Epilepsy: A Comprehensive Textbook
2nd Edition
© 2008 Lippincott Williams & Wilkins
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Chapter 12
General Neuropathology of Epilepsy
Michael A. Farrell
Ingmar Blümcke
Negar Khanlou
Harry V. Vinters
Introduction
The history of the study of structural brain changes in patients with intractable epilepsy is characterized by continuing debate concerning the primacy of neuropathologic abnormalities in seizure genesis in temporal lobe epilepsy (TLE) (see Chapter 13), and intractable seizure disorders in infants and children,4,156,157 and subtle cortical cytoarchitectural alterations in primary generalized epilepsy.113,119 This chapter will focus on neocortical pathologic abnormalities and will rely for the most part on studies using human tissue. Specific structural alterations in brain tissue, which may serve as a final common pathway for the development of many diverse epilepsy-associated conditions, are discussed. Neuropathologic changes that may be attributed to epilepsy, including the neuropathologic consequences of status epilepticus (SE), are also discussed. Characteristic neuropathologic conditions that result in epilepsy syndromes (excluding developmental malformations but including epilepsy-associated neoplasms) are described.
Are There Unique Morphologic Substrates That Subserve Intrinsic Epileptogenicity in Human Neocortex?
Advances in epilepsy neuroimaging53,54,144,158 have created new challenges for the diagnostic neuropathologist, but also provide a unique opportunity to better characterize the nature of the epileptogenic lesion. A key issue in the investigation of patients with lesional epilepsy is to determine the relative contribution of the lesion and of the surrounding perilesional brain tissue to seizure genesis. Virtually all epilepsy-associated lesions may also occur in the absence of epilepsy. What, then, distinguishes the lesion that has caused epilepsy from the one that has not? Is there an underlying genetic basis for epilepsy susceptibility in such patients, and/or are there unique structural changes present in the perilesional brain tissue that provide the pathologic substrate for seizure generation? There is good evidence that some lesions are of themselves intrinsically epileptogenic; in this regard dysplastic cortical tissue is hyperexcitable.34,110 However, hyperexcitability alone is insufficient for seizure genesis. None of the epilepsy lesions has ever been shown to demonstrate spontaneous depolarization using current patch clamp techniques in an in vitro environment. Furthermore, it is clear that some lesions such as cavernous angiomas cannot be intrinsically epileptogenic, and in such cases alterations in the surrounding cortex will almost certainly provide the key to understanding seizure genesis.178
It is useful to consider a number of definitions that relate to the epileptogenic lesion and surrounding brain tissue. The lesion itself may or may not contain functionally active neural tissue. The epileptogenic zone is the area located immediately adjacent to the lesion, which is essential for seizure genesis and whose removal is generally considered to be essential for improved seizure control.17 Usually, but not always, the epileptogenic zone includes the seizure onset zone. Ideally, the functional deficit zone, which by modern neuroimaging techniques is shown to have functional abnormalities during seizure development, overlaps with the epileptogenic zone, though again this may not always be the case. Ictal symptoms result when an area of cortex is activated during epileptiform discharge and is referred to as the symptomatogenic zone. Interictal spikes utilized in the past for localization purposes reflect activity in an irritative zone, which may or may not be included within the epileptogenic zone. Finally, there is a defined area from which the seizure typically begins, referred to as the seizure onset zone. Ideally, the area in the immediate vicinity of the epileptogenic lesion would include all of the above zones, though seldom does this occur in practice. Spectacular advances in neuroimaging have led to a situation whereby the pathologist in receipt of tissue originating from epilepsy surgery can now be more certain that the resected material includes the epileptogenic zone. Additional techniques such as magnetoencephalography (MEG) have been used to map the extent of the epileptogenic zone surrounding relatively inert epilepsy-inducing lesions such as cavernomas.92,124
In attempting to determine if there is a specific pathologic change in the epileptogenic zone, immediate difficulties are encountered in terms of procuring adequate control tissue. Comparison of perilesional tissue from patients without epilepsy with the perilesional epileptogenic zone from patients with epilepsy, both having similar underlying lesions, would go a long way toward resolving the nature of any epilepsy-induced brain changes. Rarely has this been achieved. Nevertheless, new developments in molecular and pathologic techniques have provided a unique opportunity to answer questions regarding specific structural changes in the epileptogenic zone.40,41,118,121,182 Standard immunocytochemical techniques have now been supplemented with a bewildering array of sophisticated analytic techniques capable of probing the genetic and neurochemical profile of individual neurons within an epileptogenic zone. Laser capture microscopy facilitates analysis of individual neurons both in terms of neurochemical profile and surface receptor expression. Coupled with microarray studies of gene expression, it is now possible to build a very accurate genetic profile of individual neurons arising within the epileptogenic zone.27 Additionally, in vitro slice current-clamp recordings have been obtained from neurons in dysplastic brain tissue.139
Any morphologic approach to the study of the epileptogenic zone must go some way to explaining the key neurophysiologic
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events in seizure genesis, namely, the recruitment and repetitive and sustained synchronous discharge of groups of neurons. Since the first Golgi studies, there has been awareness that epileptogenesis is associated with altered synaptic morphology in groups of neurons. More recently, the concept of an intrinsic deficit in neuronal function has been confirmed by the demonstration of genetically determined alterations in structural and functional properties of neuronal ion channels.64,170
Decreased Inhibition–Increased Excitation
Morphologic studies to date have focused on the demonstration of decreased inhibition or increased excitation in the epileptogenic zone. At the very least the concept of decreased inhibition (γ-aminobutyric acid [GABA]-ergic) is simplistic and does little to elucidate the sequential change that undoubtedly take place in the epileptogenic zone as seizures become more chronic, more prolonged, and generally more severe. Attempts to determine the severity of loss of inhibitory interneurones108,120 coupled with the extent of increased excitation, resulting perhaps from axonal sprouting leading to new facilitated excitatory pathways,135 is perhaps beyond the resolution of even the sophisticated neuropathology techniques outlined above. Probing more deeply, it is difficult to see how alterations in receptor density expression on individual neurons might be used to define the origin of an epileptic focus, especially as evidence for the existence of intrinsically epileptic neurons is still not completely convincing.76,93,111,126,149 In an individual epileptogenic zone it may well be that very subtle alterations in inhibition combined with reorganization of excitatory circuits (glutamatergic) will be sufficient to result in epileptogenesis. The complexity of the decreased inhibition–increased excitation concept is illustrated by studies on chandelier cells and other cortical inhibitory interneurons in epileptogenic brain tissue, in which there is considerable variation of results within and between individual cases.6,48,49,71,88
The Neocortex in Temporal Lobe Epilepsy
Human neocortical neurons can, in response to stimulation, generate bursts of action potentials, which are caused by activation of N-methyl-D-aspartate (NMDA) receptors.13,14,65 Neurons adjacent to cavernous angiomas show spontaneous excitatory and inhibitory synaptic events and, following stimulation, demonstrate multiple action potentials.178 Spontaneous inhibitory potentials related to GABA receptor activation may also be demonstrated in human brain slices.12,15,165 Pharmacologic manipulation of receptors can lead to generation of epileptiform activity in resected neocortex, but receptor blockade or stimulation in isolation is often insufficient—the addition of an electrical stimulus being required to generate epileptiform discharges.52 Nevertheless, there is increasing evidence that synchronization, a key element in the generation of epileptiform discharges, is in part mediated by GABA receptor–mediated potentials in epileptogenic neocortex.43
Cortical Dysplasia (CD)
The spectrum of cortical dysplasia (CD)128 almost certainly extends beyond the classic description of Taylor et al., in which a combination of balloon cells and large malorientated neurons with coarse Nissl substance were the defining pathologic features.166 Detailed morphometric studies of human temporal neocortex obtained from patients undergoing resective surgery for TLE has shown a significant increase in mean neuronal somal volume in neocortical and ectopic white matter neurons.26 This subtle form of CD is not recognizable without recourse to morphometry. It is reasonable to assume that the neurophysiologic properties of classic “Taylor type” CD might also be present in subtle CD.126 For many years it has been recognized that CD tissue shows a general decrease in density of inhibitory neurons and an increase in excitatory neurons. However, detailed quantitative analysis of CD demonstrates considerable variation in the distribution and severity of GABAergic system alterations both within and between cases.3,30,64,159,167 Additionally, these studies have demonstrated considerable variation in the number of synapses per neuron both between different cases and within individual cases. The difficulty with all of these studies is a determination of the contribution of the epileptic activity itself to alterations in synaptic density, especially in terms of functional reorganization that might contribute to new synapse formation.
Intracellular recordings from the giant neurons of CD (but not from the balloon cells) show evidence of hyperexcitability when depolarized, in contrast to the balloon cells, which are essentially inert.34 Additionally, these large neurons have larger voltage-gated currents than normal-appearing neurons. Furthermore, the large neurons have increased immunoreactivity for glutamergic receptor subunits such as NMDA and also show alterations in the composition of NMDA subunits when compared with normal-appearing neurons from nonepileptic tissue.33 Intriguingly, some but not all “normal” neurons from CD tissue show similar consistent variations in NMDA subunit expression. However, in spite of all the excellent work that utilizes human epileptic tissue in vitro, it has not been possible, to date, to demonstrate intrinsic spontaneous epileptiform activity.
A Role for Glial Cells in Epileptogenesis
More recently, the contribution of the astrocytic component in any epileptogenic zone has received attention.42,68 Astrocytes are functionally active and express ion channels and neurotransmitter receptors similar to neurons. Astrocytes play a key role in modulating the neuronal extracellular environment. Long believed to be a relatively inert cell type, it is now widely recognized that astrocytes, through their ability to buffer potassium, may contribute to neuronal hyperexcitability.160 In virtually all structural lesions associated with epilepsy there are increased numbers of astrocytes either within or surrounding the lesion. Astrocytes possess voltage-activated potassium [K+] channels through an inwardly rectifying K+ channel (KIR), which have a critical role in buffering potassium levels.10,78,82,151 Fluctuations in extracellular calcium and potassium levels might well be the ionic basis for conversion of regular firing neurons into burst firing neurons capable of functioning as pacemaker neurons having the ability to recruit other neurons. There is recent evidence that genetic alterations in KIR channel subunits may contribute to the development of epilepsy susceptibility.68,163 Such alterations in potassium channel function might also be due to environmental factors. Impaired clearance of extracellular potassium could result in neuronal hyperexcitability. What is required now is a comparative study of glial cell functional properties in epileptic and nonepileptic brain tissue.
In summary, although there have been spectacular advances in neuroimaging and in the array of molecular techniques available to study the epileptogenic zone, the evidence, to date, for common underlying epilepsy-specific pathologic abnormalities that distinguish the epileptogenic zone surrounding an inert epileptic lesion from nonepileptogenic tissue surrounding a similar lesion is difficult to delineate.
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Common Neuropathologic Changes That Result From Epilepsy
The effects of recurrent and prolonged seizures on the developing brain and also on the fully formed adult brain require careful consideration. Before discussing whether or not specific neuropathologic changes develop as a consequence of recurrent and prolonged seizures, it is necessary to examine whether or not there are recognizable clinical deficits that occur as a consequence of seizure activity. Intuitively, all clinicians involved in the care of patients with epilepsy suspect that frequent and/or prolonged seizures amounting to status epilepticus (SE) are harmful to the developing and mature brain. Gradual decline in school performance and behavior is frequently attributed to the effects of recurrent seizure activity in children. However, a careful examination of the literature reveals a paucity of detailed long-term prospective studies that attempt to correlate seizure frequency over many years with objective measures of cognitive function. Nevertheless, in a critical review of the studies to date (however imperfect), a statistically significant relationship was confirmed between the number of seizures or the presence of SE and decreased scores on cognitive performance.50 The effect on cognitive performance was greater for patients having uncontrolled seizures of the generalized tonic–clonic type. A similar effect was not seen with partial epilepsy. When neuroimaging findings are included, it has been shown that brain atrophy in temporal lobe epilepsy as measured by quantitative magnetic resonance imaging (MRI) is the primary mediator of the effect of epilepsy duration on neuropsychological morbidity.127
In relation to the specific issue of intellectual decline following SE in adult patients, the problem is more difficult to resolve. Significant memory impairment may occur as a result of SE, though in the majority of instances this is not permanent. Frequently SE is a reflection of underlying cerebrovascular or other serious systemic disease, the presence of which more likely determines the patient’s subsequent intellectual and cognitive performance. In a series of 1,685 patients with epilepsy who underwent comprehensive neuropsychological testing, comparison of IQs and Wechsler Adult Intelligence Scale (WAIS) scores between those who experience SE and a control group who did not, failed to demonstrate any significant intellectual decline following SE.1 Although the study may be criticized on the suitability of the WAIS-R test for measuring all cognitive functions, particularly amnesia and memory, it was not possible to demonstrate any long-lasting intellectual dysfunction.
Neuroimaging Studies
Before attempting to determine if epilepsy causes seizure-induced (recurrent unprovoked or SE) permanent neuronal injury, several confounding factors must be considered, including the neurotoxicity of antiepileptic drugs, the neuropathologic consequences of any systemic illness associated with epilepsy, any brain injury sustained during seizure episodes, and the initial precipitating event such as a prolonged febrile seizure, together with the nature of the underlying process that may have caused the epilepsy to develop in the first place. It is immediately obvious that human pathologic studies are unlikely to be able to tease out these interdependent variables. Longitudinal prospective imaging studies can readily detect alterations in the volumes of specific regions such as the hippocampus and the neocortical ribbon. Surprisingly, and although in their infancy, such studies have shown that progressive brain atrophy is not an inevitable accompaniment of epilepsy and that when volume loss does occur, it does so independently of seizure frequency and antiepileptic drug usage.101 In fact, it is felt that any developing atrophy is more likely to be due to a combination effect of normal aging and the underlying disease process that caused the epilepsy to occur in the first place. It must be stressed that such studies are difficult to execute and will require large numbers and several years of follow-up.
Patients with temporal lobe epilepsy demonstrate mean reductions of from 4% to 6.6% in cerebellar volume when compared with nonepileptic control patients; in general, a longer duration of TLE with an increased lifetime number of generalized tonic–clonic seizures were present in those with cerebellar atrophy. Furthermore, the cerebellar atrophy appeared to occur independently of cerebral cortical atrophy.75
Recent neuroimaging studies, especially those which measure water diffusion through the brain, have demonstrated alterations in diffusivity after both prolonged seizure activity and single seizures. Single seizures may be followed by focal changes in diffusion-weighted imaging (DWI), which invariably return to interictal levels within a few hours.147 The pathologic correlate of the altered DWI is as yet unknown, though it is likely that transient edema may occur. Alterations in DWI that have developed following prolonged seizure or SE79 have gradually returned to interictal levels, though in a few instances the changes in DWI have been followed by brain atrophy.96 SE with minor or no motor disturbance (i.e., nonconvulsive SE), either generalized or focal, may be associated with MRI changes.37 Thus, although the neuroimaging evidence for seizure-induced neuronal injury is beginning to accumulate, currently it is difficult to be certain of the long-term significance of these changes in terms of clinically apparent brain injury.
Human Pathologic Studies
In a few well-documented human pathologic studies, it has been possible to demonstrate neuronal injury that has clearly occurred as a direct result of seizure activity. In a detailed imaging and autopsy study, a 28-year-old man was shown—during 5 months of idiopathic convulsive SE—to develop evolution of generalized cerebral cortical atrophy with severe neuronal loss and gliosis. The patient had not become hypoxic or hypotensive in the course of the illness.132 In another report, a 9-year-old girl with refractory focal SE developed progressive generalized brain atrophy over a 3-year period during which the MRI showed progression from normal through increased focal T2 signal to generalized atrophy. Brain biopsy demonstrated neuronal loss and gliosis.51 Again, there was no evidence of any confounding variable such as hypotension or hypoxia. Crossed cerebellar atrophy has been demonstrated by MRI,94,116 positron emission tomography (PET),85 and pathologically97,164 in the cerebellar hemisphere contralateral to the cerebral hemisphere from which unilateral persistent seizure activity arose, thereby providing good evidence for enhanced neuronal activity, transmitted via corticocerebellar pathways, as the likely explanation for neuronal injury.
Although the neuropathologic consequences of SE in humans have not been extensively studied in recent years,154,175 there is good evidence from autopsy examinations that widespread neuronal necrosis with varying degrees of gliomes-odermal proliferation may occur,103 though not invariably so, after SE.38 There is general agreement that the severity of such neuronal injury is less in children than in adults.70 The hippocampus shows the most striking changes, with widespread neuronal necrosis. Similar changes may be present in the thal-amus and in a patchy distribution throughout the neocortex. The extent of any associated astrogliosis or microglial cell proliferation depends, to a large extent, on the duration of a given patient’s survival following SE. Repeated episodes of SE could result in sufficiently severe degrees of neuronal loss to eventually lead to cortical atrophy.
Controversy has arisen in relation to watershed/borderzone ischemic lesions occurring in SE. In a review of the neuropathologic consequences of SE,28 which cited the classic work of
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Corsellis and Bruton, it was suggested that watershed distribution necrosis is feature of SE. In subsequent correspondence, Bruton29 explicitly stated that such lesions were not described in his original publication. In reply, the editors cited incorrect referencing, declaring that the description of watershed lesions in SE should have been credited to the classic work of Norman,123 originally published in 1966 and reprinted in 1987. Unfortunately, however, a very careful scrutiny of the original 1966 work and of the subsequent 1987 reprint has failed to locate any reference whatsoever to watershed lesions in the brains of patients dying of SE. It is our belief that neuronal necrosis having a watershed distribution cannot be attributed to SE alone and that some other contributory factor, such as profound hypotension, should be sought, either as the cause of or a complication of SE.
Common Brain Lesions Associated with Epilepsy
In this section, selected features of several characteristic neuropathologic entities associated with seizure disorders are described. Structural features of these lesions (and their relationship to epilepsy) will be emphasized and selectively illustrated. Especially in patients with temporal lobe epilepsy, “dual pathology” (e.g., mesial temporal/hippocampal sclerosis together with cortical dysplasia or a cortical neoplasm) is not infrequently encountered.146
Neoplasms
Both primary and secondary (metastatic) neoplasms of the central nervous system (CNS) are characterized by their distinctive histologic appearance, location(s), and immunohistochemical phenotype. Preoperative neuroimaging studies, including magnetic resonance spectroscopy (to look for levels of N-acetylaspartate, choline, and creatine, as well as choline:creatine ratios) may be helpful in predicting how aggressive a neoplasm is likely to be.57 The predicted biologic behavior of primary brain tumors is reflected in how they are categorized according to the World Health Organization (WHO) classification system.90,91 When astrocytic tumors are considered as a major subset of all infiltrating glial neoplasms (gliomas), their degree of malignancy is readily ascertained by examining distinctive histologic features present in the tumor—characteristics that can quite accurately be evaluated in a simple hematoxylin-eosin–stained tissue section.46 Unfortunately, these grading parameters appear to be less useful in evaluating CNS tumors in the pediatric age group.66 However, the neuropathologic diagnosis and study of brain neoplasms is now being rapidly refined using tools of immunohistochemistry and molecular genetics.112 These methodologies will almost certainly supersede evaluation of the subjective or semi-objective histologic criteria upon which tumor diagnosis is now based, in terms of their predictive value. Immunohistochemical techniques can detect evidence of tumor differentiation along astrocytic and/or neuronal lines, or (in the case of a metastasis) suggest a site of origin of the neoplasm, even when this is not apparent on initial workup of a given patient. Assessment of the “proliferative potential” of tumor cells can now be undertaken by using one or more several straightforward immunohistochemical markers (e.g., anti-Ki-67), many of them effectively used in paraffin sections,133,134 thereby allowing for meaningful studies on archival material. Without question, modifications of the histopathologic approach to classify CNS neoplasms have also resulted from recent molecular-genetic studies. Further advances in the “molecular pathology” of CNS neoplasia are likely to revolutionize how we categorize and treat gliomas, which remain highly refractory to even the “best” medical therapy. Association between allelic losses and sensitivity to polychemotherapy in oligodendrogliomas58,63,81,171 or epigenetic regulation of D-6-methylguanine-DNA methyltransferase (MGMT) with better responsiveness to temozolomide are hallmarks of this progress.74 Even tumors that we have in the past “lumped together” (e.g., using the term glioblastoma) are now known to have distinctive molecular signatures (defined by patterns of expression of epidermal growth factor receptor [EGFR] components and PTEN) that predict how these neoplasms are likely to respond to EGFR kinase inhibitors.114 Highly individualized therapy for primary brain tumors is likely to result from such advances. Further analysis of the complex molecular genetic interface between familial brain tumor syndromes (e.g., neurofibromatosis) and neurocutaneous disorders/phakomatoses is rapidly evolving.95,102,103,112
The study of neoplasms associated with epilepsy, which in general tend to behave in an anomalous (and usually fairly benign) fashion, by means of these new cellular and molecular tools will be of particular interest. However, it is important to remember that any intra-axial neoplasm, in particular one with a cortical (especially hippocampal) component (Fig. 1), can cause seizures, as can any extra-axial tumor that significantly compresses, displaces, or invades the cerebral hemispheres. In one large series of almost 500 patients with brain metastases, seizures were noted at the time of presentation or at some point during the course of the illness in over 25% of individuals. Seizure likelihood was highest with melanoma (occurring in two thirds of affected individuals), while tumors that had spread to the CNS from lung, breast, or an unknown primary were also a common cause of seizures.55 Seizures have been estimated to occur in 80% of low-grade (2 out of 4) glioma patients, in almost one third of those with high-grade glioma, 20% of those who harbor a meningioma, and one tenth of patients with primary CNS lymphoma.77 The pathophysiology of tumor-related seizures is multifactorial and extremely complex (for an excellent topical review, see reference 148). Important factors that contribute to tumor-related seizures may include a relative loss of inhibitory synapses or inhibitory interneurons in tumor-adjacent tissue, subtle pH alterations (peritumoral pH is slightly alkaline), ion level changes (e.g., decreased extracellular Mg2+), amino acid fluctuations (e.g., affecting alanine, phosphoethanolamine, and glutamine), enzymatic derangements and increased excitatory activity in peritumoral tissue secondary to abnormal glutamatergic transmission associated with altered receptor subunit expression, and abnormal intercellular communication resulting from derangements in gap junction proteins (e.g., connexins CX43 on astrocytes, CX32 on oligodendroglia, and CX26 and CX32 on neurons).
FIGURE 1. Tumors associated with intractable epilepsy, resected from two different patients. Note clear demarcation of the tumors from surrounding brain (indicated by arrows). Tumor shown in panel A is significantly hemorrhagic, whereas neoplasm in panel B is relatively homogeneous with focal cavitation. Both tumors clearly involve the cortex. (See the color insert.)
Table 1 Brain Tumors Associated with Epilepsy
Consecutive series of 722 tumor specimens obtained from the German neuropathologic data bank for epilepsy surgery
Tumor Entity WHO grade Number (%) Age (yr) Duration (yr)
Ganglioglioma I 423 (58) 25 13.6
DNET I 129 (17) 26.9 12.9
Astrocytoma, pilocytic I 37 (5) 27.2 17.2
Astrocytoma, isomorphic variant* I 13 (2) 29.4 17.8
Astrocytoma, pleomorphic and xanthochromic II 22 (3) 30.7 17.0
Astrocytoma, fibrillary II 40 (6) 33.5 8.6
Oligodendroglioma II 36 (5) 36.6 11.1
Astrocytoma, anaplastic III 22 (3) 40.1 3.2
DNET, dysembryoplastic neuroepithelial tumor; WHO, World Health Organization.
Consecutive series of 722 tumor specimens obtained from the German neuropathologic data bank for epilepsy surgery (www.epilepsie-register.de).
* A new epilepsy-associated isomorphic variant of diffuse astrocytomas was recently described.101 Number of patients encountered in our series (% of total, n = 722). Age at operation, duration of epilepsy. Note that 82% of all patients were under age 30 and had a seizure history of more than 13 years at the time of operation.
The proportion of tumors seen among resected specimens from epileptic patients varies tremendously among epilepsy surgery centers, depending obviously on the interests and expertise of local clinicians as well as referral patterns to a given institution. In large series describing the neuropathologic features of temporal lobe resections carried out for pharmacoresistent seizures, neoplasms account for 25% to more than 50% of the resultant specimens.104,105,131,179,180,181 Some tumors (see below) may coexist with foci of cortical disorganization or dysplasia. In patients with pharmacoresistent TLE, dual and even multiple lesions may be encountered (e.g., hippocampal sclerosis together with malformations of cortical development and/or low-grade neoplasms).56 The range of tumors encountered in patients with TLE is variable and includes the full spectrum of primary brain tumors, although gangliogliomas, pilocytic astrocytomas, and dysembryoplastic neuroepithelial tumors (WHO grade I tumors) are unusually common.179,180,181 Extratemporal resections for intractable epilepsy also often yield neoplasms, usually of low histologic grade and having histopathologic features comparable to those encountered in
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the temporal lobes. All studies—in both adults and children—emphasize the remarkably high likelihood of patients being seizure free (i.e., an Engel class I outcome) after tumor resection, even when only a “lesionectomy” is performed.31,67 The Bonn group, with one of the world’s largest experiences of epilepsy-associated neoplasia, has emphasized that biologically aggressive infiltrating glial tumors or tumors with a ganglion cell component (astrocytoma or ganglioglioma WHO grade III) are distinctly unusual among tumor resections performed for intractable seizure disorders.104 The biologic behavior and appearance of some of the specific tumor types commonly encountered are worth reviewing in greater detail (see Table 1).
FIGURE 2. Ganglioglioma. A. Prominent vascularity in the tumor, with scattered perivascular lymphocytes (arrows). Arrowhead indicates a granular eosinophilic (cytoid) body; several of these are shown at higher magnification in panel B. Arrow in panel B shows a lobulated, dysmorphic nucleus. C. Several lobulated and bizarre nuclei are seen, though at least one cell (at right) retains neuronal features, including nucleolated nucleus and basophilic cytoplasm. D. Several dysmorphic neurons (e.g., highlighted by arrow). (All sections stained with hematoxylin & eosin.) (See the color insert.)
Ganglioglioma
This tumor has been recognized as a distinct entity at least since the 1930s.112 Several excellent clinicopathologic reviews of experience with this entity have been published in recent years, including detailed immunohistochemical and mutational analyses that link them to malformative lesions (cortical
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dysplasia, tubers of tuberous sclerosis).22,25,106,136,152,155,183 Most commonly, epileptic seizures are the initial clinical manifestation of gangliogliomas (GGs), with focal neurologic deficits the presenting feature in fewer than 10% of cases. Patients may be symptomatic for long time periods (sometimes 10 to 20 years or more) before they come to surgical attention. Most often found in a supratentorial location, GGs are frequently encountered in the temporal lobes, and sometimes even in unusual loci such as the optic chiasm.100 Their histopathologic features and clinical behavior both suggest that these neoplasms are very slow growing (the vast majority are WHO grade I), and they seem to be most effectively treated by complete or radical surgical excision. When these tumors are resected in patients with intractable epilepsy, there is almost always a marked improvement in the seizure disorder, or at least a diminution in seizure frequency and severity; often, the surgery is curative.22,136,152,155,183 The UCLA group has estimated that progression-free survivals after gross total resection of both low- and high-grade GGs was almost identical, 78% and 75%, respectively, while these rates were 63% and 25% after subtotal resection.152
FIGURE 3. Gangliogliomas often extend into the subarachnoid space, even when they otherwise lack malignant (high-grade) features. Arrows indicate pial margin; large excrescence of tumor is seen at upper left. (Hematoxylin & eosin stain.) (See the color insert.)
FIGURE 4. Immunohistochemical features of ganglioglioma. Panel A shows a section immunostained with antisynaptophysin, whereas panels B and C show sections immunostained with primary antibodies to neurofilament. All antibodies “decorate” atypical and dysmorphic neurons; antineurofilament also highlights neuronal processes throughout the field. (See the color insert.)
GGs are characterized by an admixture of neoplastic glial elements and atypical and disorganized neuronal (ganglion) cells (Figs. 2 and 3), sometimes including binucleate or multinucleate forms and ganglion cells with dysmorphic nuclei. (A rare variant of this tumor is composed exclusively of atypical neurons, and thus more appropriately described as a gangliocytoma.) Gliosis and calcification are common in and around the neoplasm, as are cytoid bodies.112 The greatest challenge to the surgical neuropathologist is to distinguish ganglioglioma from an infiltrating glial neoplasm that extends into normal cortex; in the latter situation, neurons retain their distinctly characteristic cytologic and nuclear features. (This differential diagnosis may be extremely problematic, even impossible, at the time of frozen section/intraoperative consultation.) Most GGs are WHO grade I or II, the difference between these two grades being highly subjective, though such tumors are characterized by a relatively uniform glial component and the absence of mitoses. The glial element within the tumor may include elongated bipolar cells, typical gemistocytes, and sometimes even foci resembling oligodendroglioma. With increasing cytologic atypia and mitotic activity (usually in the glial component), the tumor grade increases to III; rarely, an otherwise typical glioblastoma (WHO grade IV) has a significant neuronal component and is thus presumed to have originated from a GG. Regions of cortex adjacent to a GG may show clear evidence
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of cortical dysplasia,40,117 and these tumors frequently extend into the subarachnoid space (Fig. 3).
Immunohistochemistry with antibodies to CD34 and MAP2 may further help to distinguish between dysplastic/neoplastic ganglion cells and entrapped normal neurons.21,22,24,112,136 As expected, the glial element within a GG is usually glial fibrillary acidic protein (GFAP) immunoreactive (though only rarely is this immunoreactivity uniform throughout the neoplasm), while the ganglionic/neuronal component is immunoreactive with antibodies to neurofilament and synaptic proteins, especially synaptophysin (Fig. 4).112 Synaptophysin immuno-stains often show a pattern of punctate immunoreactivity along ganglion cell membranes. Given the appearances of GGs, it is tempting to speculate that atypical neuronal cells within the tumors are “generating” epileptic seizure activity; however, the authors are aware of no good electrophysiologic evidence for this. There is a relative paucity of molecular genetic data on these tumors, though they frequently show polymorphisms (but not mutations) of the genes associated with tuberous sclerosis complex (TSC1 and TSC2). Ultrastructural examination of GGs, which is seldom necessary to confirm the diagnosis, shows cytoplasmic dense core vesicles (usually 125 to 180 nm in diameter) and occasional synapselike contacts between cells, the latter probably an explanation for the distinctive membranous punctate synaptophysin immunoreactivity that is a “signature” of GG, though also seen in other CNS lesions, including cortical dysplasia and the cortical tubers of tuberous sclerosis. Recent immunocytochemical and immunoblot investigations have found prominent neuronal expression of multidrug transporter proteins, including multidrug resistance–associated protein 1 (MRP1) and P-glycoprotein, in both gangliogliomas and cortical dysplasia. Major vault protein (MVP), which may also play a role in multidrug resistance, was found to be prominently expressed in GG.7,9 One obvious implication of such studies is that overexpression of molecules related to multidrug resistance may contribute to
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the intractability of tumor-related seizures. GGs and dysembryoplastic neuroepithelial tumors (see below) also contain a significant complement of microglia—their density correlating with duration of a given epilepsy as well as with seizure frequency prior to tumor resection—suggesting a functional relationship to the seizure-causing lesion, though of unclear causal significance.8 Expression of survivin, an antiapoptotic protein, has been detected in the astrocytic component of GGs—expression in more than 5% of cells being associated with more aggressive tumor behavior.143 Reelin pathway components disabled-1 and p35 have been examined using molecular techniques in GGs and were found to contain no mutations, although the relevant gene transcripts were seen in lower levels in GGs than controls.83 Immunolaser microdissection together with in situ reverse transcription and real-time polymerase chain reaction (RT-PCR) methodology has been used to study neuronal elements within GGs. The rather straightforward conclusion reached (that GGs contain neuronal elements with compromised or atypical differentiation) is perhaps less important than the compelling evidence that such technology can be used to study epilepsy-associated tumors and malformative lesions in exquisite molecular detail.62
GGs are relatively uncommon tumors in children, in whom they are also most frequently encountered in a supratentorial location, usually in the temporal lobes.67 A variant of GG with associated dense desmoplasia, appropriately termed desmoplastic ganglioglioma (DIG), has been described in infants and children.35,125 Rarely, as with almost any other neoplasm that usually behaves in an indolent fashion, an otherwise typical example of GG shows malignant “degeneration,” with the neoplastic transformation affecting both the glial and neuronal components or the glial component alone.2,22,112 On rare occasions, GG may evolve into glioblastoma.89 However, the vast majority of GGs are benign, with only a 3% recurrence rate, 2% malignant progression, and 1% death according to one series of 184 patients with a median follow-up period of 8 years.105
Dysembryoplastic Neuroepithelial Tumors
This category of neoplasm, identified and defined <20 years ago,44,45,112 shows extremely indolent behavior and a very strong association with epilepsy. Dysembryoplastic neuroepithelial tumors (DNETs) almost always occur in association with partial seizures that start before the age of 20 years, often with no associated neurologic deficit or evidence for a neurocutaneous disorder/phakomatosis. Neoplasms that would now probably be classified as DNETs were described by other names in earlier reports.112 Even though represented disproportionately in epilepsy surgery centers, they constitute just over 1% of CNS neuroepithelial tumors in those under 20 years of age, and only about 0.2% of such lesions in older patients. Large series show a slightly higher incidence of DNETs in men than in women. On gross inspection, DNETs give the appearance of “mucoid nodules situated within an expanded cortical ribbon.”112 Histologically, the tumors are characterized by (a) cortical location (most often in the temporal lobes, though DNETs have been reported in virtually all regions of the central neuraxis); (b) multinodular architecture, the nodules showing astrocytic, oligoastrocytic, or pure oligodendroglial differentiation with admixed normal-appearing neurons and astrocytes (Fig. 5); (c) foci of (nearby) cortical disorganization/dysplasia; (d) a glioneuronal element showing a columnar or alveolar structure perpendicular to the cortical surface; and (e) a characteristic appearance of neurons that appear to be floating or suspended within the myxoid matrix of the tumor.
“Simple” and “complex” forms of the tumor have been defined, the latter characterized by zones almost identical to pilocytic or fibrillary astrocytoma or oligoastrocytoma. DNETs may show nuclear atypia (among the glial element) and infrequent mitoses, although of interest is the finding in some laboratories that markers of cell proliferation can label a high proportion of cells in some regions of the tumor, a surprising observation in view of the widely held view that these mass lesions may be more akin to malformations/hamartomas than true neoplasms. They are almost always considered to be WHO grade I tumors. DNETs have slow growth, as reflected in low labeling indices for the proliferating cell marker MIB-1 (Ki-67). Neuronal cells within DNETs have been shown to be immunolabeled with antibodies to a developmentally regulated embryonal form of the neural cell adhesion molecule (E-NCAM).179 Not surprisingly, DNETs can also be immunolabeled with GFAP and a variety of neuronal markers, including β-tubulin, microtubule-associated protein-2 (MAP-2), phosphorylated and nonphosphorylated neurofilament, NeuN neuronal nuclear protein, synaptophysin, and myelin oligodendrocyte glycoprotein, among others.72,112 There is an excellent chance of complete freedom from seizures with total removal of a DNET.36,44,45,112,122 Just as with GGs (see above), the “epileptogenicity” of DNETs may result from foci of cortical dysplasia adjacent to the neoplasm, rather than the tumor itself—which has obvious implications for its definitive surgical treatment, ascertainment of “tumor-free” resection margins, etc.145,161
FIGURE 5. Dysembryoplastic neuroepithelial tumor. A,B. Representative fields in the tumor show sheets of relatively uniform round, oligodendroglia-like cells with compact nuclei and microcystic spaces. Panel C shows cells with distinctly neuronal phenotype (arrows). Neuron at right of this panel appears to be “suspended” in a vaguely mucoid matrix. Panel D shows a mitotic figure (arrow), an unusual feature in this neoplasm. (All sections stained with hematoxylin & eosin.) (See the color insert.)
Pleomorphic Xanthoastrocytoma
Pleomorphic xanthoastrocytoma (PXA), initially defined and characterized by Kepes in the early 1970s,86,87 usually appears as a superficially growing lesion with a meningeal component in young people (meningocortical PXA); presentation is usually before the age of 30 years, although as with most tumors, “outlier” examples have been encountered in older patients. PXA occurs with equal frequency in male and female patients.47,112 Ten of 47 patients documented in a review of the literature119 died at a mean of 7.5 years after diagnosis. A longstanding (mean, 4 years; range, 3 months to 16 years) history of seizures is found in almost 80% of affected patients.80 Almost one third of tumors recur following initial resection, but a 70% 10-year survival rate compares favorably with that of glioblastoma. The tumor may arise from subpial astrocytes and shows novel histopathologic features (Fig. 6): A prominent xanthomatous or foam cell component, bizarre nuclear atypia and pleomorphism with a relative paucity of mitotic figures and regions of necrosis, and frequent mononuclear inflammatory infiltrates. Some who describe this neoplasm comment on its biphasic appearance, one “phase” including compact spindle-shaped cells in a fascicular pattern, the other composed of large eosinophilic astrocyte-like cells (sometimes multinucleated) containing foamy cytoplasm.112
Special stains and immunohistochemistry demonstrate that many of the cells in a PXA are immunoreactive with anti-GFAP (Fig. 7) antibodies and have a rich reticulin network among nests of tumor cells or surrounding individual tumor cells. In addition, almost 75% of tumor specimens can be labeled with antibodies against the CD34 epitope.140 A difficult differential diagnosis may be between gigantocellular glioblastoma and PXA; immunohistochemical approaches to making this distinction have been suggested (e.g., using antibodies to different neuronal antigens).109 A rare “pigmented” variant of PXA has been described.153 Although PXA is graded as WHO II, it is recognized that anaplastic transformation may occur if there are more than five mitoses per ten high-power fields found on microscopic examination—these tumors are sometimes described as “pleomorphic xanthoastrocytoma with anaplastic features” (which seems oddly redundant) and designated WHO grade III112
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Novel, Rare and “Emerging” Tumor Entities
An isomorphic variant of diffuse astrocytomas has been identified from a series of 207 long-term epilepsy-associated tumors (LEATs).23,150 These tumors can occur in different lobes, including a temporal location; diffusely infiltrate the neocortex; and express GFAP. In contrast to ordinary astrocytomas, neither MAP2 nor p53 are expressed within them and the proliferative activity is very low (Ki-67 labeling index usually <1%). By use of Kaplan-Meier curves, this isomorphic subtype had 50% fewer recurrences at 7.5 years and an estimated long-term survival of 80%. Temporal location did not influence the outcome, and the presence of epilepsy per se in affected patients was also not a prognostic factor.
A novel epilepsy-related clinicopathologic entity was recently designated as angiocentric neuroepithelial tumor (ANET).98,174 Neuropathologic hallmarks of ANETs include an angiocentric polarity with GFAP-positive fusiform and bipolar astrocytic cells arranged around blood vessels. There is also a neuronal component, which may be best visualized using immunohistochemical markers for synaptophysin, chromogranin, or neurofilament protein. An ependymal component may also be present (expressing epithelial membrane antigen [EMA] immunoreactivity) and most tumors show stalk-like extensions to the ventricle on MRI.
FIGURE 6. Pleomorphic xanthoastrocytoma. All panels (from hematoxylin & eosin–stained sections) show a pleomorphic neoplasm composed of spindled or compact cytoplasmic elements. Panel B shows a sparse lymphoid infiltrate, a common finding in this tumor. Xanthomatous or foamy cells sometimes aggregate into small groups (arrow in panel C). Cells with foamy, clear, and multiloculated cytoplasm and pleomorphic nuclei are highlighted in panel D. Despite this, mitoses are relatively rare in this tumor. (See the color insert.)
In considering LEAT, ANET, and other “new” tumors, there has been an unfortunate and disorienting tendency to “re-review” clinicopathologic material and to redefine tumor entities, including those associated with epilepsy.32 For example, DNETs would in most instances have simply been described as astrocytomas, oligoastrocytomas (mixed gliomas), or gliomas before the “birth” of this new entity—the nosology of which, however, is now widely accepted. This means that earlier series describing tumor-associated epilepsy or epilepsy-associated tumors need to be re-evaluated in light of the newly evolving tumor nomenclature, which perhaps has created some confusion and an implicit tendency to discount older studies of epilepsy-associated CNS neoplasms, but has led to a more realistic appreciation of the neurobiology of tumors that cause (or are often associated with) seizures.
Meningioangiomatosis (MA), a rare entity, deserves mention because of its strong association with intractable epilepsy and its unique nosology—understanding MA involves the combined study of neurogenetics and vascular, malformative, and neoplastic diseases of the CNS.69 This lesion often occurs with
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neurofibromatosis type 2 (NF2) and usually presents before the age of 20 years with headache and intractable seizures. Grossly, the lesions appear as plaque-like structures overlying the cortex, single in sporadic examples but often multiple when present in the context of NF2. Neuropathologic features in a resection specimen include disorganized and gliotic islands of neuroglial tissue surrounding thickened, sclerotic, and focally calcified blood vessels, which may in turn contain meningothelial elements in their walls—psammoma body-like structures may be present in the adjacent brain, which may also harbor an overlying meningioma (Fig. 8).
Brain Inflammation and Epilepsy
One of the most common “inflammatory” lesions encountered in corticectomies (including temporal lobectomies) for epilepsy is the chronic inflammatory reaction (often with a pronounced granulomatous component) that is left by depth electrodes implanted for preoperative monitoring purposes within the brain parenchyma. Leaving aside the obvious fact that any inflammatory disorder of the brain (especially viral encephalitides, e.g., caused by herpes simplex or West Nile virus infection) may be accompanied by seizure activity, evidence is emerging of an increasingly important role for brain inflammation in epilepsy (see Chapter 25). Steroids and adrenocorticotropic hormone (ACTH) have powerful anticonvulsant effects, especially in children with infantile spasms or West syndrome. Seizure activity is regularly associated with a cerebrospinal fluid (CSF) pleocytosis and elevated CSF proinflammatory cytokines. Though controversial, evidence is emerging that patients who develop temporal lobe epilepsy with hippocampal sclerosis (TLE-HS) following febrile convulsions may have been at risk for developing TLE-HS because of polymorphisms in the interleukin (IL)-1β-511T allele.84 Studies of temporal lobes resected from patients with temporal lobe epilepsy have demonstrated overexpression of NFκB, a transcription factor involved in acute inflammation.39 There is indirect evidence that new-onset refractory status epilepticus (NORSE) may have an inflammatory basis in that many patients have an antecedent
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inflammatory/infectious illness and CSF usually shows a pleocytosis.177 A subgroup of patients with encephalitis may go on to develop postencephalitic catastrophic epilepsy with progressive brain atrophy due to persistence of the inflammatory process.11,169
FIGURE 7. Pleomorphic xanthoastrocytoma (PXA). A. Atypical mitosis, a relatively rare finding in most PXAs (Hematoxylin & eosin–stained section.) B. Glial fibrillary acidic protein–immunostained section shows prominent cytoplasmic immunoreactivity. (See the color insert.)
FIGURE 8. Meningioangiomatosis, with overlying meningioma. A. Arrows indicate the interface between brain parenchyma (lower portion of the image) and meningioma (above). The brain parenchyma shows thickened, focally calcified blood vessels surrounding islands of disorganized neuroglial tissue. Details of the parenchymal abnormality are seen in panel C; arrow (in C) highlights a region of dystrophic calcification. Panel B shows a thrombosed thickened artery (arrow) with prominent smooth muscle cell hyperplasia in its wall. (All sections stained with hematoxylin & eosin.) (See the color insert.)
Table 2 Rasmussen Syndrome: Diagnostic Criteria
Rasmussen encephalitis (RE) can be diagnosed if either all three criteria of Part A or two out of three criteria of Part B are present. Check first for the features of Part A, then, if these are not fulfilled, of Part B.
PART A:
  1. Clinical focal seizures (with or without epilepsia partialis continua) and unilateral cortical deficit(s)
  2. Electroencephalographic (EEG) unihemispheric slowing with or without epileptiform activity and unilateral seizure onset
  3. Magnetic resonance imaging (MRI) unihemispheric focal cortical atrophy and at least one of the following:
    1. Gray or white matter T2/fluid-attenuated inversion recovery (FLAIR) hyperintense signal
    2. Hyperintense signal or atrophy of the ipsilateral caudate head
PART B:
  1. Clinical epilepsia partialis continua or progressive* unilateral cortical deficit(s)
  2. MRI progressive* unihemispheric focal cortical atrophy
  3. Histopathology T-cell-dominated encephalitis with activated microglial cells (typically but not necessarily forming nodules) and reactive astrogliosis
Numerous parenchymal macrophages, B cells, or plasma cells or viral inclusion bodies exclude the diagnosis of RE.
* “Progressive” means that at least two sequential clinical examinations or MRI studies are required to meet the respective criteria. To indicate clinical progression, each of these examinations must document a neurologic deficit, and this must increase over time. To indicate progressive hemiatrophy, each MRI must show hemiatrophy, and this must increase over time (Reproduced with permission from Bien CG, Granata T, Antozzi C, et al. Pathogenesis, diagnosis and treatment of Rasmussen encephalitis: a European consensus statement. Brain. 2005;128:454-471.)
Rasmussen Syndrome
Rasmussen syndrome (RS; Rasmussen encephalitis [RE]), the classic form of epilepsy-associated chronic inflammatory disorder, is characterized by intractable focal seizures (usually epilepsia partialis continua [EPC]) with progressive hemiparesis, both attributed to chronic pathogen-free inflammation of gray and white matter, with progression to unihemispheric atrophy.137,138,141 A recent European consensus meeting on RS has formulated diagnostic criteria, which incorporate clinical, electroencephalographic (EEG), MR, and pathologic findings19 (see Table 2). The cause of RS remains a mystery. Although the pathologic appearances of affected brain tissue suggest a chronic viral infection, no such virus has ever been consistently isolated from RS brain tissue or discovered within it using modern molecular techniques (e.g., PCR).59,173 Circulating anti-glu-R3 antibodies were reported to be of etiologic importance in some patients with RS,5,142 but subsequently these antibodies were found to also occur in other seizure disorders.107,176 Furthermore, it has never been possible to passively transfer RS to animals using glu-R3 antibodies. Very recently, autoantibodies against the NMDA glutamate receptor (NMDA-type GluR) ∊2 subunit and its epitopes were reported in RS patients.162 However, although the initial report is highly promising, the diagnostic specificity of GluR∊2 for RS remains to be confirmed. Any explanation for RS will ultimately have to account for the unihemispheric nature of the disorder. Rarely have pathologic studies demonstrated bihemispheric involvement.168
Neuropathologic Findings
The neuropathology of RS is said to comprise four merging stages,19,20,129 the earliest of which is characterized by inflammation, especially perivascular lymphocytes, and microglial nodule formation within brain parenchyma, but little morphologic evidence of neuronal injury. In stage 2, lymphocytic infiltration increases in density and both astrocytes and microglial cells become more extensive in distribution, tending to involve all cortical layers—a so-called “panlaminar” pattern of cortical inflammation and gliosis. Patchy neuronal loss may be present. In stage 3 the neuronal population is depleted either patchily or in a panlaminar pattern, with severe cortical degeneration and gliosis. In stage 4 there is profound cortical atrophy with gliosis and vacuolation of the neuropil, rising to the level of cavitation in many cases (Figs. 9 and 10). Frequently, areas of relative cortical normality surround zones of atrophic cortex. This geographically defined severe pathologic change, often seen a few micrometers away from relatively (or entirely!) normal brain parenchyma, means that a negative brain biopsy taken with the intent of establishing the diagnosis of RE never truly excludes the diagnosis, because of the risk of sampling an unaffected region in a cerebral hemisphere that actually harbors RS. Occasionally, dual pathology including malformative elements of cortical dysplasia or vascular malformations and chronic inflammation are seen in a corticectomy originating from an epilepsy patient, suggesting that the two lesions may be etiologically connected, though the precise mechanism of this linkage remains speculative.73
FIGURE 9. Rasmussen encephalitis (RE). Panel A shows extensive cortical cavitation, in one region affecting an entire gyrus (arrows). Panel B shows a more circumscribed region of cortical injury showing faint cystic cavitation, delineated by the arrows. Panel C shows detail of the region of microvacuolization, with intense astrocytic gliosis. (All panels are from sections stained with hematoxylin & eosin.) (See the color insert.)
There is little interlobar variation in severity of the disease, though usually the occipital cortex is less severely involved than
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the others. Subcortical white matter may show evidence of axonal injury in the form of neuroaxonal spheroids, though whether this is secondary to Wallerian degeneration or represents a separate cytotoxic attack on axons is uncertain. Deep central gray matter may also be involved. Areas completely devoid of inflammation or neuronal loss may be located in close proximity to areas showing intense inflammation and cell loss. Furthermore, the inflammation/neuronal destruction varies in its timing and progression from area to area. Early changes consisting of inflammation only may be located adjacent to areas showing intense neuronal loss and gliosis. In this respect the regional variability in timing and intensity of inflammation is similar to other immune-mediated neurologic disorders of unknown etiology such as multiple sclerosis. However, the almost unique unilateral nature of RS separates it from all other immune-mediated disorders of the nervous system. Ultrastructural studies of RE/RS have failed to demonstrate viral particles consistently in brain biopsies/resections from affected patients, though rarely measles virus-like particles have been noted; rare cerebral endothelial cells in one case contained tubuloreticular inclusions of the type usually seen in skeletal muscle endothelium of patients with dermatomyositis.130 Gene expression profiling of a brain specimen from an RE patient has shown a dramatic increase in expression of several genes related to inflammation, and a pronounced down-regulation of several GluRs, especially GluR4.16
Immunopathology/Immunopathogenesis
The lymphocytic infiltrate in RS brain consists predominantly of CD8-positive T cells.18,61 The lymphocytes lie adjacent to major histocompatibility complex (MHC) class I(+)–expressing neurons and contain granzyme B, which has been suggested as the local mediator of T-cell–mediated cytotoxic neuronal death in RS.18 There is little evidence to support a humoral process in that B cells, immunoglobulin, and complement are rarely found in RS brain tissue. The T-cell infiltrate is of relatively restricted clonality,99 but as with oligoclonal bands in MS, this does not provide much enlightenment on possible or likely immunogenic stimuli that evoked the response in the first place.
As indicated above, the patchy nature of the inflammatory infiltrate in RS raises the possibility that brain biopsy, even in patients with relatively well-established disease, might yield a spuriously negative result. Therefore, the recently formulated diagnostic criteria for RE,19 which include clinical and neuroimaging considerations, are a welcome addition; adherence to these criteria may obviate the need for brain biopsy in future. However, the validity of the criteria awaits testing in prospective studies.
FIGURE 10. Rasmussen encephalitis/Rasmussen syndrome. A. Arrows indicate a poorly defined inflammatory/microglial nodule. B. Prominent angiocentric chronic inflammation in a region of brain with slight rarefaction and gliosis. Notice patchy nature of the inflammatory infiltrate. C. A meningeal vein showing dense transmural lymphocytic infiltrate without evidence of injury of the vessel wall or thrombus. (All panels are from sections stained with hematoxylin & eosin.) (See the color insert.)
Treatment
Hemispherectomy remains the mainstay of RS treatment. Decisions to offer hemispherectomy are based on the patient’s age; involvement of dominant hemisphere; severity of motor and speech deficits at the time of presentation; and the severity of seizures. The primary goal is to minimize seizure frequency and severity and, where possible, to preserve motor and language functions. In many cases this goal is not obtainable. Paradoxically, seizure activity may subside spontaneously in the later stages of the illness. A therapeutic algorithm is included in the
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consensus report on RE/RS.19 To date, trials of treatment have not taken place and most outcome reports are anecdotal. Individualized treatments carefully chosen on the basis of patient’s age, neurologic deficit, seizure frequency, and phase of the illness will remain the basis for management in the immediate future. Carefully designed multicenter trials will almost certainly be essential to establish optimal therapeutic guidelines for this rare disorder.
It has been suggested that the unilaterality of RE may in part be due to a synergy between seizures and the underlying inflammatory process.19 However, other brain lesions that give rise to intractable partial epilepsy generally do not show inflammatory changes similar to those seen in RE, so it is difficult to argue that the inflammatory changes are a secondary phenomenon, although we have seen rare cases in which cortical dysplasia is accompanied by focally prominent chronic inflammation, prompting consideration of “dual pathology” (malformative and inflammatory) in these individuals. Also, in our experience, some patients with fatal classic RS may be found at autopsy to have little or no evidence of an underlying inflammatory process, showing instead intense gliosis ± atrophy, restricted to one cerebral hemisphere. These cases are particularly difficult to understand. While the inflammatory process may have burned itself out by the time of death, the possibility remains that these unusual cases represent another disease process.
Recent insights into possible mechanisms of virally triggered immune-mediated encephalitis may go some way toward explaining RE/RS. Neonatal mice eliminate lymphocytic choriomeningitis virus (LCMV) from all tissues except the brain, where the virus persists for several years. These viral-rich neurones remain in perfect harmony with virus-specific cytotoxic T cells. Later, following exposure in adulthood to wild-type LCMV (the precipitating virus), cytotoxic T cells are triggered to attack mouse brain, causing an encephalitis similar in many respects to that seen in adult humans with RE. Infiltrating T cells exhibit biased receptor usage highly suggestive of an antigen-specific process.115
Destructive Lesions
Destructive lesions, with the appearance of regions of cystic encephalomalacia, are commonly encountered in corticectomies for epilepsy, especially in infants and children.60,172 They are presumed to represent sequelae of intrauterine, perinatal, or (rarely) postnatal brain infarcts and/or hemorrhages, the etiology of which is multifactorial, extremely complex, and beyond the scope of this chapter. For an excellent recent monograph on pathophysiologic mechanisms important in the evolution of destructive brain lesions that may cause seizures, see reference 69.
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Summary and Conclusions
Neuropathology has made vital contributions to understanding morphologic substrates of seizure disorders. This has rarely, however, been done in isolation—simple morphologic characterization of epileptogenic lesions has finite value. Rather, important advances have resulted from synergistic interactions between neuropathologists and their clinical colleagues, electrophysiologists, and (especially in recent years) neuroradiologists. The combined multidisciplinary approach to analysis of complex lesions is illuminating. Indeed, one of the great challenges going forward will be to closely compare neurohistologic findings in epileptogenic tissue with its appearances assessed using (preoperative) high-resolution and metabolic neuroimaging studies. Neurophysiologists will continue to provide important information on whether structurally abnormal tissue is also functioning in such a way as to produce abnormal discharges that may manifest as seizures—the disconnect between morphologic and functional abnormalities can often be striking and, paradoxically, informative. These correlations will be facilitated by new approaches to examining gene expression patterns in tissue, something that is now done almost routinely. High-throughput methodologies such as tissue microarray118 will be useful for comparing signaling pathway regulation in vast numbers of (surgically resected) brain specimens. The novel properties of neoplasms that cause seizures (especially GGs and DNETs; see above) will be better understood through the same molecular genetic approaches that have yielded crucial data—ones that now greatly impact treatment strategies—on high-grade gliomas. Unlike the situation with high-grade gliomas, however, most tumors that cause seizures are cured by an operation. Rasmussen encephalitis remains, unfortunately, nearly as enigmatic as it was when first described almost 50 years ago. There is much work to be done!
Acknowledgements
HVV was supported in part by the Daljit S. & Elaine Sarkaria Chair in Diagnostic Medicine. Carol Appleton assisted with preparation of the figures.
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