrome. A number of established brain tumors are reorganized, including medulloblastomas and primitive neuroectodermal tumors, in an attempt to more closely align classification with current understanding of central nervous system neoplasia. Objective. —To summarize and discuss the most significant updates in the 4th edition for the practicing surgical pathologist, including (1) changes in grading among established entities; (2) newly codified tumor entities, variants, patterns, and syndromes; and (3) changes in the classification of existing brain tumors. Data Sources. —The primary source for this review is the WHO Classification of Tumours of the Central Nervous System, 4th edition. Other important sources include the 3rd edition of this book and the primary literature that supported changes in the 4th edition. Conclusions. —The new edition of the WHO blue book reflects advancements in the understanding of brain tumors in terms of classification, grading, and new entities. The changes introduced are substantial and will have an impact on the practice of general surgical pathologists and neuropathologists.

Abstract Context. —Malformations of cortical development (MCDs) are an important cause of pharmacoresistent epilepsy and are frequently diagnosed in surgical pathology. The lack of uniform tissue processing and standard histopathologic nomenclature to describe MCDs has resulted in diagnostic ambiguity. Objective. —To describe the immunohistochemical findings of MCDs from a relatively large surgical epilepsy cohort and incorporate terminology that more adequately reflects the histopathologic findings into a contemporary classification of MCD. Design. —Utilizing the Mayo Clinic Rochester Surgical Pathology Database and patient records, 53 patients with previous intractable epilepsy and a known malformation of cortical development were identified. All of the cohort's paraffin embedded surgical specimens were resectioned and stained with hematoxylin-eosin, Luxol fast blue/cresyl violet, neurofilament protein, and glial fibrillary acidic protein. Each specimen was reviewed histologically and categorized according to a proposed focal MCD classification scheme that substitutes cytoarchitectural dysmorphism for cortical dysplasia and architectural disorganization for microdysgenesis. Results. —An MCD was recognized in 49 patients and grouped into 1 of the following 4 categories: (1) cytoarchitectural dysmorphism with balloon cells (n = 19), (2) cytoarchitectural dysmorphism without balloon cells (n = 12), (3) architectural disorganization (n = 8), or (4) polymicrogyria (n = 9). Conclusions. —The histopathologic features of focal MCD in a large epilepsy surgical cohort by using practical immunohistochemistry and a contemporary MCD classification scheme are described. It is proposed that the term focal cortical dysplasia be renamed as focal malformations of cortical development.