Acta Neuropathol (2010) 119:7–35 major opportunistic pathogen in the CNS of AIDS patients [248], infect a wide range of cell types within the CNS including astrocytes, ependyma, and microvascular endo- thelium. A mosquito-borne ﬂavivirus that has recently appeared in North America, West Nile virus (WNV) infects a variety of tissues throughout the body, but within the CNS appears to favor neurons over astrocytes [8]. ‘Neu- ronotropism’ of viruses is shared by other agents, e.g., the rabies virus, which also appears to spare astrocytes, though the proliferation of uninfected reactive astrocytes is an inevitable result of rabies virus-associated encephalomyeli- tis. JC virus, a human polyomavirus of the Polyomaviridae family, shows selective infection and eventual destruction of oligodendroglia in immunosuppressed individuals, leading to neurologic deterioration caused by progressive multifocal leukoencephalopathy (PML). JC virus may also infect astrocytes, and in situ PCR techniques suggest an even broader repertoire of cells that are vulnerable to JC virus infection [132, 250]. In this context it is also interesting to note that effector CD8? T cells form immunological synapses with virally infected astrocytes, resulting in pro- nounced changes in astrocyte morphology (and presumably in function as well) as well as potential clearance of infected cells [12, 13]. When bacterial (and some fungal) microorganisms cause a leptomeningitis, a clinical imperative is to prevent this meningitis from evolving into a meningo-encephalitis or cerebritis that leads to signiﬁcant injury, necrosis, and inﬂammation of the brain parenchyma with far more seri- ous neurologic morbidity than an infection isolated to the subarachnoid space. The anatomic structure largely responsible for preventing parenchymal injury in the presence of meningitis is the glia limitans, formed at the pial-subarachnoid interface by plump foot processes of reactive astrocytes, ﬁbromeningeal cells, and an overlying basement membrane, in a manner that shares similarities with glia scar formation (Fig. 4d). A breach of the glia limitans may occur because of toxins released by the inﬂammatory inﬁltrate associated with a meningitis (espe- cially the toxic molecules released by polymorphonuclear leukocytes/PMN) or frank necrosis of brain parenchyma underlying an inﬂammatory inﬁltrate resulting from occlusion/thrombosis of meningeal vessels. Seizure disorders/epilepsy Reactive astrogliosis is variable, but often prominent, in almost all forms of seizures, and is perhaps most notable in the setting of hippocampal sclerosis, the most common neuropathological substrate of intractable temporal lobe epilepsy [64]. Astrocytes proliferate in regions of pyrami- dal neuron loss, usually the endfolium and CA1 segments. In mouse models of severe epilepsy, reactive astrocytes 21 lose their non-overlapping domains and exhibit a tenfold increase in overlapping processes, concurrent with an increase in synaptic spine density [169]. The nature of reactive astrogliotic changes varies with the intensity and duration of the seizure disorder. The morphologic substrates of epileptic disorders are becoming understood as high-resolution neuroimaging techniques guide neurosurgeons to likely ‘epileptogenic foci’, thereby enabling surgical removal and providing novel lesions for pathologic examination from patients who are relatively ‘early’ in the course of their epileptic disorder [64, 150, 152]. The neuropathological ﬁndings within the foci of cortical dysplasia found in severe intractable epilepsy include pronounced dyslamination of the neocortex, neuro- nal dysmorphism and massive enlargement (‘giant’ neurons), gemistocyte-like ‘balloon cells’ [47]. Of interest is that some of these cellular elements show immunohisto- chemical evidence suggesting differentiation along both neuronal and astrocytic lines [47]. The most severe examples of focal cortical dysplasia (FCD) closely resemble the tubers found within the neocortex of individuals with tuberous sclerosis complex (TSC), and cells within severe FCD or TSC tubers exhibit distinct mechanisms for activating components of insulin-signaling pathways important in cell growth and metabolism, probably reﬂecting a modulating effect of TSC1 and TSC2 gene products on these pathways [152, 246]. It is also interesting to note that pronounced astrocytic abnormalities have been described in severe FCD with intractable pediatric epilepsy, including astrocytes with high densities of Rosenthal ﬁbers (Fig. 6b, c), comparable to those seen in Alexander’s disease [111], a genetic disorder with mutation of the GFAP gene that is also associated with seizures and other symptoms (see below). In addition to simply being passive responders to neu- ronal changes caused by seizure activity, various lines of recent evidence suggest that reactive astrocytes may play functional roles in mechanisms causing seizures and epi- lepsy, particularly in chronic relapsing forms. For example, various antiepileptic therapeutic agents block calcium- signaling in astrocytes [240]. In mesial temporal lobe epilepsy with hippocampal sclerosis, neuropathological ultrastructural evaluations suggest that reduced levels of AQP4 and dystrophin in perivascular foot-processes of astrocytes and reactive astrocytes may lead to perturbed water ﬂux through astrocytes with impaired buffering of K? and an increased propensity for seizures [61, 212]. In Rasmussen’s encephalitis, seizures are associated with perivascular reactive astrogliosis and pronounced hyper- trophy of astrocyte endfeet (Fig. 6a), as well as with areas of apparent astrocyte apoptosis and loss, and certain evi- dence suggests that autoimmune induced (cytotoxic T lymphocyte-mediated) perturbation of astrocyte function and astrocyte degeneration may contribute to the seizure 123