Melinda L. Estes

Astrocyte expression of mRNA encoding cytokines IP-10 and JE/MCP-1 in experimental autoimmune encephalomyelitis.

Mononuclear leukocytes preferentially accumulate in the central nervous system (CNS) during the course of experimental autoimmune encephalomyelitis (EAE). To address factors that govern leukocyte trafficking in EAE, we monitored expression of nxRNAs encoding IP‐10 and JE/MCP‐1, which are members of a family of chemoattractant cytokines. A transient burst of IP‐10 and JE/MCP‐1 mRNA accumulation in the CNS occurred, in close relation to the onset of histologic and clinical disease. In situ hybridizations showed, unexpectedly, that astrocytes were the major source of mRNAs encoding IP‐10 and JE/MCP‐1. These observations implicate astrocyte‐derived cytokines as potential chemoattractants for inflammatory cells during EAE.—Ransohoff, R. M., Hamilton, T. A., Tani, M., Stoler, M. H., Shick, H. E., Major, J. A., Estes, M. L., Thomas, D. M., Tuohy, V. K. Astrocyte expression of mRNA encoding cytokines IP‐10 and JE/MCP‐1 in experimental autoimmune encephalomyelitis. FASEB J. 7: 592‐600; 1993.

Mixed vascular malformations of the brain: clinical and pathogenetic considerations.

The clinical relevance of any scheme for classification of vascular malformations of the brain remains controversial. Widely accepted pathologic classifications include discrete venous, arteriovenous, capillary, and cavernous malformations. Of 280 cases of possible vascular malformations evaluated by a single cerebrovascular service during a 5-year period, 14 were instances of mixed vascular malformations including definite features of more than one pathologically discrete type of malformation within the same lesion. There were six instances of mixed cavernous and venous malformations in the same lesion; in all instances, the cavernous malformation accounted for the clinical presentation. There were three cases of mixed venous and arteriovenous malformations (arterialized venous malformations), presenting with the typical histoarchitectural appearance of a venous malformation, but with arteriovenous shunting; all cases were symptomatic, two with hemorrhage and one with focal neurological symptoms. There were five cases of predominantly cavernous malformations with features of arteriovenous malformation or capillary telangiectasia in the same lesion. These five cases presented clinically as angiographically occult lesions indistinguishable from a cavernous malformation. Lesions including a venous malformation were recognizable preoperatively because of characteristic imaging features of the venous malformation. Other mixed vascular malformations were indistinguishable on diagnostic studies from pure cavernous malformations. Of the 14 mixed vascular malformations, 11 included a cavernous malformation that was usually responsible for the symptomatic presentation. In the other three cases, manifestations of clinical lesions were due to arteriovenous shunting within a venous malformation. We conclude that mixed vascular malformations of the brain are rare entities with distinct clinical, radiological, and pathological profiles. Their identification generates several hypotheses about common pathogenesis or causation-evolution among different types of lesions.

Mixed Vascular Malformations of the Brain

The clinical relevance of any scheme for classification of vascular malformations of the brain remains controversial. Widely accepted pathologic classifications include discrete venous, arteriovenous, capillary, and cavernous malformations. Of 280 cases of possible vascular malformations evaluated by a single cerebrovascular service during a 5-year period, 14 were instances of mixed vascular malformations including definite features of more than one pathologically discrete type of malformation within the same lesion. There were six instances of mixed cavernous and venous malformations in the same lesion; in all instances, the cavernous malformation accounted for the clinical presentation. There were three cases of mixed venous and arteriovenous malformations (arterialized venous malformations), presenting with the typical histoarchitectural appearance of a venous malformation, but with arteriovenous shunting; all cases were symptomatic, two with hemorrhage and one with focal neurological symptoms. There were five cases of predominantly cavernous malformations with features of arteriovenous malformation or capillary telangiectasia in the same lesion. These five cases presented clinically as angiographically occult lesions indistinguishable from a cavernous malformation. Lesions including a venous malformation were recognizable preoperatively because of characteristic imaging features of the venous malformation. Other mixed vascular malformations were indistinguishable on diagnostic studies from pure cavernous malformations. Of the 14 mixed vascular malformations, 11 included a cavernous malformation that was usually responsible for the symptomatic presentation. In the other three cases, manifestations of clinical lesions were due to arteriovenous shunting within a venous malformation. We conclude that mixed vascular malformations of the brain are rare entities with distinct clinical, radiological, and pathological profiles. Their identification generates several hypotheses about common pathogenesis or causation-evolution among different types of lesions.

Coexistence of neoplasia and cortical dysplasia in patients presenting with seizures.

Summary: Tumors and cortical dysplasia are associated with epilepsy, but few studies have examined the coexistence of neoplasia and dysplasia in these patients. We studied 13 patients (age 4–29 years) with recurrent seizures of 1 month to 21‐year’ duration (median 72 months). Ten patients were aged <21 years. Imaging studies localized the lesion to the temporal lobe (10 patients), parietal lobe (2 patients), and frontal lobe (1 patient). Tumors included ganglioglioma (8 patients), dysembryoplastic neuroepithelial tumor (DNT) (3 patients), and low‐grade as‐ trocytoma (2 patients). Cortical dysplasia, including atypical aggregates of neurons (6 patients), multifocal loss of the cortical laminar architecture (7 patients), and neurons in the molecular layer of the cortex (3 patients) were observed near but separate from the tumor. Coexistence of certain tumors with cortical dysplasia, most frequently observed in the pediatric population, suggests a hamar‐tomatous/dysplastic nature of the neoplasms.

Clinical outcome after complete or partial cortical resection for intractable epilepsy

This is the first epilepsy surgery series to analyze the definition of “completeness” of resection, based solely on results of chronic scalp and subdural EEG recording. When patients had complete removal of all cortical areas with ictal and interictal epileptiform discharges, the clinical outcome was usually good. When areas with epileptiform discharges were left behind, good outcome was significantly less frequent. This correlation between complete resection and good outcome was independent of the presence or absence of CT-detected structural lesions or sharp waves on post-resection electrocorticography. These results support completeness of resection, defined by prolonged extraoperative EEG, as an important factor in seizure surgery.

Ganglioglioma and intractable epilepsy : Clinical and neurophysiologic features and predictors of outcome after surgery

Summary: Purpose: To review the clinical, neurophysiologic, and radiological data of patients with ganglioglioma who had undergone evaluation and surgery in our Epilepsy Program.

Chloroquine neuromyotoxicity. Clinical and pathologic perspective.

Six cases of toxic myopathy and/or neuropathy with chloroquine and/or hydroxychloroquine therapy are described. Two patients had unique clinical and pathologic evidence of cardiomyopathy secondary to chloroquine or hydroxychloroquine therapy. One patient had polyneuropathy secondary to chloroquine toxicity. This may be the first documentation of several features of chloroquine/hydroxychloroquine toxicity: morphologic changes in human peripheral nerve in chloroquine toxicity; chloroquine/hydroxychloroquine cardiomyopathy diagnosed by endomyocardial biopsy; and hydroxychloroquine myotoxicity. Chloroquine is a neuromyotoxin that affects nerves and cardiac and skeletal muscles. Discontinuation of chloroquine and hydroxychloroquine resulted in marked improvement in most cases. The reversibility of the symptoms emphasizes the importance of recognizing potential signs of nerve, muscle, and cardiac toxicity in patients being treated with chloroquine or hydroxychloroquine.

Temporal lobe epilepsy in early childhood

To explore the electroclinical features of temporal lobe epilepsy (TLE) in early childhood, we studied results of video‐EEG and other tests of 14 children aged 16 months to 12 years selected by seizure‐free outcome after temporal lobectomy. Four children had mesiotemporal sclerosis, 1 had cortical dysplasia, and 9 had low‐grade temporal neoplasms. The children had complex partial seizures (CPS) with symptomatology similar to that of adults with TLE, including decreased responsiveness and automatisms. Automatisms tended to be simpler in the younger children, typically limited to lip smacking and fumbling hand gestures. Scalp/sphenoidal EEC showed anterior/inferior temporal interictal sharp waves and unilateral temporal seizure onset in the 4 children with mesiotemporal sclerosis and in the child with cortical dysplasia, but EEG findings in 9 children with low‐grade temporal tumors were complex, including multifo‐cal interictal sharp waves or poorly localized or falsely lateralized EEG seizure onset. In children without tumors, video‐EEG was critical to localization of the epi‐leptogenic zone for resection, but in patients with tumors video‐EEG was less localizing and its main value was to confirm that the reported behaviors were epileptic seizures with semiology typical of temporal lobe onset.

Human astrocytes proliferate in response to tumor necrosis factor alpha.

Two different human astrocytic cell lines derived from adult epilepsy surgical specimens were exposed in vitro to concentrations of 1-100 ng/ml recombinant tumor necrosis factor alpha (TNF alpha). Results indicated dose-dependent stimulation of DNA synthesis and proliferation. Both of these effects were abrogated by treatment with monoclonal antibody specific for TNF alpha but not by irrelevant murine IgG. Immunocytochemical characterization of TNF alpha-treated and control cultures indicated that greater than 98% of proliferating cells contained cytoplasmic glial fibrillary acidic protein (GFAP), and were therefore astrocytic in nature. These studies demonstrate that growth of adult human non-neoplastic astrocytes is stimulated by TNF alpha, an inflammatory cytokine produced primarily by macrophages but also by astrocytes.

Cortical dysplasia: A histopathologic study of 52 cases of partial lobectomy in patients with epilepsy☆

In utero migrational abnormalities account for most cases of cortical dysplasia. The histopathologic appearance of cortical dysplasia is often varied, making recognition and classification difficult. We studied 52 patients with cortical dysplasia who underwent partial lobectomy for medically intractable seizures in order to devise a simple histopathologic classification schema. The incidence of observed dysplasia in lobectomy specimens over an 11-year period (n = 360) was 14%. Patients ranged in age from 3 months to 47 years at the time of surgery (mean, 19 years; 29 male and 23 female patients). The temporal lobe was involved in 34 patients, frontal lobe in 18, parietal lobe in four, and occipital lobe in three. In three patients multiple lobes showed dysplasia. Dysplasia was right-sided in 29 patients and left-sided in 23 patients. Dysplasia was focal in 23 patients, multifocal in four patients, and diffuse in 25 patients. Three main histologic patterns of cortical dysplasia were observed: (1) a cortical laminar architectural disorganization and/or malalignment of neurons (26 patients), (2) clusters of atypical neurons and glia within the cortex (28 patients), and (3) a hypercellular molecular layer with increased numbers of neurons and glia (31 patients). In 23 patients more than one pattern of dysplasia was identified. Coexistent tumors were present in 13 patients, including ganglioglioma (eight patients), dysembryoplastic neuroepithelial tumor (three patients), and low-grade astrocytoma (two patients). Tuberous sclerosis was present in four patients. We conclude that most types of cortical dysplasia can be divided into three main histologic patterns, facilitating the recognition of dysplasia. In addition to the known association with tuberous sclerosis, tumors may coexist with cortical dysplasia.