Literature Review: Support for caregivers of children on the ketogenic diet for epilepsy and other neurologic disorders.

Epilepsy affects millions of people and when medications are insufficient to maintain seizure control, individuals are diagnosed with refractory epilepsy (RE). Medical ketogenic diet therapy (KDT), a diet high in fat and low in carbohydrates and sufficient in protein, is a well-established treatment for RE. However, compliance is one of the main reasons for discontinuation of KDT and, with pediatric RE patients, the ability of informal caregivers, typically family members, to maintain diet adherence is vital for successful KDT treatment. The central role that informal caregivers play for effective KDT implementation is recognized, however, there is a need to elucidate the rationale and theoretical underpinnings of effective KDT caregiver support programs to inform best practices. Therefore, this systematic literature review aims to identify the existing fundamental understandings of KDT caregiver support to help build a foundation of theory-based knowledge to promote evidenced practice. After screening 137 publications, three studies that discussed potential underlying components of effective caregiver support were included in this review. These articles followed a similar approach as they 1) employed qualitative methods delving into caregiver needs, 2) findings highlighted the importance of support from family, friends, fellow caregivers and their child's medical team, and 3) the inclusion of caregiver support findings were a supplement to the main purpose of the manuscript. Research focused on KDT caregivers is in its infancy. There is a clear need for the systematic examination of support for KDT caregivers to build a foundation for effective support programs and to increase the access to quality support programming to foster KDT implementation, desirable patient outcomes, and caregiver well being. In this article we discuss opportunities to apply self-determination theory to the KDT caregiver support research and practice.

The impact of low-energy, partially hydrolysed enteral formula on gastrointestinal symptoms and weight in children with neurological impairment: a multicentre retrospective study.

BACKGROUND: Neurological impairment (NI) relates to disorders of the central nervous system. The specific aetiology of NI varies but includes genetic, congenital abnormalities or brain injury. In children with severe NI, feeding impairments can lead to undernutrition, and some children require a feeding tube. Although tube feeding improves overall nutritional status, it has also been associated with excess body fat. Commercially available enteral formulas that are low in energy, hydrolysed and nutritionally adequate for protein and micronutrients are available to mitigate gastrointestinal symptoms and obesity. METHODS: This is a retrospective multicentre study of children who attended NI clinics between January 2022 and July 2023. Data were collected before and 1 month after receiving a low-energy, partially hydrolysed enteral formula (0.6 kcal/mL) on demographic data (age, sex, ethnicity and NI diagnosis), anthropometric measurements (weight, height, weight-for-age Z-score, height-for-age Z-score, body mass index [BMI] Z-score) and feed regimen (feed volume, total fluids and type of formula/supplements). RESULTS: Dietitians collected data on 28 children, the median age was 7 years (interquartile range [IQR] 3, 8). The most frequently recorded NI was cerebral palsy, in 13 of 28 children (48%). Before the formula switch, the most frequently reported gastrointestinal symptom was constipation, in 13 of 28 children. Within 1 month of switching to a low-energy, hydrolysed formula, 10 of the 13 (77%) children reported an improvement in constipation. Before the formula switch, all 28 children were experiencing excessive weight gain. After the formula was switched to low-energy, hydrolysed formula, dietitians reported that 20 of the 28 (76%) children's weight either stabilised or reduced after 1 month. There was no statistically significant difference in weight-for-age Z-score or BMI Z-scores postswitch of formula (p-value 0.1 and 0.09, respectively). Fibre intake increased significantly from 3.3 to 8.1 g/day (p-value < 0.01) after formula switch. The number of children whose feed regimens were simplified after switching to a low-energy, partially hydrolysed formula was 24 of 28 (91%). CONCLUSIONS: Children with an NI who have gastrointestinal symptoms may benefit from a low-energy, hydrolysed enteral formula to maximise feed tolerance and promote healthy weight gain. In addition, changing to a low-energy, hydrolysed formula may simplify feed regimens by eliminating the need for additional electrolytes, multivitamins and fluid boluses. Healthcare professionals should be knowledgeable about the effectiveness and availability of a low-energy, hydrolysed formula.

Effects of fasting, feeding and exercise on plasma acylcarnitines among subjects with CPT2D, VLCADD and LCHADD/TFPD.

BACKGROUND: The plasma acylcarnitine profile is frequently used as a biochemical assessment for follow-up in diagnosed patients with fatty acid oxidation disorders (FAODs). Disease specific acylcarnitine species are elevated during metabolic decompensation but there is clinical and biochemical heterogeneity among patients and limited data on the utility of an acylcarnitine profile for routine clinical monitoring. METHODS: We evaluated plasma acylcarnitine profiles from 30 diagnosed patients with long-chain FAODs (carnitine palmitoyltransferase-2 (CPT2), very long-chain acyl-CoA dehydrogenase (VLCAD), and long-chain 3-hydroxy acyl-CoA dehydrogenase or mitochondrial trifunctional protein (LCHAD/TFP) deficiencies) collected after an overnight fast, after feeding a controlled low-fat diet, and before and after moderate exercise. Our purpose was to describe the variability in this biomarker and how various physiologic states effect the acylcarnitine concentrations in circulation. RESULTS: Disease specific acylcarnitine species were higher after an overnight fast and decreased by approximately 60% two hours after a controlled breakfast meal. Moderate-intensity exercise increased the acylcarnitine species but it varied by diagnosis. When analyzed for a genotype/phenotype correlation, the presence of the common LCHADD mutation (c.1528G > C) was associated with higher levels of 3-hydroxyacylcarnitines than in patients with other mutations. CONCLUSIONS: We found that feeding consistently suppressed and that moderate intensity exercise increased disease specific acylcarnitine species, but the response to exercise was highly variable across subjects and diagnoses. The clinical utility of routine plasma acylcarnitine analysis for outpatient treatment monitoring remains questionable; however, if acylcarnitine profiles are measured in the clinical setting, standardized procedures are required for sample collection to be of value.

Nutraceuticals in Neurological Disorders.

Neurological diseases are one of the major healthcare issues worldwide. Posed lifestyle changes are associated with drastically increased risk of chronic illness and diseases, posing a substantial healthcare and financial burden to society globally. Researchers aim to provide fine treatment for ailing disorders with minimal exposed side effects. In recent decades, several studies on functional foods have been initiated to obtain foods that have fewer side effects and increased therapeutic activity. Hence, an attempt has been made to unravel several extraction techniques to acquire essential bioactive compounds or phytochemicals from therapeutically active food products. This has led to the conception of the term functional foods being meddled with other similar terms like "pharmafoods," "medifoods", "vitafoods", or "medicinal foods". With a dire need to adhere towards healthy options, the demand of nutraceuticals is widely increasing to combat neurological interventions. An association between food habits and the individual lifestyle with neurodegeneration has been manifested, thereby proposing the role of nutraceuticals as prophylactic treatment for neurological interventions. The current review covers some of the major neurological disorders and nutraceutical therapy in the prevention of disease.

Palmitoylethanolamide: A Nutritional Approach to Keep Neuroinflammation within Physiological Boundaries-A Systematic Review.

Neuroinflammation is a physiological response aimed at maintaining the homodynamic balance and providing the body with the fundamental resource of adaptation to endogenous and exogenous stimuli. Although the response is initiated with protective purposes, the effect may be detrimental when not regulated. The physiological control of neuroinflammation is mainly achieved via regulatory mechanisms performed by particular cells of the immune system intimately associated with or within the nervous system and named "non-neuronal cells." In particular, mast cells (within the central nervous system and in the periphery) and microglia (at spinal and supraspinal level) are involved in this control, through a close functional relationship between them and neurons (either centrally, spinal, or peripherally located). Accordingly, neuroinflammation becomes a worsening factor in many disorders whenever the non-neuronal cell supervision is inadequate. It has been shown that the regulation of non-neuronal cells-and therefore the control of neuroinflammation-depends on the local "on demand" synthesis of the endogenous lipid amide Palmitoylethanolamide and related endocannabinoids. When the balance between synthesis and degradation of this bioactive lipid mediator is disrupted in favor of reduced synthesis and/or increased degradation, the behavior of non-neuronal cells may not be appropriately regulated and neuroinflammation exceeds the physiological boundaries. In these conditions, it has been demonstrated that the increase of endogenous Palmitoylethanolamide-either by decreasing its degradation or exogenous administration-is able to keep neuroinflammation within its physiological limits. In this review the large number of studies on the benefits derived from oral administration of micronized and highly bioavailable forms of Palmitoylethanolamide is discussed, with special reference to neuroinflammatory disorders.

Ketogenic diet ­ mechanism of action and perspectives for the use in the therapy: data from clinical studies / Dieta ketogeniczna - mechanizm dzialania i perspektywy zastosowania w terapii: dane z badan klinicznych.

Ketogenic diet is a high fat and very low-carbohydrate nutritional approach that induces increased production of ketone bodies, which serve as an alternative to glucose energetic substrates. Since almost a century ketogenic diet has been used in the therapy of refractory epilepsy, especially in children. Because of the pleiotropic effect of ketogenic diet on physiology, including inflammation, oxidative stress, energy balance and signaling pathways, in recent years scientists have been intensively exploring the use of it in the treatment of other diseases. In the present article current clinical studies regarding the possibility of using the ketogenic diet in the treatment of obesity, diabetes, neurological disorders and cancer has been reviewed alongside with potential mechanisms responsible for the therapeutic effect of ketogenic diet in these diseases. The metabolic processes engaged in nutritional ketosis and practicals aspects of ketogenic dieting have been also discussed.

Going Against the Grains: Gluten-Free Diets in Patients Without Celiac Disease-Worthwhile or Not?

While the gluten-free diet (GFD) is the only known effective therapy for celiac disease, in recent years it has become increasingly popular in the USA and worldwide, with many believing it to be more "healthful" and others claiming that it has beneficial effects for health conditions, many extraintestinal, other than celiac disease. This review examines the evidence for use of the GFD in patients without celiac disease who self-report intestinal and/or extraintestinal symptoms (non-celiac gluten sensitivity), as well as for enhancement of athletic performance and treatment of autism, rheumatoid arthritis, and psychiatric disorders. Overall, the evidence for use of GFDs in conditions other than celiac disease is poor. Though non-celiac gluten sensitivity may ultimately emerge as a biomarker-defined condition, a large proportion of patients with apparent non-celiac gluten sensitivity have, after careful investigation, an alternative diagnosis. In light of this, and coupled with the potential physical and psychological harms associated with the avoidance of gluten, initiating a GFD should not be encouraged for people who have these other conditions or are seeking physical/athletic enhancement.

[Aspects of nutrition for prevention and treatment of chronic neurological diseases]. / Aspekte der Ernährung zur Prävention und Therapie chronisch neurologischer Erkrankungen.

Chronic neurodegenerative and neuroinflammatory diseases, such as idiopathic Parkinson's syndrome, amyotrophic lateral sclerosis and multiple sclerosis, represent a therapeutic challenge. Their pathophysiology is not well understood and a cure for any of these diseases is not possible. Over the past decades lifestyle and nutritional habits in modern industrial nations have changed and evidence is increasing that the prevalence of chronic diseases as well their clinical presentation are also changing. Epidemiological investigations indicate that nutritional components might have an impact on the pathogenesis of chronic neurological diseases. A profound understanding of these correlations could foster a better prevention as well as treatment of such chronic disabling diseases. This continuing medical education article summarizes the current understanding of selected nutritional components and their effect on the development and clinical course of chronic neurological disorders.

Recent Trends in Potential Therapeutic Applications of the Dietary Flavonoid Didymin.

Didymin (isosakuranetin 7-O-rutinoside) is an orally bioactive dietary flavonoid glycoside first found in citrus fruits. Traditionally, this flavonoid has long been used in Asian countries as a dietary antioxidant. Recent studies have provided newer insights into this pleiotropic compound, which could regulate multiple biological activities of many important signaling molecules in health and disease. Emerging data also presented the potential therapeutic application of dietary flavonoid glycoside didymin against cancer, neurological diseases, liver diseases, cardiovascular diseases, and other diseases. In this review, we briefly introduce the source and extraction methods of didymin, and summarize its potential therapeutic application in the treatment of various diseases, with an emphasis on molecular targets and mechanism that contributes to the observed therapeutic effects. The dietary flavonoid didymin can be used to affect health and disease with multiple therapeutic targets, and it is anticipated that this review will stimulate the future development of this potential dietary medicine.

[Neurological disorders associated with gluten sensitivity]. / Nevrologicheskie rasstroistva, assotsiirovannye s chuvstvitel'nost'iu k gliutenu.

The review considers the pathogenetic, clinical, and therapeutic aspects of neurological disorders associated with gluten sensitivity. Gluten ataxia and polyneuropathy are most common. The clinical features of neurological disorders in patients with gluten sensitivity and the effects of a gluten-free diet are described.

Ketogenic diets: from cancer to mitochondrial diseases and beyond.

BACKGROUND: The employment of dietary strategies such as ketogenic diets, which force cells to alter their energy source, has shown efficacy in the treatment of several diseases. Ketogenic diets are composed of high fat, moderate protein and low carbohydrates, which favour mitochondrial respiration rather than glycolysis for energy metabolism. DESIGN: This review focuses on how oncological, neurological and mitochondrial disorders have been targeted by ketogenic diets, their metabolic effects, and the possible mechanisms of action on mitochondrial energy homeostasis. The beneficial and adverse effects of the ketogenic diets are also highlighted. RESULTS AND CONCLUSIONS: Although the full mechanism by which ketogenic diets improve oncological and neurological conditions still remains to be elucidated, their clinical efficacy has attracted many new followers, and ketogenic diets can be a good option as a co-adjuvant therapy, depending on the situation and the extent of the disease.

Most patients with long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency develop pathological or subnormal retinal function.

AIM: There have been few studies on long-term electroretinographic findings in patients with long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHADD). This study correlated long-term electroretinographic findings with age, metabolic control and clinical symptoms. METHODS: We examined 12 Swedish patients with LCHADD. Visual acuity testing, fundus examinations, optical coherence tomography and electroretinography were performed. The results were correlated to age, the levels of 3-hydroxyacylcarnitine and acylcarnitine and clinical metabolic control. RESULTS: Blindness or moderate visual impairment was found in two patients. Retinal pigmentation, atrophy and fibrosis were present in 11, seven and one of the patients, respectively, and optical coherence tomography showed retinal thinning in three of the six patients examined. Electroretinography was performed on 11 of the 12 patients. It was pathological, with reduced rod and cone responses, in five patients, subnormal in four and was related to poor clinical metabolic control and severe neonatal symptoms. Repeated electroretinographies revealed reduced function with increasing age. CONCLUSION: More than 80% of the LCHADD patients developed pathological or subnormal retinal function. This was more pronounced in patients with neonatal symptoms, but ameliorated by strict dietary treatment. Annual ophthalmological follow-ups, with electroretinography every second or third year, are recommended.

Earlier diagnosis and strict diets improve the survival rate and clinical course of long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency.

AIM: Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHADD) is a severe metabolic disease that, without treatment, often leads to premature death or serious handicap. The aim of this study was to evaluate the clinical course of LCHADD with the homozygous 1528G>C (E510Q) mutation when patients underwent strict dietary treatment. METHODS: From 1997 to 2010, 16 patients with LCHADD were diagnosed in Finland. They were followed up, and data were prospectively collected as they emerged. Clinical data before diagnosis were retrospectively collected from hospital records. This cohort was compared with an earlier cohort of patients diagnosed from 1976 to 1996. RESULTS: The disease presented from birth to five months of age with failure to thrive, hypotonia, hepatomegaly, metabolic acidosis, cardiomyopathy and hypoketotic hypoglycaemia. In this cohort, the therapeutic delay was 0-30 days and the survival rate at the end of the study was 62.5% compared with 10-year survival rate of 14.3% for the earlier cohort. The survivors were in good overall condition, but some of them had developed mild retinopathy or mild neuropathy. CONCLUSION: Earlier diagnosis and stricter dietary regimes improved the survival rates and clinical course of patients with LCHADD in Finland. However, improvements in therapy are still needed to prevent the development of long-term complications, such as retinopathy and neuropathy.

Increased and early lipolysis in children with long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency during fast.

Children with long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHAD) have a defect in the degradation of long-chain fatty acids and are at risk of hypoketotic hypoglycemia and insufficient energy production as well as accumulation of toxic fatty acid intermediates. Knowledge on substrate metabolism in children with LCHAD deficiency during fasting is limited. Treatment guidelines differ between centers, both as far as length of fasting periods and need for night feeds are concerned. To increase the understanding of fasting intolerance and improve treatment recommendations, children with LCHAD deficiency were investigated with stable isotope technique, microdialysis, and indirect calometry, in order to assess lipolysis and glucose production during 6 h of fasting. We found an early and increased lipolysis and accumulation of long chain acylcarnitines after 4 h of fasting, albeit no patients developed hypoglycemia. The rate of glycerol production, reflecting lipolysis, averaged 7.7 ± 1.6 µmol/kg/min, which is higher compared to that of peers. The rate of glucose production was normal for age; 19.6 ± 3.4 µmol/kg/min (3.5 ± 0.6 mg/kg/min). Resting energy expenditure was also normal, even though the respiratory quotient was increased indicating mainly glucose oxidation. The results show that lipolysis and accumulation of long chain acylcarnitines occurs before hypoglycemia in fasting children with LCHAD, which may indicate more limited fasting tolerance than previously suggested.

Two novel mutations in the BCKDK (branched-chain keto-acid dehydrogenase kinase) gene are responsible for a neurobehavioral deficit in two pediatric unrelated patients.

Inactivating mutations in the BCKDK gene, which codes for the kinase responsible for the negative regulation of the branched-chain α-keto acid dehydrogenase complex (BCKD), have recently been associated with a form of autism in three families. In this work, two novel exonic BCKDK mutations, c.520C>G/p.R174G and c.1166T>C/p.L389P, were identified at the homozygous state in two unrelated children with persistently reduced body fluid levels of branched-chain amino acids (BCAAs), developmental delay, microcephaly, and neurobehavioral abnormalities. Functional analysis of the mutations confirmed the missense character of the c.1166T>C change and showed a splicing defect r.[520c>g;521_543del]/p.R174Gfs1*, for c.520C>G due to the presence of a new donor splice site. Mutation p.L389P showed total loss of kinase activity. Moreover, patient-derived fibroblasts showed undetectable (p.R174Gfs1*) or barely detectable (p.L389P) levels of BCKDK protein and its phosphorylated substrate (phospho-E1α), resulting in increased BCKD activity and the very rapid BCAA catabolism manifested by the patients' clinical phenotype. Based on these results, a protein-rich diet plus oral BCAA supplementation was implemented in the patient homozygous for p.R174Gfs1*. This treatment normalized plasma BCAA levels and improved growth, developmental and behavioral variables. Our results demonstrate that BCKDK mutations can result in neurobehavioral deficits in humans and support the rationale for dietary intervention.

Ketogenic diets, mitochondria, and neurological diseases.

The ketogenic diet (KD) is a broad-spectrum therapy for medically intractable epilepsy and is receiving growing attention as a potential treatment for neurological disorders arising in part from bioenergetic dysregulation. The high-fat/low-carbohydrate "classic KD", as well as dietary variations such as the medium-chain triglyceride diet, the modified Atkins diet, the low-glycemic index treatment, and caloric restriction, enhance cellular metabolic and mitochondrial function. Hence, the broad neuroprotective properties of such therapies may stem from improved cellular metabolism. Data from clinical and preclinical studies indicate that these diets restrict glycolysis and increase fatty acid oxidation, actions which result in ketosis, replenishment of the TCA cycle (i.e., anaplerosis), restoration of neurotransmitter and ion channel function, and enhanced mitochondrial respiration. Further, there is mounting evidence that the KD and its variants can impact key signaling pathways that evolved to sense the energetic state of the cell, and that help maintain cellular homeostasis. These pathways, which include PPARs, AMP-activated kinase, mammalian target of rapamycin, and the sirtuins, have all been recently implicated in the neuroprotective effects of the KD. Further research in this area may lead to future therapeutic strategies aimed at mimicking the pleiotropic neuroprotective effects of the KD.

[Nutrition and dietary supplements in neurological diseases]. / Ernährung und Nahrungsergänzungsmittel bei neurologischen Erkrankungen.

"Healthy" diets and supplements are widely used for prevention and disease modification in vascular, inflammatory and degenerative neurological diseases. Apart from a large number of cross-sectional and prospective cohort studies, there are only few interventional studies on individual dietary measures. A recent study confirmed the stroke preventive effect of a Mediterranean diet rich in olive oil and nuts; a ketogenic diet reduces seizure frequency in epilepsy. Supplementation of riboflavin, magnesium and coenzyme Q10 are probably effective in migraine prophylaxis. Creatine can improve muscle strength in muscular dystrophy and myositis. There is insufficient evidence to recommend any of the many dietary supplements, such as vitamins, omega-3 fatty acids and other substances for the prevention or improvement of all other neurological diseases. This review critically evaluates the present data on the role of nutrition and dietary supplements in neurological diseases.

Diet and Nutrients in Rare Neurological Disorders: Biological, Biochemical, and Pathophysiological Evidence.

Background/Objectives: Rare diseases are a wide and heterogeneous group of multisystem life-threatening or chronically debilitating clinical conditions with reduced life expectancy and a relevant mortality rate in childhood. Some of these disorders have typical neurological symptoms, presenting from birth to adulthood. Dietary patterns and nutritional compounds play key roles in the onset and progression of neurological disorders, and the impact of alimentary needs must be enlightened especially in rare neurological diseases. This work aims to collect the in vitro, in vivo, and clinical evidence on the effects of diet and of nutrient intake on some rare neurological disorders, including some genetic diseases, and rare brain tumors. Herein, those aspects are critically linked to the genetic, biological, biochemical, and pathophysiological hallmarks typical of each disorder. Methods: By searching the major web-based databases (PubMed, Web of Science Core Collection, DynaMed, and Clinicaltrials.gov), we try to sum up and improve our understanding of the emerging role of nutrition as both first-line therapy and risk factors in rare neurological diseases. Results: In line with the increasing number of consensus opinions suggesting that nutrients should receive the same attention as pharmacological treatments, the results of this work pointed out that a standard dietary recommendation in a specific rare disease is often limited by the heterogeneity of occurrent genetic mutations and by the variability of pathophysiological manifestation. Conclusions: In conclusion, we hope that the knowledge gaps identified here may inspire further research for a better evaluation of molecular mechanisms and long-term effects.

Scoping Review of Available Culinary Nutrition Interventions for People with Neurological Conditions.

People with neurological conditions may face barriers to meal preparation. Culinary nutrition interventions aim to facilitate the building of knowledge and skills for meal preparation. This scoping review aims to map the available evidence for culinary nutrition interventions for people with neurological conditions and evaluate the quality of these interventions based on program design, delivery and evaluation. After a systematic search of online databases (MEDLINE, CINAHL, Embase, Scopus and Proquest) and reference lists, a total of ten publications describing nine interventions were included. Most interventions were designed for people with stroke and/or Transient Ischemic Attack (n = 3) and Multiple Sclerosis (n = 3); others were for traumatic brain injury (n = 1), mild dementia (n = 1) and Parkinson's Disease (n = 1). Overall, the included culinary nutrition interventions had good program delivery (inclusion of motivational experiences, delivered by appropriate health providers) but needed improvements in program design (lack of consumer engagement and neurological symptom accommodations) and evaluation (lack of complete process, outcome and impact evaluations). In conclusion, the evidence base for culinary nutrition interventions for people with neurological conditions remains sparse. To bridge the gap between theory and practice, it is important to consider the following aspects in culinary nutrition intervention planning/improvement: (I) the involvement of consumers; (II) the accommodation/tailoring for post-condition effects; and (III) the coverage of all disease-specific culinary nutrition aspects.

Unlocking Dietary Strategies to Combat Neurological Disorders.

The acquisition of novel insights derived from the biological and genetic profiles of patients will pave the way for tailored interventions and guidance, facilitated by pioneering methodologies and investigations in research. Such advancements will lead to shifts in dietary patterns and proactively mitigate the onset of neurological disorders.