Noninflammatory Changes of Microglia Are Sufficient to Cause Epilepsy.

Microglia are well known to play a critical role in maintaining brain homeostasis. However, their role in epileptogenesis has yet to be determined. Here, we demonstrate that elevated mTOR signaling in mouse microglia leads to phenotypic changes, including an amoeboid-like morphology, increased proliferation, and robust phagocytosis activity, but without a significant induction of pro-inflammatory cytokines. We further provide evidence that these noninflammatory changes in microglia disrupt homeostasis of the CNS, leading to reduced synapse density, marked microglial infiltration into hippocampal pyramidal layers, moderate neuronal degeneration, and massive proliferation of astrocytes. Moreover, the mice thus affected develop severe early-onset spontaneous recurrent seizures (SRSs). Therefore, we have revealed an epileptogenic mechanism that is independent of the microglial inflammatory response. Our data suggest that microglia could be an opportune target for epilepsy prevention.

Emerging devices for epilepsy.

About 30% of people with epilepsy continue to have seizures despite a growing array of antiseizure drugs. For some of these people, surgical resection of brain tissue is an effective therapeutic option. For others, the likelihood of seizure freedom is low, and has not improved much despite the introduction of several new antiseizure drugs. The vagus nerve stimulator is the only device approved by the Food and Drug Administration (FDA), but it rarely results in freedom from seizures. Recently, 2 approaches to electrical stimulation of the brain have been reported. One device has been approved for use in Canada and in Europe, and it seems likely that one or more such devices will be approved for use in the United States. We examine some of the data from these studies in the context of the current FDA-approved drugs and devices.

Pharmacological inhibition of the mammalian target of rapamycin pathway suppresses acquired epilepsy.

Inhibition of mTOR by rapamycin has been shown to suppress seizures in TSC/PTEN genetic models. Rapamycin, when applied immediately before or after a neurological insult, also prevents the development of spontaneous recurrent seizures (epileptogenesis) in an acquired model. In the present study, we examined the mTOR pathway in rats that had already developed chronic spontaneous seizures in a pilocarpine model. We found that mTOR is aberrantly activated in brain tissues from rats with chronic seizures. Furthermore, inhibition of mTOR by rapamycin treatment significantly reduces seizure activity. Finally, mTOR inhibition also significantly suppresses mossy fiber sprouting. Our findings suggest the possibility for a much broader window for intervention for some acquired epilepsies by targeting the mTOR pathway.

The national temporal lobectomy survey.

OBJECTIVE: To assess selection criteria for temporal lobectomy and to evaluate the process for pre-surgical evaluation, informed consent, and the definition of success. METHODS: We constructed an electronic survey instrument composed of 26 questions and sent it to epileptologists and neurosurgeons at 105 US epilepsy centers. RESULTS: While variation with the number of drug failures that signify pharmacoresistance and surgical candidacy exists, there does appear to be a consensus. The definition of a successful surgery also varies. Furthermore, physicians differ with regard to appropriate preoperative tests that determine surgical candidacy and may predict surgical outcome. The informed consent process provided is thorough for some aspects of surgery and incomplete for other significant aspects. CONCLUSION: The data show that the neurological community currently does not have consistent definitions and practices in the management of pharmacoresistant epilepsy. Therefore, there appears to be need for developing a unified approach.

Infant botulism: two recent cases and literature review.

Infant botulism is a cause for significant pediatric morbidity in the United States, though early recognition and supportive care can greatly improve clinical outcomes. Since the approval of human botulism immune globulin by the United States Food and Drug Administration (FDA) for the treatment of infant botulism in 2003, the importance of prompt initiation of therapy has been emphasized, with clinical suspicion remaining the mainstay of diagnosis. In this report, 2 cases of infant botulism are described. Each presented to the Pediatric Neurology service at our institution in Upstate New York in the spring and summer months of 2007 and were felt to be related to markedly dusty environmental conditions and the probable ingestion of C. botulinum organisms present in soil. Following this, a comprehensive review of the literature regarding infant botulism in the United States is presented, wherein the pathophysiology, clinical features, epidemiology, and treatment are discussed.

Deficiency of fatty acid-binding proteins in mice confers protection from development of experimental autoimmune encephalomyelitis.

Fatty acid-binding proteins (FABPs) act as intracellular receptors for a variety of hydrophobic compounds, enabling their diffusion within the cytoplasmic compartment. Recent studies have demonstrated the ability of FABPs to simultaneously regulate metabolic and inflammatory pathways. We investigated the role of adipocyte FABP and epithelial FABP in the development of experimental autoimmune encephalomyelitis to test the hypothesis that these FABPs impact adaptive immune responses and contribute to the pathogenesis of autoimmune disease. FABP-deficient mice exhibited a lower incidence of disease, reduced clinical symptoms of experimental autoimmune encephalomyelitis and dramatically lower levels of proinflammatory cytokine mRNA expression in CNS tissue as compared with wild-type mice. In vitro Ag recall responses of myelin oligodendrocyte glycoprotein 35-55-immunized FABP(-/-) mice showed reduced proliferation and impaired IFN-gamma production. Dendritic cells deficient for FABPs were found to be poor producers of proinflammatory cytokines and Ag presentation by FABP(-/-) dendritic cells did not promote proinflammatory T cell responses. This study reveals that metabolic-inflammatory pathway cross-regulation by FABPs contributes to adaptive immune responses and subsequent autoimmune inflammation.

Cognition-induced epilepsy associated with specific emotional precipitants.

A 32-year-old woman with primary generalized epilepsy described absence events precipitated by talking about childhood sexual abuse, her epilepsy, or her father's difficulties with schizophrenia. She was referred for assessment of suspected psychogenic nonepileptic events. During simultaneous video/EEG monitoring, 30 absence seizures were recorded, 28 of which occurred while discussing one of these three specific precipitants. No nonepileptic events were seen. This finding highlights the importance of thorough investigation of ambiguous events, and confirms that specific emotional precipitants can induce seizures in susceptible people with epilepsy.

Acute ischemic stroke and hypothyroidism.

BACKGROUND: In Kentucky, the incidence and mortality associated with stroke are among the highest in the United States. Treatment of modifiable risk factors can significantly prevent stroke. Identification of additional risk factors may further reduce stroke risk. Hypothyroidism is linked to altered lipid metabolism and is associated with hyperhomocysteinemia. In this study, we examined a possible association between acute ischemic stroke (AIS) and hypothyroidism. METHODS: Records were reviewed on all consecutive patients admitted to the University of Louisville Stroke Center with a diagnosis of AIS or transient ischemic attack (TIA). RESULT: Our data revealed that 12% of patients with AIS or TIA had hypothyroidism. A significant difference was found between the prevalence of hyperhomocysteinemia in patients with hypothyroidism (45.4%) compared with the prevalence of hyperhomocysteinemia in euthyroid patients (27.8%). CONCLUSION: Hypothyroidism is common in patients with AIS and TIA. Elevated homocysteine levels associated with hypothyroidism suggest that hypothyroidism may represent a modifiable stroke risk factor. Prospective studies are needed to verify this association.