Inflammation and Epilepsy: The Foundations for a New Therapeutic Approach in Epilepsy?

Emerging data from experimental epilepsy models and resected human brain tissue support the proposed involvement of innate immune system activation and consequent inflammation in epilepsy. Key mediators of this process include interleukin-1β, high-mobility group box protein 1 (HMGB1), and Toll-like receptor (TLR) signaling. These recent findings constitute the basis for a novel avenue of drug development in epilepsy, one that is not only distinct from previous approaches but uniquely based on sound neurobiological evidence.Inflammatory pathways are widely acknowledged to contribute to the pathogenesis of several neurodegenerative disorders, including multiple sclerosis and Alzheimer disease, and are known to be activated following neurologic infection, ischemic stroke, and traumatic brain injury (1). Increasing evidence also supports a link between inflammation and epilepsy, both in terms of epileptogenesis and the long-term consequences of seizures (2). Complex febrile seizures in childhood have long been associated with the later development of temporal lobe epilepsy; febrile illnesses in people with otherwise well-controlled epilepsy can trigger seizures; and immunomodulatory agents such as steroids and adrenocorticotrophic hormone (ACTH) have shown efficacy in some epileptic encephalopathies and occasionally in refractory status epilepticus (3, 4).More recently, it has been reported that surgically resected brain tissue from individuals with refractory focal epilepsy displays all of the hallmarks of a chronic inflammatory state, with infiltration of leukocytes, reactive gliosis, and overexpression of cytokines and their target proteins (2). This finding is backed up by data from studies of animal models that confirm the intimate involvement of inflammatory mechanisms in the generation of epileptic discharges and in the cellular damage associated with focal-onset seizures (2). Targeting brain inflammation may accordingly represent a novel therapeutic strategy for epilepsy, consistent with efforts to shift focus away from the symptomatic control of seizures to disease-modifying treatments that better target the underlying pathological mechanisms.     

Will Brain Cells Derived From Induced Pluripotent Stem Cells or Directly Converted From Somatic Cells (iNs) Be Useful for Schizophrenia Research?

The reprogramming of nonneuronal somatic cells to induced pluripotent stem cells and their derivation to functional brain cells as well as the related methods for direct conversion of somatic cells to neurons have opened up the possibility of conducting research on cellular disease models from living schizophrenia patients. We review the published literature on schizophrenia that has used this rapidly developing technology, highlighting the need for specific aims and reproducibility. The key issues for consideration for future schizophrenia research in this field are discussed and potential investigations using this technology are put forward for critical assessment by the reader.Key words: induced pluripotent stem cells, model, brain cells, schizophrenia, experimental design     

Sleep and Epilepsy: A Key Role for Nitric Oxide?

PURPOSE: It has been suggested that nitric oxide (NO) is involved in sleep mechanisms and in the pathophysiology of epilepsy. Data are, however, controversial because it is not clear whether NO facilitates sleep or waking, or whether it exerts pro-or antiepileptic influences. METHODS: The question was considered through NO voltammetric measurements and electroencephalographic recordings performed in GAERS rats (Genetic Absence Epilepsy Rat from Strasbourg): an experimental model of "petit-mal" human disease. Regulatory processes of sleep and epilepsy were studied after administration of a NO synthase inhibitor [l-arginine-p-nitroanilide (l-ANA) 100 mg/kg i.p.], a NO donor (SIN-1 100 ng/2 microl i.c.v.), and the antiepileptic drugs used in clinic [valproate (VPA 200 mg/kg i.p.) and ethosuximide (ESM 100 mg/kg i.p.)]. RESULTS: In GAERS rats, spontaneous circadian organizations of spike-wave discharges and paradoxical sleep (PS) occur in an opposite way; spontaneous NO concentrations are higher during seizures than during wakefulness, slow-wave sleep, and PS, respectively. l-ANA induces a disappearance of NO peak, an epileptic induction, and a loss of PS while SIN-1 induces opposite effects. Antiepileptic effects of VPA and ESM are associated with a PS increase and a significant release of NO. CONCLUSIONS: These results indicate that NO could be, in GAERS rats, a central piece in the reciprocal inhibitory mechanisms regulating the induction of PS and spike-wave discharges. NO could prevent absence epilepsy and act as an antiepileptic substance in facilitating PS. Antiepileptic efficiency of VPA and ESM may work through their ability to release NO. A track for a new treatment of petit-mal disease in children can be envisioned.     

Epilepsy: a classification for all seasons?

Epilepsy classification is close to the heart of every clinician because it affects every consultation. Acceptance of change to fundamental concepts is difficult and implementation of new ideas requires considerable effort. It is therefore not surprising that the 2010 Organization of the epilepsies has evoked much passion and its fair share of criticism and controversy. Debate has been positive and has already led to modifications and gradual acceptance of the new framework. Although classification will never be perfect and continues to evolve with increasing knowledge, the time for updating our thinking to reflect current concepts and scientific understanding is well and truly here. Ongoing discussion will help to further mature the new organization.     

Slow Hyperpolarization in Cortical Neurons: A Possible Mechanism Behind Vagus Nerve Simulation Therapy for Refractory Epilepsy?

PURPOSE: Recent studies have shown that chronic, intermittent stimulation of the left vagus nerve (VNS) decreases the frequency, duration, and/or intensity of seizures in some patients with medically refractory focal seizures. Although VNS is being used in an increasing number of patients, the neuronal mechanism behind VNS therapy of refractory epileptic seizures is yet unclear. METHODS: In vivo intracellular recordings were used to study responses elicited by the VNS in pyramidal neurons of the parietal association cortex in anesthetized rats. RESULTS: Low-intensity trains of VNS, which activated predominantly myelinated fibers (100 microA, 30 Hz, 0.5 millisecond, 20 seconds), elicited a slow hyperpolarization (onset latency 17.4 +/- 2.0 seconds, amplitude -4. 7 +/- 0.6 mV, duration 35 +/- 3.2 seconds; n = 19). Increasing the intensity of VNS to recruit nonmyelinated vagal fibers (200 microA) led to an increase in the magnitude of the response in some neurons while failed to evoke a response in others. On increasing the stimulus intensity to 500 microA, only one in nine neurons exhibited a visible response. All recorded and visualised neurons were pyramidal cells in cortical layer V. CONCLUSIONS: Stimulus intensities that activate predominantly myelinated fibers (less than 200 microA) were most effective to induce slow vagal hyperpolarization. It is suggested that slow hyperpolarization may be one of the mechanisms that underlie the seizure-reducing effect of VNS, by means of reducing the excitability in neurons that would be involved in propagation of seizure activity. As the balance of activity in myelinated and nonmyelinated primary vagal afferents influenced the effect of VNS stimulation, it is likely that the effect of VNS is modulated as changes occur in the underlying vagal tone.     

From facial mimicry to emotional empathy: A role for norepinephrine ?

Tendency to mimic others' emotional facial expressions predicts empathy and may represent a physiological marker of psychopathy. Anatomical connectivity between amygdala, cingulate motor cortex (M3, M4), and facial nucleus demonstrates a potential neuroanatomical substrate for mimicry, though pharmacological influences are largely unknown. Norepinephrine modulation selectively impairs negative emotion recognition, reflecting a potential role in processing empathy-eliciting facial expressions. We examined effects of single doses of propranolol (beta-adrenoceptor blocker) and reboxetine (selective norepinephrine reuptake inhibitor) on automatic facial mimicry of sadness, anger, and happiness, and the relationship between mimicry and empathy. Forty-five healthy volunteers were randomized to 40 mg propranolol or 4 mg reboxetine. Two hours after drug subjects viewed and rated facial expressions of sadness, anger, and happiness, while corrugator, zygomatic, and mentalis EMG were recorded. Trait emotional empathy was measured using the Balanced Emotional Empathy Scale. EMG confirmed emotion-specific mimicry and the relationship between corrugator mimicry and empathy. Norepinephrine modulation did not alter mimicry to any expression or influence the relationship between mimicry and empathy. Corrugator but not zygomaticus mimicry predicts trait empathy, consistent with greater anatomical connectivity between amygdala and M3 coding upper facial muscle representations. Although influencing emotion perception, norepinephrine does not influence emotional facial mimicry or its relationship with trait empathy.     

Post-Psychiatry: A New Orthodoxy?

This article examines the character and purported aims of post-psychiatry, a new endeavor aimed at linking psychiatry with elements of post-modernity. While not strictly a “movement” in psychiatry, post-psychiatry represents a growing impatience, in some quarters, to conventional approaches to psychiatric practice. It has the potential to challenge established assumptions about what is necessary for the management and care of psychiatric patients and to articulate concerns about the use of coercion in psychiatric practice. In particular, post-psychiatry is responsive to current threats to the perceived hegemony of psychiatry, notably in the increasing acceptance of non-medical approaches to psychological distress and in the internal professional conflicts concerning the diagnosis, treatments for and the social purpose of psychiatry. The article outlines various reflections on the reform of psychiatry and considers some features of the impact of post-modern theory on psychiatry.     

Psychiatric Care in Epilepsy Surgery: Who Needs It?

At present there is considerable variability in the psychiatric evaluation and follow-up of patients in epilepsy surgery programs globally. There is a large body of research now demonstrating heightened risk for psychological disturbance in surgically remedial patients before and after surgery. This evidence provides a compelling case for the routine provision of psychiatric and psychological treatment to optimize the benefits of epilepsy surgery and patient outcomes. In a comprehensive model of care, presurgical psychiatric and psychosocial evaluation plays an integral role in shaping the team''s understanding of surgical candidacy and the patient''s capacity for informed consent. After surgery, efficacious treatment of psychiatric comorbidity increases the likelihood of seizure freedom as well as optimizes psychosocial functioning and quality of life. By contrast, failure to treat can allow psychiatric comorbidity to persist or psychological difficulties to develop as the patient adjusts to life after surgery.     

Benign Partial Epilepsy in Infancy: Myth or Reality?

PURPOSE: Benign partial epilepsy in infancy (BPEI) was first described by Watanabe in 1987. The aim of this study is to describe a series of infants from the United States to characterize this entity further. METHODS: Among patients with the diagnosis of epilepsy followed up at our institution between 2002 and 2004, those satisfying the criteria for BPEI were included in a retrospective study. RESULTS: Sixteen (10.2%) of 150 patients with new onset of epilepsy younger than 2 years were identified. The mean age at seizure onset was 8 months. Four (25%) infants had a family history of benign seizures. All infants were neurologically and developmentally normal at the onset of seizures. The seizures occurred in clusters in 75% of patients, predominantly in wakefulness. The initial manifestation was behavioral arrest with staring (69%) and apnea with cyanosis or pallor (37.5%). These symptoms were followed by deviation of eyes or head or both (56%), mild clonic movements (31%), or increased limb tone (35%). Secondary generalization was noticed in 37.5% of patients. All infants had normal interictal EEGs and brain MRIs. Ictal EEGs disclosed electrographic seizures in 50% of patients (temporal origin in 62% and central in 38%). Fifteen (94%) patients were treated with AEDs with good response. The mean duration of treatment was 12.4 months. The final developmental assessment of all patients was normal. CONCLUSIONS: We believe that BPEI exists as a unique entity and should be included in the differential diagnosis of epilepsies in infancy with partial origin.