New Promising Therapeutic Avenues of Curcumin in Brain Diseases.

Curcumin, the dietary polyphenol isolated from Curcuma longa (turmeric), is commonly used as an herb and spice worldwide. Because of its bio-pharmacological effects curcumin is also called "spice of life", in fact it is recognized that curcumin possesses important proprieties such as anti-oxidant, anti-inflammatory, anti-microbial, antiproliferative, anti-tumoral, and anti-aging. Neurodegenerative diseases such as Alzheimer's Diseases, Parkinson's Diseases, and Multiple Sclerosis are a group of diseases characterized by a progressive loss of brain structure and function due to neuronal death; at present there is no effective treatment to cure these diseases. The protective effect of curcumin against some neurodegenerative diseases has been proven by in vivo and in vitro studies. The current review highlights the latest findings on the neuroprotective effects of curcumin, its bioavailability, its mechanism of action and its possible application for the prevention or treatment of neurodegenerative disorders.

Perinatal encephalopathy, the syndrome of intracranial hypertension and associated diagnostic labels in the Commonwealth of Independent States: a systematic review.

BACKGROUND: The WHO reports excessive rates of ill-defined neurological diagnoses and ineffective and potentially harmful drug treatments in children in the Commonwealth of Independent States (CIS). Collectively termed perinatal encephalopathy and the syndrome of intracranial hypertension (PE-SIH), these diagnoses are important contributors to perceived childhood morbidity and disability in the CIS. A systematic compilation of information on PE-SIH is lacking. METHODS: We systematically reviewed publications between 1970 and 2020 on PE-SIH in Azerbaijani, English, Russian and Ukrainian languages and summarised information on PE-SIH. RESULTS: We identified 30 publications (70% in Russian) published 1976-2017. The diagnosis of PE-SIH was either based on unreported criteria (67% of reports), non-specific clinical features of typically developing children or those with common developmental disorders (20% of reports) or cranial ultrasound (13% of reports). The reported proportion of children with PE-SIH in the study samples ranged from 31% to 99%. There were few published studies on reassessments of children diagnosed with PE-SIH, and these did not confirm neurological disease in the majority of children. Treatments included multiple unlicenced drugs without established effectiveness and with potential unwanted effects. CONCLUSION: This review suggests that PE-SIH is a medical diagnostic label that is used in numerous children without substantive associated disease. The diagnosis and treatment of PE-SIH is a multidimensional, iatrogenic, clinical and public health problem in the CIS. With increasing use of evidence-based medicine guidelines in the region, it is hoped that PE-SIH will gradually disappear, but actions to accelerate this change are nevertheless needed.

Mitochondria as a target for neuroprotection: role of methylene blue and photobiomodulation.

Mitochondrial dysfunction plays a central role in the formation of neuroinflammation and oxidative stress, which are important factors contributing to the development of brain disease. Ample evidence suggests mitochondria are a promising target for neuroprotection. Recently, methods targeting mitochondria have been considered as potential approaches for treatment of brain disease through the inhibition of inflammation and oxidative injury. This review will discuss two widely studied approaches for the improvement of brain mitochondrial respiration, methylene blue (MB) and photobiomodulation (PBM). MB is a widely studied drug with potential beneficial effects in animal models of brain disease, as well as limited human studies. Similarly, PBM is a non-invasive treatment that promotes energy production and reduces both oxidative stress and inflammation, and has garnered increasing attention in recent years. MB and PBM have similar beneficial effects on mitochondrial function, oxidative damage, inflammation, and subsequent behavioral symptoms. However, the mechanisms underlying the energy enhancing, antioxidant, and anti-inflammatory effects of MB and PBM differ. This review will focus on mitochondrial dysfunction in several different brain diseases and the pathological improvements following MB and PBM treatment.

Isolated involvement of corpus callosum in metronidazole-induced encephalopathy with concomitant peripheral neuropathy: A case report.

RATIONALE: Metronidazole is widely used for treating infection of anaerobic bacteria and protozoa. Metronidazole is generally well tolerated, although metronidazole-associated peripheral neuropathy (PN) and metronidazole-induced encephalopathy (MIE) have been reported as rare side effects. The most common sites of MIE involve the bilateral dentate nucleus of the cerebellum. Herein, we present a rare case of MIE with isolated corpus callosum involvement, with concomitant metronidazole-associated PN. PATIENT CONCERNS: A middle-aged man with ulcerative colitis was diagnosed with amoebic dysentery because of unhygienic eating. After receiving metronidazole (1.8 g/d, cumulative dose 61.2 g) for >1 month, he started to complain of continuous paresthesia of the limbs, and intermittent speech problems. Magnetic resonance imaging demonstrated an isolated lesion in the splenium of the corpus callosum. DIAGNOSIS: A diagnosis of reversible splenial lesion syndrome and PN was made. Given the patient's medical history, MIE and metronidazole-associated PN were considered. INTERVENTIONS: Metronidazole was stopped. Mecobalamine and vitamin B1 were used for adjuvant treatment. OUTCOMES: At 1.5 months after stopping metronidazole, his symptoms of numbness and hyperesthesia had not improved, although he felt less ill. The isolated lesion disappeared on follow-up magnetic resonance imaging. At 6 months later, the hyperesthesia symptoms remained, and he was unable to resume his previous work. CONCLUSIONS: Physicians should consider MIE in their differentials for reversible splenial lesion syndrome when encountering a patient with a history of metronidazole medication and symptoms of encephalopathy, especially with concomitant PN. Early identification of this metronidazole-related complication and early cessation of the drug are essential for treatment.

Consulting with a folk deity before making decisions: spiritual practices in parents facing end-of-life decisions for their child on life support with brain stem dysfunction.

Background: Adolescents with brain stem dysfunction may undergo many invasive treatments, and parents are often faced with making the decision to withdraw treatment. However, in the face of their child's death, the spiritual practices of parents dealing with end-of-life decision-making remain under investigated.Purpose: This study explores the spiritual practices in parents making end-of-life decisions for adolescents on life support with brain stem dysfunction.Method: A descriptive phenomenological study was conducted through in-depth interviews with three parents of two adolescents in Taiwan. Data were analysed using Colaizzi's seven-step protocol.Results: Three main themes emerged: (1) faith during decision-making, (2) struggles during decision-making, (3) transformation during decision-making. The findings indicate that "transforming the nature of hope" is the essence of the experience.Conclusion: Family-centred care, gaining insight into parental spiritual practices, and developing culturally-appropriate care are recommended.

White matter injury after neonatal encephalopathy is associated with thalamic metabolite perturbations.

BACKGROUND: Although thalamic magnetic resonance (MR) spectroscopy (MRS) accurately predicts adverse outcomes after neonatal encephalopathy, its utility in infants without MR visible deep brain nuclei injury is not known. We examined thalamic MRS metabolite perturbations in encephalopathic infants with white matter (WM) injury with or without cortical injury and its associations with adverse outcomes. METHODS: We performed a subgroup analysis of all infants recruited to the MARBLE study with isolated WM or mixed WM/cortical injury, but no visible injury to the basal ganglia/thalamus (BGT) or posterior limb of the internal capsule (PLIC). We used binary logistic regression to examine the association of MRS biomarkers with three outcomes (i) WM injury score (1 vs. 2/3); (ii) cortical injury scores (0/1 vs. 2/3); and (iii) adverse outcomes (defined as death, moderate/severe disability) at two years (yes/no). We also assessed the accuracy of MRS for predicting adverse outcome. FINDINGS: Of the 107 infants included in the analysis, five had adverse outcome. Reduced thalamic N-acetylaspartate concentration [NAA] (odds ratio 0.4 (95% CI 0.18-0.93)) and elevated thalamic Lactate/NAA peak area ratio (odds ratio 3.37 (95% CI 1.45-7.82)) were significantly associated with higher WM injury scores, but not with cortical injury. Thalamic [NAA] (≤5.6 mmol/kg/wet weight) had the best accuracy for predicting adverse outcomes (sensitivity 1.00 (95% CI 0.16-1.00); specificity 0.95 (95% CI 0.84-0.99)). INTERPRETATION: Thalamic NAA is reduced in encephalopathic infants without MR visible deep brain nuclei injury and may be a useful predictor of adverse outcomes. FUNDING: The National Institute for Health Research (NIHR).

Recommendations for the Nonpharmacological Treatment of Apathy in Brain Disorders.

Apathy is a common neuropsychiatric syndrome observed across many neurocognitive and psychiatric disorders. Although there are currently no definitive standard therapies for the treatment of apathy, nonpharmacological treatment (NPT) is often considered to be at the forefront of clinical management. However, guidelines on how to select, prescribe, and administer NPT in clinical practice are lacking. Furthermore, although new Information and Communication Technologies (ICT) are beginning to be employed in NPT, their role is still unclear. The objective of the present work is to provide recommendations for the use of NPT for apathy, and to discuss the role of ICT in this domain, based on opinions gathered from experts in the field. The expert panel included 20 researchers and healthcare professionals working on brain disorders and apathy. Following a standard Delphi methodology, experts answered questions via several rounds of web-surveys, and then discussed the results in a plenary meeting. The experts suggested that NPT are useful to consider as therapy for people presenting with different neurocognitive and psychiatric diseases at all stages, with evidence of apathy across domains. The presence of a therapist and/or a caregiver is important in delivering NPT effectively, but parts of the treatment may be performed by the patient alone. NPT can be delivered both in clinical settings and at home. However, while remote treatment delivery may be cost and time-effective, it should be considered with caution, and tailored based on the patient's cognitive and physical profile and living conditions.

Crigler-Najjar Syndrome Type 1: Pathophysiology, Natural History, and Therapeutic Frontier.

BACKGROUND AND AIMS: We describe the pathophysiology, treatment, and outcome of Crigler-Najjar type 1 syndrome (CN1) in 28 UGT1A1 c.222C>A homozygotes followed for 520 aggregate patient-years. APPROACH AND RESULTS: Unbound ("free") bilirubin (Bf ) was measured in patient sera to characterize the binding of unconjugated bilirubin (BT ) to albumin (A) and validate their molar concentration ratio (BT /A) as an index of neurological risk. Two custom phototherapy systems were constructed from affordable materials to provide high irradiance in the outpatient setting; light dose was titrated to keep BT /A at least 30% below intravascular BT binding capacity (i.e., BT /A = 1.0). Categorical clinical outcomes were ascertained by chart review, and a measure (Lf ) was used to quantify liver fibrosis. Unbound bilirubin had a nonlinear relationship to BT (R2  = 0.71) and BT /A (R2  = 0.76), and Bf as a percentage of BT correlated inversely to the bilirubin-albumin equilibrium association binding constant (R2  = 0.69), which varied 10-fold among individuals. In newborns with CN1, unconjugated bilirubin increased 4.3 ± 1.1 mg/dL per day. Four (14%) neonates developed kernicterus between days 14 and 45 postnatal days of life; peak BT  ≥ 30 mg/dL and BT /A ≥ 1.0 mol:mol were equally predictive of perinatal brain injury (sensitivity 100%, specificity 93.3%, positive predictive value 88.0%), and starting phototherapy after age 13 days increased this risk 3.5-fold. Consistent phototherapy with 33-103 µW/cm2 •nm for 9.2 ± 1.1 hours/day kept BT and BT /A within safe limits throughout childhood, but BT increased 0.46 mg/dL per year to reach dangerous concentrations by 18 years of age. Liver transplantation (n = 17) normalized BT and eliminated phototherapy dependence. Liver explants showed fibrosis ranging from mild to severe. CONCLUSION: Seven decades after its discovery, CN1 remains a morbid and potentially fatal disorder.

Interictal epileptiform discharges in sleep and the role of the thalamus in Encephalopathy related to Status Epilepticus during slow Sleep.

EEG activation of interictal epileptiform discharges (IEDs) during NREM sleep is a well-described phenomenon that occurs in the majority of epileptic syndromes. In drug-resistant focal epilepsy, IED activation seems to be related to slow wave activity (SWA), especially during arousal fluctuations, namely phase A of the cyclic alternating pattern (CAP). Conversely, in childhood focal epileptic syndromes, including Encephalopathy related to Status Epilepticus during slow Sleep (ESES), IED activation seems primarily modulated by sleep-inducing and maintaining mechanisms as reflected by the dynamics of spindle frequency activity (SFA) rather than SWA. In this article, we will review the effect of sleep on IEDs with a particular attention on the activation and modulation of IEDs in ESES. Finally, we will discuss the role of the thalamus and cortico-thalamic circuitry in this syndrome.

Towards a Pragmatic Approach to a Psychophysiological Unit of Analysis for Mental and Brain Disorders: An EEG-Copeia for Neurofeedback.

This article proposes what we call an "EEG-Copeia" for neurofeedback, like the "Pharmacopeia" for psychopharmacology. This paper proposes to define an "EEG-Copeia" as an organized list of scientifically validated EEG markers, characterized by a specific association with an identified cognitive process, that define a psychophysiological unit of analysis useful for mental or brain disorder evaluation and treatment. A characteristic of EEG neurofeedback for mental and brain disorders is that it targets a EEG markers related to a supposed cognitive process, whereas conventional treatments target clinical manifestations. This could explain why EEG neurofeedback studies encounter difficulty in achieving reproducibility and validation. The present paper suggests that a first step to optimize EEG neurofeedback protocols and future research is to target a valid EEG marker. The specificity of the cognitive skills trained and learned during real time feedback of the EEG marker could be enhanced and both the reliability of neurofeedback training and the therapeutic impact optimized. However, several of the most well-known EEG markers have seldom been applied for neurofeedback. Moreover, we lack a reliable and valid EEG targets library for further RCT to evaluate the efficacy of neurofeedback in mental and brain disorders. With the present manuscript, our aim is to foster dialogues between cognitive neuroscience and EEG neurofeedback according to a psychophysiological perspective. The primary objective of this review was to identify the most robust EEG target. EEG markers linked with one or several clearly identified cognitive-related processes will be identified. The secondary objective was to organize these EEG markers and related cognitive process in a psychophysiological unit of analysis matrix inspired by the Research Domain Criteria (RDoC) project.

Isoniazid-induced encephalopathy in an end-stage renal disease patient - A case report and literature review.

Patients with end stage renal disease have higher risk of tuberculosis due to lower cell-mediated immunity. Standard regime of anti-tuberculosis contains isoniazid where neurological side effects such as seizure and encephalopathy have been documented. We present a case of isoniazid-induced encephalopathy in a haemodialysis patient. A literature review on isoniazid-induced encephalopathy was done. Recognition of this condition is important as it is reversible with cessation of isoniazid and institution of high dose pyridoxine.

Use of standard enteral formula versus enteric formula with prebiotic content in nutrition therapy: A randomized controlled study among neuro-critical care patients.

OBJECTIVE: To compare use of standard enteral formula versus enteric formula with prebiotic content in terms of nutrition therapy related outcomes among neurocritical care patients. METHODS: A total of 46 adult neurocritical care patients who received nutrition therapy with standard enteral formula (SEF group; n = 23) or enteral formula with prebiotic content (EFPC group; n = 23) during their hospitalization in intensive care unit (ICU) were included in this prospective randomized controlled study. Data on patient demographics (age, gender), diagnosis, co-morbid diseases, anthropometrics, length of stay (LOS) in hospital and ICU, Nutritional Risk Screening (NRS-2002) score, and Acute Physiology and Chronic Health (APACHE-II) score were recorded at enrollment. Data on daily nutritional intake [total energy (kcal/day), carbohydrate (g/day), protein (g/day), lipid (g/day), FOS (g/day), enteral volume (ml/day), fluid in enteral product (ml/day) and fluid intake (ml/day)], achievement of target dose [total fluid intake in enteral product (ml)/20 h], laboratory findings (blood biochemistry and complete blood count), complications and drug treatments were recorded on Day 1, Day 4, Day 7, Day 14 and Day 21 of nutrition therapy in SEF and EFPC groups. RESULTS: Use of EFPC compared to SEF was associated with significantly higher total energy, carbohydrate, protein, lipid, enteral volume and fluid intake (p values ranged from <0.05 to <0.001) on each day of nutrition therapy. Target dose was achieved by majority of patients (86.9%) and at day 4 of nutrition therapy in most of patients (71.7%) in the overall study population. Patients in the EFPC group had a non-significant tendency for higher rate (95.7% vs. 78.3%) and earlier (87.0% vs. 56.5% on day 4) achievement of target dose, lower rate (8.7% vs. 56.5%) and faster amelioration (none vs. 52.2% were diarrheic on day 7) of diarrhea and lesser need for insulin (56.5% vs. 13.0%, p = 0.002). Nutrition therapy was associated with significant decrease in prealbumin (Day 14 vs. Day 1, p < 0.05 for both), albumin (Day 14 vs. day 1, p < 0.01 for SEF, p < 0.05 for PEF), hemoglobin (Day 14 and Day 21 vs. Day 1and Day 14 vs. Day 4, p < 0.001 for each for SEF, Day 7, Day 14 and Day 21 vs. Day 1, p < 0.01 for each for PEF) and hematocrit (Day 14 and Day 21 vs. Day 1, p < 0.001 for each for both) levels in both SEF and EFPC groups. CONCLUSIONS: In conclusion, our findings revealed achievement of target nutritional intake in majority of neurocritical care patients via nutrition therapy, whereas EFPC was associated with a non-significant tendency for more frequent and earlier achievement of target dose along with significantly lower rate and faster amelioration of diarrhea as compared with SEF group. Prealbumin and albumin levels remained below the normal range, whereas C reactive protein (CRP) and white blood cell (WBC) were over the normal range throughout the nutrition period in both groups, while creatinine and urea levels were higher in EFPC than in SEF group. Hence, our findings seem to emphasize the importance of avoiding protein debt in provision of nutrition therapy and the likelihood of deterioration of nutritional status in elderly neurocritical care patients despite provision of early enteral nutrition support due to complex and deleterious inflammatory and metabolic changes during critical illness.

Approaches for Reducing the Risk of Early-Life Iron Deficiency-Induced Brain Dysfunction in Children.

Iron deficiency is the most common micronutrient deficiency in the world. Women of reproductive age and young children are particularly vulnerable. Iron deficiency in late prenatal and early postnatal periods can lead to long-term neurobehavioral deficits, despite iron treatment. This may occur because screening and treatment of iron deficiency in children is currently focused on detection of anemia and not neurodevelopment. Anemia is the end-stage state of iron deficiency. The brain becomes iron deficient before the onset of anemia due to prioritization of the available iron to the red blood cells (RBCs) over other organs. Brain iron deficiency, independent of anemia, is responsible for the adverse neurological effects. Early diagnosis and treatment of impending brain dysfunction in the pre-anemic stage is necessary to prevent neurological deficits. The currently available hematological indices are not sensitive biomarkers of brain iron deficiency and dysfunction. Studies in non-human primate models suggest that serum proteomic and metabolomic analyses may be superior for this purpose. Maternal iron supplementation, delayed clamping or milking of the umbilical cord, and early iron supplementation improve the iron status of at-risk infants. Whether these strategies prevent iron deficiency-induced brain dysfunction has yet to be determined. The potential for oxidant stress, altered gastrointestinal microbiome and other adverse effects associated with iron supplementation cautions against indiscriminate iron supplementation of children in malaria-endemic regions and iron-sufficient populations.

Hashimoto encephalopathy in pediatric patients: Homogeneity in clinical presentation and heterogeneity in antibody titers.

OBJECTIVE: Hashimoto encephalopathy is an autoimmune encephalopathy characterized by elevated antithyroid antibodies and a favorable response to corticosteroid. This study delineated the clinical characteristics of pediatric Hashimoto encephalopathy and the significance of low antithyroid antibody titers in diagnosis and treatment. SUBJECTS AND METHODS: Clinical manifestations, antibody titers, and treatment responses were retrospectively reviewed in six consecutive children diagnosed with Hashimoto encephalopathy between August 2008 and July 2016. RESULTS: Age at diagnosis was 10-17years. Presenting symptoms were seizures, altered consciousness, behavioral changes, psychosis, tremor, and dystonia. Thyroid function was normal in five patients, and one had hypothyroidism prior to the encephalopathy. Antithyroid antibody titer was increased at presentation in five patients and one week later in the other. Antibody levels were extremely varied (anti-thyroglobulin, 20.5-2318.0U/ml; anti-thyroid peroxidase, 12.5-2231.0U/ml; reference range, <60U/ml) and <180U/ml in two patients. Electroencephalogram was abnormal in five patients. Brain magnetic resonance imaging was unremarkable. Four patients responded to high-dose corticosteroid and one improved with additional intravenous immunoglobulin. The remaining patient did not respond to both treatments and normalized after plasmapheresis. Autoantibody titers decreased with treatment response in the acute stage. Two patients with low antibody titers showed similar clinical presentations and responses. CONCLUSIONS: The clinical presentations and treatment responses in Hashimoto encephalopathy were similar, irrespective of antithyroid antibody titer. Because the initial antithyroid antibody titers can be normal or mildly-elevated, follow-up testing of antithyroid antibodies is required in patients who are clinically suspect for Hashimoto encephalopathy.

Mutations in SLC5A6 associated with brain, immune, bone, and intestinal dysfunction in a young child.

The human sodium-dependent multivitamin transporter (hSMVT) is a product of the SLC5A6 gene and mediates biotin, pantothenic acid, and lipoate uptake in a variety of cellular systems. We report here the identification of mutations R94X, a premature termination, and R123L, a dysfunctional amino acid change, both in exon 3 of the SLC5A6 gene in a child using whole genome-scanning. At 15 months of age, the child showed failure to thrive, microcephaly and brain changes on MRI, cerebral palsy and developmental delay, variable immunodeficiency, and severe gastro-esophageal reflux requiring a gastrostomy tube/fundoplication, osteoporosis, and pathologic bone fractures. After identification of the SLC5A6 mutations, he responded clinically to supplemental administration of excess biotin, pantothenic acid, and lipoate with improvement in clinical findings. Functionality of the two mutants was examined by 3H-biotin uptake assay following expression of the mutants in human-derived intestinal HuTu-80 and brain U87 cells. The results showed severe impairment in biotin uptake in cells expressing the mutants compared to those expressing wild-type hSMVT. Live cell confocal imaging of cells expressing the mutants showed the R94X mutant to be poorly tolerated and localized in the cytoplasm, while the R123L mutant was predominantly retained in the endoplasmic reticulum. This is the first reporting of mutations in the SLC5A6 gene in man, and suggests that this gene is important for brain development and a wide variety of clinical functions.

Hemorrhagic Encephalopathy From Acute Baking Soda Ingestion.

Baking soda is a readily available household product composed of sodium bicarbonate. It can be used as a home remedy to treat dyspepsia. If used in excessive amounts, baking soda has the potential to cause a variety of serious metabolic abnormalities. We believe this is the first reported case of hemorrhagic encephalopathy induced by baking soda ingestion. Healthcare providers should be aware of the dangers of baking soda misuse and the associated adverse effects.

Stimulus induced bursts in severe postanoxic encephalopathy.

OBJECTIVE: To report on a distinct effect of auditory and sensory stimuli on the EEG in comatose patients with severe postanoxic encephalopathy. METHODS: In two comatose patients admitted to the Intensive Care Unit (ICU) with severe postanoxic encephalopathy and burst-suppression EEG, we studied the effect of external stimuli (sound and touch) on the occurrence of bursts. RESULTS: In patient A bursts could be induced by either auditory or sensory stimuli. In patient B bursts could only be induced by touching different facial regions (forehead, nose and chin). When stimuli were presented with relatively long intervals, bursts persistently followed the stimuli, while stimuli with short intervals (<1s) did not induce bursts. In both patients bursts were not accompanied by myoclonia. Both patients deceased. CONCLUSIONS: Bursts in patients with a severe postanoxic encephalopathy can be induced by external stimuli, resulting in stimulus-dependent burst-suppression. SIGNIFICANCE: Stimulus induced bursts should not be interpreted as prognostic favourable EEG reactivity.