Michael Gruenthal

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.

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.

Core elements of epilepsy diagnosis and management: expert consensus from the Leadership in Epilepsy, Advocacy, and Development (LEAD) faculty

ABSTRACT Background: Although epilepsy is relatively common, only a limited number of specialized epilepsy centers exist in the United States. Therefore, epilepsy diagnosis and management frequently occur in the community setting. This can complicate patient management and suboptimal care is a potential concern. Delayed recognition and inadequate treatment increase the risk of subsequent seizures, brain damage, disability, and death from seizure-related injuries. To identify core elements of epilepsy management that should be offered to all patients, the Leadership in Epilepsy, Advocacy, and Development (LEAD) faculty assessed current practical issues and identified practices to improve patient care and outcomes. Scope: This paper presents a consensus opinion formed from a survey of 26 current LEAD faculty members, who answered 105 questions about epilepsy diagnosis and patient evaluation, treatment decisions, lifelong monitoring, and the management of special patient subgroups. Consensus agreement was concluded when ≥50% of the faculty provided the same answer. The results were compiled and areas of consensus are included in this report. The recommendations provided in this commentary are limited by the scope of the survey. Findings: Consensus was reached on several minimum standard patient management practices. Primary among these minimum standards of care is the need for diagnosis including a detailed medical history, neurological examination, discussions with caregivers, and diagnostic tests including electroencephalograms and magnetic resonance imaging. As the overall goals of therapy include seizure freedom, minimizing side effects, and improving quality of life and long-term safety, therapy decisions should consider parameters that affect these goals, including potential adverse effects of therapy. Antiepileptic drug selection should consider coexisting conditions for possible exacerbation of disease and potential drug–drug interactions. Conclusions: The core elements of epilepsy management identified here suggest minimum standards that can be used across all settings to improve consistency and quality of epilepsy diagnosis and care.

Noninflammatory Changes of Microglia Are Sufficient to Cause Epilepsy

Summary 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 hippo-campal 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.

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.

From patterns to patients What can we tell people with newly diagnosed epilepsy

When seeing a patient with newly diagnosed epilepsy, perhaps the most fundamental question asked is, “If I take this medication, will I ever have another seizure?” The answer is not straightforward or satisfying. Lacking a simple diagnostic test to tell us the best treatment and prognosis, we rely on a statistical estimate based on the epilepsy syndrome and other factors. In this issue of Neurology ®, Brodie et al.1 seek to add to our understanding of prognosis by reporting the results of a study designed to evaluate the likelihood of seizure control in adolescents and adults with newly diagnosed epilepsy for whom treatment was initiated. The study extends their previously …

Comment: Should we induce ketosis in super-refractory status epilepticus?

Persistent or re-emergent status epilepticus occurs in as many as 20% of patients treated with conventional pharmacotherapy for refractory status epilepticus.1 The prognosis associated with this “malignant” or “super-refractory” status epilepticus (SRSE) is not universally poor, making therapeutic efforts worthwhile in some cases. Unfortunately, the literature is dominated by anecdotal reports of last-resort therapies that offer little evidence to guide treatment.2

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.