Similarly, it is important to check the blood levels of seizure medications when changes in metabolism are expected or in the context of suspected toxicity, but a routine practice of blood-level monitoring is a waste of time and resources.Second, better evidence is needed to guide the initiation, choice, and discontinuation of seizure medications. For example, while traditional seizure medications such as clobazam may be highly effective to treat pediatric drop attacks, newer but significantly more expensive treatments are now available. Without robust analyses comparing the effectiveness and the cost of the traditional versus novel medication options, the choice of the ideal treatment remains controversial.Another glaring controversy is the timing and safety of medication withdrawal after successful epilepsy surgery where patient goals of independence and freedom from cost and adverse effects of seizure medications must be weighed against the risks of recurrent breakthrough seizures and downstream effects of reinstated seizure precautions such as driving restrictions.Lastly, the recent increase in the use of invasive electroencephalography recordings brings with it its own challenges to define indications and ideal methods for intracranial evaluations. Subdural electrodes have the advantage of permitting extraoperative ictal recordings in addition to mapping of eloquent cortex. Stereo EEG evaluations offer the ideal intracranial method for electroclinical correlations of an epileptic network.Intraoperative electrocorticography has been equally successful in guiding surgical resections based on definition of epileptiform repetitive discharges.
Given the lack of any direct comparative effectiveness studies and similar published long-term outcomes,hydroponic rack the choice of one invasive EEG method over the other is largely dependent on the expertise of a center’s neurosurgical and epileptology faculty. In summary, controversies and epilepsy management abound, reflecting a need for more robust data.The symposium addressed topics related to the consequences of febrile status epilepticus in children and in developing animals. The goal was to address the consequences including hippocampal injury and development of hippocampal sclerosis and mesial temporal lobe epilepsy.Dr Dale C Hesdorrfer addressed the epidemiology of status epilepticus and where FSE fits in. In new ILAE definitions of SE while for treatment purposes, the revised definition is 5 minutes, for the study of consequences, the 30-minute definition remains appropriate. Time to treatment unfortunately remains much longer than we would like. Mortality of SE, while primarily a function of etiology, remains substantial. Febrile status epilepticus rarely stops on its own without administration of AEDs. Dr Shlomo Shinnar, who moderated the symposium, then discussed data on the consequences of FSE with an emphasis on results of the FEBSTAT study .Hippocampal injury as reflected in increased hippocampal T2 signal on magnetic resonance imaging occurs in about 12% of cases. When hippocampal injury is present, there is substantial shrinkage of the hippocampi within a year and development of anatomic hippocampal sclerosis, though epilepsy has likely not yet developed. Children with evidence of acute hippocampal injury had a different cytokine profile than those without such evidence and from those with a fever but no seizure.
As a group, children with FSE had somewhat smaller hippocampi at baseline than a control group with simple febrile seizures.Subsequent hippocampal growth is impaired in children with febrile SE. Dr David Masur then presented data on cognitive outcomes of children with FSE.Data from prior studies, most of which did not explicitly study memory, were reviewed. In FEBSTAT, overall intelligence was normal. In children with evidence of acute hippocampal injury, memory as measured by the Wide Range Assessment of Memory and Learning particularly verbal memory, was impaired 5 years later. This is even in the absence of epilepsy. In children with normal imaging memory appears to be intact. Dr Tallie Z Baram then presented the animal data that help explain findings in humans. In immature rats, hyperthermia produces seizures.Febrile status epilepticus produces epilepsy after a silent period with duration of FSE determining severity of resulting epilepsy.Febrile status epilepticus also results in enduring memory deficits with impaired function of hippocampal place cells. Inflammation may play a key role. An improved understanding of the mechanisms involved can inform future trials to prevent development of epilepsy and memory deficits following febrile SE.There is a known and close interaction between sleep and epilepsy. Understanding this complex relationship has far reaching implications. It is now evident that risk of interictal activity and seizures in different human epilepsy types and syndromes varies depending on sleep states, and rapid eye movement stage is universally the least permissive to seizures.However, little is known about the effects of state transitions on seizures, and experimental research suggests an increased risk of seizures in transitions from REM.
But what may be the molecular correlates of the circadian variation of epileptic excitability? There has been an explosion in research elucidating the underlying molecular mechanisms of the circadian rhythm and how this influences multiscale functions in the brain from basic cellular functions to larger scale networks. Recent studies have identified the molecular controls of the circadian clock that is regulated by the CLOCK/Brain and Muscle ARNT-like 1 system. It has been shown that core clock genes, clock circadian regulator, CLOCK and BMAL1 contribute to epileptic excitability.Interestingly, mTOR regulates BMAL1 proteostasis and TSC mouse models show abnormal circadian rhythms that can be corrected following genetic lowering of BMAL1 levels.On the contrary, BMAL1 functions as a translational factor that links circadian timing to the mTOR signaling pathway and BMAL1 knockout mice have lowered seizure thresholds.Decreased CLOCK protein levels were seen in resected brain tissue from patients with intractable epilepsy and that these changes can alter cortical circuits.Tying together BMAL1/CLOCK and mTOR pathways may provide additional insights into epileptogenesis and potential novel drug targets. Sleep is an important process in memory creation through regulation of normal synaptic homeostasis. Animal studies have demonstrated abnormal synaptic potentiation induced by epileptiform activity and seizures. In patients with focal epilepsy, a high density EEG study uncovered a widespread increase in slow wave activity, a marker of increased synaptic strength or excitability, that correlated with the burden of epileptic activity and cognitive impairment.Seizures during sleep can not only impair learning but increase mortality risk in patients with epilepsy. Clinical studies have demonstrated that sudden unexpected death in epilepsy is more common during sleep. The mechanisms for this increased risk is unclear, but rodent studies suggest that serotonin is important in arousal, in postictal recovery of respiratory function, and as a modulator of seizure severity.Improved understanding of the role of the serotonergic system in sleep, seizure susceptibility,hydroponic shelf and in the overall circadian regulation will be important in our search for preventative treatments for SUDEP.In the first presentation on “Polypharmacy: Predictable and unpredictable interactions,” Dr Dean Naritoku highlighted the complexities of predicting drug interactions from established data. Older anti-epileptic drugs tend to have more predictable changes, primarily induction or inhibition, whereas newer agents are less predictable because they may inducesome CYP isozymes and inhibit others.Finally, the newest agents may be least predictable for clinicians simply because of their limited experience. Thus, vigilance for interactions is always needed. In the second presentation on “Improving measurements of seizure control, including use of wearables,” Dr Tobias Loddenkemper presented data on the low reliability of patient reporting of seizure frequency, partly but not only due to patients’ lack of awareness of their seizures. Fortunately, multiple convenient wearable devices for detecting seizure activity have become or are soon to become available; some of these are Food and Drug Administration -cleared and show promising data for reliable detection of tonic-clonic seizures. More sophisticated mulitmodality devices and software will soon follow.In the third presentation on “Cannabidiol and medical marijuana: Use, misuse, and patient self-medication,” Dr Tyler E. Gaston defined important terms used when discussing cannabis products with patients and families, reviewed the current evidence for the use of pharmaceutical grade cannabidiol for epilepsy, and discussed issues with unreliable consistency of labeling of artisanal cannabis products. The only high-quality evidence to date is the use of pharmaceutical-grade cannabidiol for Lennox-Gastaut and Dravet syndromes, leading to US FDA approval with these indications.In the final presentation, “Towards self-management of acute seizures: Expanding out-of-hospital treatment options,” Dr James Cloyd first discussed current approved and off-label options for management of seizure emergencies.
Products under development include intra-pulmonary, buccal, and intranasal formulations, some of which may be available within the next 1 to 2 years. He concluded his remarks by noting that rapid advances in seizure prediction technology coupled with anti-seizure delivery systems that result in therapeutic brain concentration within minutes have the potential to prevent seizures, which could change the paradigm for managing epilepsy.Serotonin plays a crucial role in emotional processes. A considerable number of imaging studies involving pictures of emotional faces show that changes in serotonergic function are associated with changes in amygdala reactivity when viewing negative facial expressions: Acute tryptophan depletion, which reduces central serotonin synthesis, leads to higher amygdala activity when processing negative face expressions . Several studies have found that acute/subacute SSRI intervention leads to a decrease in amygdala activation . Further, when the cerebral serotonin level is pharmacologically enhanced by a three-week intervention with a selective serotonin reuptake inhibitor , the ensuing decreased cerebral [11C]SB207145- PET binding in response to pharmacologically increased brain serotonin levels is associated with lower threat-related amygdala reactivity . Whereas it is relatively clear that induction of acute and subacute changes in serotonin neurotransmission leads to changes in emotional processing, less is known about how the neural processing of emotional information is affected by chronic cerebral serotonin depletion. Ecstasy, or 3,4-methylene-dioxymethamphetamine is a widely used recreational drug that has immediate effects interms of improved mood and feelings of empathy . In this paper, we will use the term “ecstasy” when referring to the recreational human, and “MDMA” when referring to experimental human/animal studies. MDMA exerts its primary effects on the serotonin neurotransmitter system, in particular by reversing normal serotonin transporter function and hence releasing serotonin from the storage vesicles into the synaptic cleft . Animal studies show that repeated exposure to moderate and high doses of MDMA is associated with a reduction in cerebral serotonin levels and a decreased number of SERT binding sites. In humans, prolonged recreational use of ecstasy is also associated with reductions in SERT in both cortical and sub-cortical brain areas . Most , although not all , molecular imaging studies show that the accumulated lifetime intake of ecstasy correlates negatively with SERT binding, supporting a dose-dependent relationship between recreational ecstasy use and reductions in SERT binding. Thus, it also seems plausible that in humans, an ecstasy-associated reduction in SERT is associated with reduced cerebral serotonin levels, and that the SERT changes may even result from chronically reduced serotonin levels. Additional support for serotonin depletion in recreational ecstasy use comes from the finding of increased levels of the post-synaptic serotonin 2A receptor in most , although not all , studies where ecstasy users have had their serotonin 2A receptors measured. Importantly, lowering brain serotonin levels in preclinical models leads to low SERT combined with high serotonin 2A receptor levels, and low SERT has also been found to be associated with high serotonin 2A receptor levels in humans . The reduction in subcortical SERT binding in ecstasy users seems to be reversible, since a positive correlation with time of abstinence from ecstasy intake has been observed . Taken together, data from these preclinical and clinical studies indicate that there is a causal relationship between ecstasy intake and effects on the serotonergic system. Reduced SERT and serotonin after MDMA/ecstasy exposure in combination with the observed correlation between serotonin depletion and reduced SERT binding in animal studies makes it plausible that SERT binding can be regarded as a representation of the extent of chronic—but most likely reversible—serotonin depletion in long-term ecstasy users. With MDMA being an interesting and promising candidate as adjunct to psychotherapy for treatment of post-traumatic stress disorder and possibly other conditions as well , it is important to explore the possible long-term impact of this drug on serotonergic neurotransmission, as well as the functional consequences of this. Although the multiple and not always pure MDMA doses used recreationally differ from the only few—and pure—doses employed in therapy, recreational use of MDMA/ ecstasy can serve as a model for the long-term effect of repeated doses. In the present study, we used functional magnetic resonance imaging to investigate the functional effects of long-term recreational ecstasy use, representing a model of long-term serotonin depletion, on the neural basis of emotional responses in the amygdala.