22 disorder [16, 256]. Reactive astrocytes may also play a role in focal epilepsy following traumatic, ischemic, or infec- tious brain injury. Experimental evidence and modeling simulations suggest that during the BBB breakdown incurred by such insults, exposure of reactive astrocytes to albumin and other serum proteins leads to reduced clear- ance by reactive astrocytes of synaptic glutamate and K? that in turn facilitate seizure-like activity and epilepto- genesis [51, 74]. Multiple sclerosis and autoimmune inﬂammatory disorders The CNS is affected by a number of different autoimmune inﬂammatory conditions. Reactive astrogliosis is a not only a prominent feature of these conditions, but various lines of evidence point towards central roles for reactive astrocytes in key pathogenic disease mechanisms discussed below. In the most common (Charcot) type of multiple sclerosis, plaques of demyelination are interspersed with and sur- rounded by reactive astrocytes and there are widespread regions of focal reactive astrogliosis of varying intensity throughout white matter and in some regions of gray matter [117, 130]. Astrocytes in demyelinating disease may exhibit unusual nuclear and cytological features. They may contain multiple distinct nuclei, especially in chronic dis- ease. Such enlarged multinucleated astrocytes are often referred to as ‘Creutzfeldt astrocytes’ or ‘Creutzfeldt– Peters cells’ [65, 117, 163, 185]. The multiple nuclei within these astrocytes may be fragmented, such that the appear- ance of a given cell resembles an atypical or ‘granular mitosis’ of the type often encountered in high grade glio- mas. Demyelinating lesions may also exhibit astrocytes that label with markers of cell division [45]. The obvious diagnostic pitfall here is that a small biopsy from the edge of a demyelinating plaque may suggest a malignancy rather than multiple sclerosis (especially at the time of intraop- erative consultation) [45, 65, 163]. Astrocytes in multiple sclerosis may also demonstrate the phenomenon of ‘emperipolesis’, i.e., an astrocyte apparently engulﬁng one or more other cells such as oligodendroglia [81] or lym- phocytes [75]. The role of this process in the pathogenesis or progression/chronicity of multiple sclerosis is not cer- tain. It should be emphasized that both multinucleation of astrocytes and astrocyte emperipolesis also occur in other disorders, including certain tumors and longstanding spongiform encephalopathy [45, 81, 155, 217]. The roles of astrocytes in multiple sclerosis and other autoimmune inﬂammatory disorders are under intense investigation and are likely to be complex. Astrocytes can produce a wide variety of pro- or anti-inﬂammatory mol- ecules [58, 226], and can exert potent suppressive effects on inﬂammatory cells [114]. In the multiple sclerosis like 123 Acta Neuropathol (2010) 119:7–35 model condition, experimental autoimmune encephalomy- elitis (EAE), reactive astrocytes form scar like barriers around perivascular clusters of inﬂammatory cells (Fig. 1c), and transgenically targeted disruption of these perivascular astrocyte scars in EAE exacerbates the spread of inﬂammation, increases axonal degeneration, and worsens clinical signs [251]. Nevertheless, experimental evidence suggests that reactive astrocytes can exert both pro- and anti-inﬂammatory roles that are essential in EAE [23, 251] and other conditions [226]. While such ﬁndings may at ﬁrst seem at odds with each other, they may be reconciled by evidence showing that reactive astrocytes take part both in attracting inﬂammatory cells to speciﬁc sites and in restricting inﬂammatory cells to those sites by limiting their spread into adjacent healthy CNS paren- chyma [226]. Such ﬁndings further suggest that the loss of normal functions or the gain of abnormal effects by reac- tive astrocytes may contribute to disease mechanisms in multiple sclerosis and other autoimmune inﬂammatory conditions. Consistent with this idea is the recent obser- vation that the majority ([90%) of patients with neuromyelitis optica, a CNS inﬂammatory/demyelinating disease that was once considered a rare variant of multiple sclerosis, have autoantibodies to aquaporin-4, which is expressed in the CNS only on astrocyte foot processes and that the severity of clinical signs and spinal cord lesions in such patients correlate with aquaporin-4 speciﬁc antibody titers [119, 236]. The potential involvement of astrocytes in other autoimmune inﬂammatory conditions that sometimes exhibit CNS involvement, such as systemic lupus erythe- matosus, has been suggested but has not been extensively investigated [242]. Edema Astrocytes have several mechanisms through which they can inﬂuence water balance and the potential for edema, including ion channels and pumps, the water channel AQP4 and the production of molecules such as vascular endothelial growth factor (VEGF) or NO that inﬂuence endothelial cell permeability. The role of astrocytes in edema is complex and likely to be context dependent. Although excess uptake of water through AQP4 on astro- cyte endfeet can lead to cytotoxic edema [135, 157, 264], the loss of astrocytes or the failure of astrocyte AQP4 channels can also lead to vasogenic edema or accumulation of extracellular ﬂuid [33, 157, 177, 264]. Blood brain barrier integrity Integrity of the BBB is lost after many types of CNS insults including trauma and stroke. The role of astrocytes in loss or repair of BBB functions is not well understood. A role