Animal models of the ketogenic diet: what have we learned, what can we learn?

Despite its clinical use as a therapy for refractory epilepsy for more than 75 years, the ketogenic diet (KD) remains a therapy in search of an explanation. The mechanism of action of the KD is unclear and the optimal indications for its clinical use are incompletely defined. Animal models could help to elucidate these questions. Surprisingly, there have been very few animal studies of the KD, and those that have been performed are difficult to compare because of wide discrepancies in experimental methods. Earlier models concentrated on the effect of the KD on acute seizure threshold in normal (i.e. nonepileptic) animals. Recent studies are beginning to examine the longer term effects of the KD and its role in epileptogenesis. Some features of clinical experience have been replicated in animal models, including the role of ketosis, elevation of seizure threshold by both classic ketogenic and medium chain triglyceride diets, better effectiveness at younger ages, and rapid reversal of the seizure protective effect when the diet is discontinued. These parallels raise hope that pertinent clinical questions can be addressed in the more controlled setting of the research laboratory. As in the clinical arena, there has been a recent resurgence of interest in pursuing basic questions related to the ketogenic diet, using techniques of modern neuroscience. Experimental approaches such as brain slice neurophysiology, genetic models, dissection of metabolic pathways, and neurohistological techniques hold much promise in the effort to understand this intriguing alternative to standard anticonvulsants.     

The genetics of dementia with lewy bodies: what are we missing?

Dementia with Lewy bodies is a complex brain disorder and a key member of the Lewy body disease spectrum. Its genetic etiology is unclear, and information is scattered. However, the results of molecular genetic studies imply a genetic and mechanistic overlap with Alzheimer disease, Parkinson disease with dementia, and Parkinson disease. In this review, we provide a comprehensive overview of the current studies on dementia with Lewy bodies heritability, genetic etiology, and genetic heterogeneity. We conclude with a critical discussion of the missing heritability in dementia with Lewy bodies and encourage scientists to further explore the underlying mechanisms of this disease.     

Efficacy of the ketogenic diet: Which epilepsies respond?

We report the efficacy of the ketogenic diet in refractory epilepsies focusing on outcomes with regard to epilepsy syndromes and etiology in children and adults with refractory epilepsy. Sixty-four consecutive children and four adults were prospectively enrolled from 2002 to 2009; seven were excluded from analysis. The classical ketogenic diet was initiated on an inpatient basis with dietary ratios ranging from 2:1 to 4:1 fat to carbohydrate and protein. Patients were classified according to syndrome and etiology using the 1989 and more recent 2010 International League Against Epilepsy (ILAE) classification systems. Responders were defined as >50% reduction in seizure frequency compared to baseline. Syndromes included symptomatic generalized (52), genetic (idiopathic) generalized (7), and focal epilepsies (2) and etiologies included structural (24), genetic (18), and unknown (19). Twenty-nine (48%) of 61 patients were responders at 3 months. Two children became seizure-free: one with focal epilepsy of unknown etiology and another with refractory childhood absence epilepsy. Responsive syndromes included migrating partial epilepsy of infancy, childhood absence epilepsy, focal epilepsy, epilepsy with myoclonic-atonic seizures, and Dravet syndrome. Children with lissencephaly and hypoxic ischemic encephalopathy had surprisingly good responses. The ketogenic diet is an effective treatment for children and adults with refractory epilepsy. The response is predicted by type of epilepsy syndrome. Accurate characterization of the electroclinical syndrome is an important factor in decisions about timing of initiation of the ketogenic diet.     

Neonatal 192 IgG-saporin lesion of forebrain cholinergic neurons: focus on the life span?

The cholinergic immunotoxin 192 IgG-saporin can be used to effect selective, substantial and permanent lesions of basal forebrain neurons in the neonatal rat. Human neurodevelopmental disorders such as Rett and Down syndromes are characterized by early cholinergic dysfunction and cognitive impairment. Hence, the study of the neonatal 192 IgG-saporin lesioned rat should illuminate the role of cholinergic dysfunction in these human disorders. To date, we and others have failed to observe notable effects of this neonatal lesion on learning and memory, even when combined with a severe lesion of noradrenergic forebrain innervation. As well, attention seems not to be affected. However, complex problem solving (intelligence?) is compromised by the cholinergic lesion. There also appears to be reduced cortical dendritic branching indicative of synapse loss but further research is needed to characterize this. Even if the synapse loss due to neonatal cholinergic lesion is modest and thus insufficient to cause a significant neurodevelopmental dysfunction, its consequences may be devastating during old age.     

Actions of orexins on individual myenteric neurons of the guinea-pig ileum: orexin A or B?

The actions of orexins (orexin A and B, 10-300 nM) on individual myenteric neurons of the guinea-pig ileum in vitro were compared using intracellular recording methods. Both orexins caused membrane depolarizations associated with an increase in input neuronal resistance in S and AH neurons via a direct action. Orexin depolarizations reversed at about -90 mV, indicating they were due to an inactivation of K+ channels. Orexins facilitated fast excitatory postsynaptic potentials without affecting postsynaptic sensitivity to acetylcholine and adenosine 5'-triphosphate, indicating that the peptides may facilitate ganglionic transmission by increasing presynaptic release of neurotransmitters. Orexin B was sometimes more effective than orexin A and vice versa. It is concluded that orexin B increased neuronal activity via mechanisms similar to orexin A in the guinea-pig myenteric plexus.     

CTOs: what is the state of the evidence?

Purpose

Community Treatment Orders (CTOs) require outpatients to adhere to treatment and permit rapid hospitalisation when necessary. They have become a clinical and policy solution to repeated hospital readmissions despite some strong opposition and the contested nature of published evidence. In this article, we appraise the current literature on CTOs from the viewpoint of Evidence-Based Medicine and discuss the way forward for using and researching CTOs.

Results

Non-randomised outcome studies show conflicting results, but their lack of standardisation of methods and measures makes it difficult to draw conclusions. In contrast, all three randomised controlled trials (RCTs) conducted concur in their findings that CTOs do not impact on hospital outcomes. No systematic review or meta-analysis has identified any clear clinical advantage to CTOs.

Conclusion

The evidence-base does not support the use of CTOs in their current form. Involuntary clinical interventions must conform to the highest standard of evidence-based care. To enable clinicians to take an evidence-based approach and to settle remaining uncertainties about the current evidence, high-quality RCTs should be designed and undertaken, using standardised outcome measures.     

The influence of the full moon on seizure frequency: myth or reality?

To investigate a possible relationship between seizure frequency and the lunar cycle, we reviewed the occurrence of seizures recorded in our epilepsy monitoring unit over a 3-year period. Analysis of the total number of seizures (epileptic plus nonepileptic) showed no significant association. A separate analysis revealed that for nonepileptic seizures, there was an increase at the full moon, and for epileptic seizures, an increase in the last quarter. We conclude that there is no "full moon" effect on seizures as a whole, although there is a possible effect on nonepileptic seizures.     

The influence of neuropathology on the FMRI signal: a measurement of brain or vein?

There is a rapidly growing literature using fMRI technology to investigate the various forms of behavioral impairment associated with brain injury and disease. Given this, surprisingly little work has been conducted to examine the influence of neuropathophysiological processes on the fMRI signal. This paper reviews the literature examining baseline alteration in cerebrovascular parameters associated with normal aging, brain injury, and brain disease. In addition, findings from three cases of individuals with severe brain trauma will be presented to show the influence of brain trauma on baseline cerebrovascular parameters measured by fMRI. The methods used here can be implemented by other investigators to accurately isolate specific hemodynamic changes that can influence the BOLD fMRI signal.     

The ketogenic diet: what has science taught us?

Despite intense and growing interest in studying the mechanisms of ketogenic diet (KD) action, and recently published studies implicating novel molecular interactions with metabolic substrates, there nevertheless remains the pragmatic and scientific challenge of sustaining continued research in this field. This is in part a consequence of limited research funding and perhaps skepticism regarding the ultimate need to understand underlying mechanisms, particularly when clinical studies have increasingly validated the efficacy of the KD and its variants. After a decade and a half of more concerted laboratory efforts to understand KD mechanisms, it would be prudent to ask - what has all this scientific research really taught us? In this regard, it is instructive to compare and contrast laboratory research in dietary approaches for epilepsy with that traditionally used to screen for potential antiepileptic drugs (AEDs). In this review, lessons learned from AED development are applied to the more recent experimental findings and approaches attempting to link metabolic changes induced by the KD to neuronal and network excitability in the brain.     

Toward the development of rational therapies in multiple sclerosis: what is on the horizon?

Although the cause of multiple sclerosis (MS) has remained obscure, many findings support an autoimmune pathogenesis on the background of a complex interaction between multiple genes and environmental factors. Accordingly, targeting the immune system has been a rational approach for the treatment of MS. The development of disease-modifying immunomodulatory drugs with partial efficacy, coupled with advances in understanding the pathophysiology and pathology of MS, has provided momentum to explore more specific and hopefully more effective immune-based therapeutic strategies. With increased knowledge and appreciation of the contribution of neurodegenerative processes to disease pathology, the therapeutic challenges, however, have become even more formidable. Future treatments will likely need both to target inflammation and to focus on promotion of neuroprotection and repair. In this review, we discuss the most promising therapeutic approaches for MS currently in the pipeline.     

The course of posttraumatic stress symptoms and functional impairment following a disaster: what is the lasting influence of acute versus ongoing traumatic events and stressors?

Purpose

Ongoing traumatic events and stressors, rather than acute sources of trauma, may shape long-term post-disaster mental health. The purpose of this study was to compare the influence of acute hurricane-related exposures and ongoing post-hurricane exposures on the short- and long-term course of posttraumatic stress symptoms (PTSS) and functional impairment (FI).

Methods

A random sample of adults (n = 658) in Galveston and Chambers Counties, Texas, was selected 2–6 months after Hurricane Ike and interviewed 3 times over 18 months. Hurricane-related exposures included traumatic events such as death of a family member due to the hurricane and stressors such as loss/damage to personal property due to the hurricane. Post-hurricane exposures included traumatic events such as sexual assault and stressors such as divorce or serious financial problems.

Results

Experiencing an acute hurricane-related traumatic event or stressor was associated with initial post-hurricane PTSS [RR = 1.92 (95 % CI = 1.13–3.26) and RR = 1.62 (1.36–1.94), respectively] and FI [RR = 1.76; (1.05–2.97) and RR = 1.74 (1.46–2.08)], respectively, and acute hurricane-related stressors were associated with a higher rate of increase in FI over time [RR = 1.09; (1.01–1.19)]. In contrast, ongoing post-hurricane daily stressors were not associated within initial PTSS and FI, but were associated with PTSS and FI at the second and third interviews.

Conclusions

While immediate postdisaster interventions may influence short-term mental health, investment in the prevention of ongoing stressors may be instrumental to manage long-term mental health status.     

The phenomenology of bipolar disorder: what drives the high rate of medical burden and determines long‐term prognosis?

Bipolar disorder (BD) has been classically described as one of episodic mood disturbances. New evidence suggests that a chronic course and multisystem involvement is the rule, rather than the exception, and that together with disturbances of circadian rhythms, mood instability, cognitive impairment, a high rate of medical burden is often observed. The current diagnostic approach for BD neither describes the multisystem involvement that the recent literature has highlighted nor points toward potential predictors of long- term outcome. In light of the new evidence that the long-term course of BD is associated with a high prevalence of psychiatric comorbidity and an increased mortality from medical disease, we propose a multidimensional approach that includes several symptom domains, namely affective instability, circadian rhythm dysregulation, and cognitive and executive dysfunction, presenting in various combinations that give shape to each individual presentation, and offers potential indicators of overall long-term prognosis.