Revisiting the Awareness and Understanding the Associations between Intracranial Tumors and Optic Neuropathy.

The aim of this paper is to report clinically various cases of intracranial tumors in patients referred to glaucoma clinic for consultation. The secondary aim was to increase the awareness of intracranial tumors in atypical cases of glaucoma. We present the retrospective analysis of five patients referred to glaucoma clinic for consultation. Due to atypical course of the disease, in addition to standard glaucoma examinations, all patients had a neurologic full visual field, color vision, and MRI done. In all patients, intracranial malignancies were found, some patients underwent surgery of the lesions with consecutive clinical improvements. Interestingly, in some patients, coexisting glaucoma was diagnosed. Patients were selected deliberately to present a wide spectrum of possible clinical scenarios when glaucoma may be complicated by intracranial tumors. Sometimes, the relevance of intracranial tumors with respect to their influence on the clinical picture of the optic nerve cannot be established. To conclude, in the "atypical cases of glaucoma" the assessment of the optic nerve may indicate the necessity of neuroimaging in differential diagnostics.

Therapeutic Use of the Ketogenic Diet in Refractory Epilepsy: What We Know and What Still Needs to Be Learned.

Ketogenic diet (KD) has been used to treat epilepsy for 100 years. It is a high-fat, low-carbohydrate, and sufficient-protein-for-growth diet that mimics the metabolic changes occurring during starvation. Except for classic KD, its modified counterparts, including modified Atkins diet and low-glycemic-index treatment, have gained grounds to increase palatability and adherence. Strong evidence exists that the KD offers protection against seizures in difficult-to-treat epilepsy and possesses long-lasting anti-epileptic activity, improving long-term disease outcome. The KD can also provide symptomatic and disease-modifying activity in a wide range of neurodegenerative diseases. In an era of highly available new anti-seizure medications (ASMs), the challenge of refractory epilepsy has still not been solved. This metabolic therapy is increasingly considered due to unique mechanisms and turns out to be a powerful tool in the hands of a skillful team. Despite decades of extensive research to explain the mechanism of its efficacy, the precise mechanism of action is to date still largely unknown. The key feature of this successful diet is the fact that energy is derived largely from fat but not from carbohydrates. Consequently, fundamental change occurs regarding the method of energy production that causes alterations in numerous biochemical pathways, thus restoring energetic and metabolic homeostasis of the brain. There are barriers during the use of this special and individualized therapy in many clinical settings worldwide. The aim of this review is to revisit the current state of the art of therapeutic application of KD in refractory epilepsy.

Results of Neuroimaging in Patients with Atypical Normal-Tension Glaucoma.

AIM: The aim of the study was to determine the frequency of pathologies which can mimic normal-tension glaucoma (NTG), observed in neuroimaging of NTG patients, and to evaluate the frequency of pathologies in determined additional indications for neuroimaging. Material and Methods. The studied group consisted of 126 NTG patients who met at least one of the following criteria: unilateral NTG, damage in the visual field (VF) inconsistent with optic disc appearance, fast VF progression, worsening of visual acuity, predominant optic disc pallor rather than optic disc excavation, diagnosis under the age of 50, and scotoma in VF restricted by a vertical line. The patients included in the research underwent MRI scans of the brain and both orbits. RESULTS: After neuroimaging, the results of 29 (23%) patients were qualified as positive; 18 (14.2%) of the identified pathologies were found to clinically affect the visual pathway. The most frequent brain pathology was intracranial meningiomas, observed in 4 patients (3.1%), followed by optic nerve sheath meningiomas diagnosed in 3 cases (2.4%), and brain glioma in 1 patient (0.8%). Pituitary gland adenomas were described in 6 patients (4.5%); 3 of the tumours were in contact with the optic chiasm. 53 (40%) patients had minimal ischemic changes in different regions of the brain. In the case of worsening BCVA or fast VF progression, the frequency of positive results was the highest (50% and 40%), whereas in the case of diagnosis at a young age and unilateral involvement, neuropathology was the rarest (0% and 6.9%). CONCLUSIONS: In the case of NTG, the decision to perform neuroimaging should be made after a detailed assessment of clinical status, rather in the event of finding the signs of possible compressive optic neuropathy than as an obligatory procedure for every patient.

Changes in tryptophan and kynurenine pathway metabolites in the blood of children treated with ketogenic diet for refractory epilepsy.

PURPOSE: There is growing evidence to support the role of the kynurenine pathway in the anticonvulsant efficacy of ketogenic diets (KDs) in refractory epilepsy. The aim of the present study was to measure blood levels of tryptophan (TRP) and its kynurenine derivatives and correlate them with seizure reduction after starting the KD in children with refractory epilepsy. METHODS: Sixteen children (9 F/7 M; 7.1 ± 5.1 years) with refractory epilepsy were treated with the KDs. Clinical efficacy and metabolic ketosis were monitored throughout the study; blood levels of TRP, kynurenine (KYN), kynurenic acid (KYNA), and 3-OH-kynurenine (3-OH-KYN) were measured at 3, 6, and 12 months on the diet and compared to the pre-KD levels. RESULTS: Out of 16 children, 14 attained a ≥50% reduction (responders) in seizure frequency 3 months after starting the KD. In the 14 responders, TRP levels decreased numerically (18-25%) but not significantly (P = 0.077) compared to the pre-KD control values. KYN levels decreased significantly (30-57%; P = 0.001) compared to the pre-KD control levels while KYNA levels significantly increased (38-96%; P < 0.001). KYNA/KYN ratios significantly increased (100-323%; P = 0.003) while 3-OH-KYN levels (P = 0.680) and KYN/TRP ratios (P = 0.385) remained unchanged. Higher concentrations of KYNA and lower concentrations of KYN (P < 0.05) were found in patients who attained a higher reduction in seizure frequencies on the KD. CONCLUSIONS: We report a pattern of changes in the blood level of kynurenines in patients with refractory epilepsy who started the KD. The results of this study further support the role of specific kynurenines (e.g. KYNA) in the efficacy of the KD in refractory epilepsy.

Therapeutic use of carbohydrate-restricted diets in an autistic child; a case report of clinical and 18FDG PET findings.

The ketogenic diet (KD) is a high-fat, adequate-protein, and low-carbohydrate diet that has been used successfully in the treatment of refractory epilepsies for almost 100 years. There has been accumulating evidence to show that the KD may provide a therapeutic benefit in autism spectrum disorders, albeit by a yet-unknown mechanism. We report a case of a 6-year-old patient with high-functioning autism and subclinical epileptic discharges who responded poorly to several behavioural and psychopharmacological treatments. The patient was subsequently placed on the KD due to significant glucose hypometabolism in the brain as revealed by an 18FDG PET. As soon as one month after starting the KD, the patient's behavior and intellect improved (in regard to hyperactivity, attention span, abnormal reactions to visual and auditory stimuli, usage of objects, adaptability to changes, communication skills, fear, anxiety, and emotional reactions); these improvements continued until the end of the observation period at 16 months on the KD. The 18FDG PET, measured at 12 months on the KD, revealed that 18F-FDG uptake decreased markedly and diffusely in the whole cerebral cortex with a relatively low reduction in basal ganglia in comparison to the pre-KD assessment. It warrants further investigation if the 18FDG PET imaging could serve as a biomarker in identifying individuals with autism who might benefit from the KD due to underlying abnormalities related to glucose hypometabolism.

Kynurenic Acid and Neuroprotective Activity of the Ketogenic Diet in the Eye.

BACKGROUND: There is growing evidence of the involvement of the kynurenine metabolic pathway and the enhancement of kynurenic acid production in the neuroprotective effects of the ketogenic diet. OBJECTIVE: Here, we review evidence implicating kynurenic acid in the efficacy of ketogenic diet in eye diseases associated with neurodegeneration. FINDINGS: Ketogenic diet and ketone bodies that are elevated during exposure to the ketogenic diet each have a neuroprotective effect on retinal ganglion cells in a rat model of Nmethyl- D-aspartate induced neuronal damage. Chronic exposure to ketogenic diet also increases kynurenic acid concentrations in discrete rat brain structures. A non-selective glutamate receptor agonist, glutamate, also decreases the production of kynurenic acid in bovine retinal slices; this effect is attenuated by acetoacetate and ß-hydroxybutyrate, two of three ketone bodies overproduced during ketogenic diet. PERSPECTIVE: Whether ketogenic diet induced enhancement of kynurenic acid production would translate into a clinically significant improvement in certain eye diseases like glaucoma and retinal neurodegenerations awaits further experimental and clinical verification.

Proconvulsant effects of the ketogenic diet in electroshock-induced seizures in mice.

Among non-pharmacological treatments, the ketogenic diet (KD) has the strongest demonstrated evidence of clinical success in drug resistant epilepsy. In an attempt to model the anticonvulsant effects of the KD pre-clinically, the present study assessed the effects of the KD against electroshock-induced convulsions in mice. After confirming that exposure to the KD for 2 weeks resulted in stable ketosis and hypoglycemia, mice were exposed to electroshocks of various intensities to establish general seizure susceptibility. When compared to mice fed the standard rodent chow diet (SRCD), we found that mice fed the KD were more sensitive to electroconvulsions as reflected by a significant decrease in seizure threshold (3.86 mA in mice on the KD vs 7.29 mA in mice on the SRCD; P < 0.05) in the maximal electroshock seizure threshold (MEST) test. To examine if this increased seizure sensitivity to electroconvulsions produced by the KD would affect anticonvulsant effects of antiepileptic drugs (AEDs), anticonvulsant potencies of carbamazepine (CBZ), phenobarbital (PB), phenytoin (PHT), and valproate (VPA) against maximal electroshock (MES)-induced convulsions were compared in mice fed the KD and SRCD. We found that potencies of all AEDs studied were decreased in mice fed the KD in comparison to those on the SRCD, with decreases in the anticonvulsant potencies ranging from 1.4 fold (PB) to 1.7 fold (PHT). Finally, the lack of differences in brain exposures of the AEDs studied in mice fed the KD and SRCD ruled out a pharmacokinetic nature of the observed findings. Taken together, exposure to the KD in the present study had an overall pro-convulsant effect. Since electroconvulsions require large metabolic reserves to support their rapid spread throughout the brain and consequent generalized tonic-clonic convulsions, this effect may be explained by a high energy state produced by the KD in regards to increased energy storage and utilization.

Ketogenic diet attenuates NMDA-induced damage to rat's retinal ganglion cells in an age-dependent manner.

OBJECTIVE: This study was conducted to investigate neuroprotective effects of a high fat/low carbohydrate and protein diet (ketogenic diet, KD) in a model of N-methyl D-aspartate (NMDA)-induced retinal ganglion cell (RGC) damage in juvenile and young adult rats. METHODS: Juvenile (30-35 days old) and young adult (56-70 days old) female Brown Norway rats were fed the KD for 21 days; rats exposed to a standard rodent diet (SRD) served as controls. The main constituents of the KD used in the present study were approximately 80% fats, 8% proteins, and less than 1% carbohydrates. On day 14 of exposure to the KD (or the SRD in the control group), each rat received a single intravitreal injection of NMDA; RGCs were then retrogradely labelled by hydroxystilbamidine on day 19 and collected on day 21 to assess the degree of damage induced by NMDA. Blood biomarkers to confirm the expected metabolic response to the KD (i.e. ketosis and hypoglycaemia) were also assessed. RESULTS: Although both the juvenile and young adult rats developed comparable ketosis and hypoglycaemia when fed the KD, NMDA-induced loss in RGCs was significantly attenuated only in juvenile rats exposed to the KD in comparison with those fed the SRD; exposure to the KD had no protective effect in young adult rats. In summary, exposure to the KD had a neuroprotective effect in NMDA-induced RGC damage in juvenile rats, but not in young adult rats. CONCLUSION: These results support further exploration of metabolic interventions to treat optic neuropathies associated with neurodegeneration.

Acute anticonvulsant effects of capric acid in seizure tests in mice.

Capric acid (CA10) is a 10-carbon medium-chain fatty acid abundant in the medium-chain triglyceride ketogenic diet (MCT KD). The purpose of this study was to characterize acute anticonvulsant effects of CA10 across several seizure tests in mice. Anticonvulsant effects of orally (p.o.) administered CA10 were assessed in the maximal electroshock seizure threshold (MEST), 6-Hz seizure threshold, and intravenous pentylenetetrazole (i.v. PTZ) seizure tests in mice. Acute effects of CA10 on motor coordination were assessed in the grip and chimney tests. Plasma and brain concentrations of CA10 were measured. Co-administration studies with CA10 and another abundant medium-chain fatty acid, caprylic acid (CA8) were performed. CA10 showed significant and dose-dependent anticonvulsant properties by increasing seizure thresholds in the 6-Hz and MEST seizure tests; it was ineffective in the i.v. PTZ seizure test. At higher doses than those effective in the 6-Hz and MEST seizure tests, CA10 impaired motor performance in the grip and chimney tests. An enhanced anticonvulsant response in the 6-Hz seizure test was produced when CA8 and CA10 were co-administered. An acute p.o. administration of CA10 resulted in dose-proportional increases in its plasma and brain concentrations. CA10 exerted acute anticonvulsant effects at doses that produce plasma exposures comparable to those reported in epileptic patients on the MCT KD. An enhanced anticonvulsant effect is observed when CA10 and the other main constituent of the MCT KD, CA8, were co-administered. Thus, acute anticonvulsant properties of CA10 and CA8 may influence the overall clinical efficacy of the MCT KD.

Anticonvulsant profile of caprylic acid, a main constituent of the medium-chain triglyceride (MCT) ketogenic diet, in mice.

The purpose of the present study was to evaluate the acute anticonvulsant effects of caprylic acid (CA), the main constituent of the medium-chain triglyceride ketogenic diet (MCT KD), in seizure tests typically used in screening for potential antiepileptic drugs in mice. Pharmacodynamic and pharmacokinetic interactions between CA and valproate (VPA) were also investigated. CA (p.o.) and VPA (i.p.) were administered 30 min before testing. Acute effects on motor coordination were assessed in the chimney test. Total plasma and brain concentrations of CA and VPA, when administered alone or in combination, were determined by high performance liquid chromatography. CA (10-30 mmol/kg) increased the threshold for i.v. pentylenetetrazole-induced myoclonic and clonic convulsions, but not tonic convulsions. CA (5-30 mmol/kg) increased the threshold for 6-Hz psychomotor seizures but was ineffective in the maximal electroshock seizure threshold test. CA (10-60 mmol/kg p.o.) impaired motor performance in the chimney test (TD(50) value, 58.4 mmol/kg). Increasing doses of CA (5-30 mmol/kg) produced proportional increases in plasma and brain exposure with constant brain/plasma partitioning. CA increased anticonvulsant potency of VPA in the maximal electroshock seizure and 6-Hz seizure tests. Co-administration of CA and VPA had no effect on brain and plasma concentrations of either compound. In summary, CA exerts acute anticonvulsant effects and potentiates the anticonvulsant effect of VPA at doses that result in plasma exposures comparable to those reported in epileptic patients on the MCT KD. Thus, this acute anticonvulsant property of CA may benefit and add to the overall clinical efficacy of the MCT KD.

A ketogenic diet may offer neuroprotection in glaucoma and mitochondrial diseases of the optic nerve.

Glaucoma is a chronic optic nerve disease in which the primary damage occurs to the retinal ganglion cell axons. Therapies that prevent the death of retinal ganglion cells should be theoretically beneficial. Despite promising preclinical studies, however, almost all clinical studies with pharmacological approaches for neuroprotection in neurologic and eye diseases, including glaucoma, have so far failed to show efficacy. As the evidence supporting the neuroprotective efficacy of a ketogenic diet (KD) in a number of neurodegenerative diseases continues to grow, it is conceivable that this metabolic approach might be useful in chronic glaucoma. Putative cellular mechanisms underlying the neuroprotective activity of the KD have been identified in neurological studies, including effects on energy metabolism, the GABA system, glutamate-mediated toxicity, antioxidant mechanisms, programmed cell death, anti-inflammatory mechanisms, and the production of kynurenic acid. Of note, the same mechanisms are thought to be involved in glaucoma. Given these mechanistic similarities, testing the KD for its efficacy in neurodegenerative diseases of the eye is proposed.

[Anticonvulsant and neuroprotective effects of the ketogenic diet]. / Przeciwdrgawkowe i neuroprotekcyjne dzialanie diety ketogennej.

Ketogenic diet has been used in treating epilepsy for more than 80 years. It is based on a drastic change of proportions in the consumption of carbohydrates, proteins and fats. In everyday diet we consume approximately 34 per cent of fats, 50 per cent of carbohydrates and 14 per cent of proteins. While ketogenic diet consists in 80-90 per cent of fats and in 10-20 per cents of carbohydrates and proteins together. Despite its indisputable effectiveness, the functioning of the ketogenic diet has not been explained. It seems that its functioning mechanism is unique and results from a number of chronic metabolic changes as well as the adaptation in the cenral nervous system that occurs during its long-term application. The most recent clinical and experimental data suggest that the ketogenic diet also has neuroprotective properties, which makes it a useful alternative therapeutic method in the modification of the natural history of the diseases related with neurodegeneration processes.

Pharmacodynamic and pharmacokinetic interactions between common antiepileptic drugs and acetone, the chief anticonvulsant ketone body elevated in the ketogenic diet in mice.

PURPOSE: Acetone is the principal ketone body elevated in the ketogenic diet (KD), with demonstrated robust anticonvulsant properties across a variety of seizure tests and models of epilepsy. Because the majority of patients continue to receive antiepileptic drugs (AEDs) during KD treatment, interactions between acetone and AEDs may have important clinical implications. Therefore, we investigated whether acetone could affect the anticonvulsant activity and pharmacokinetic properties of several AEDs against maximal electroshock (MES)-induced seizures in mice. METHODS: Effects of acetone given in subthreshold doses were tested on the anticonvulsant effects of carbamazepine (CBZ), lamotrigine (LTG), oxcarbazepine (OXC), phenobarbital (PB), phenytoin (PHT), topiramate (TPM) and valproate (VPA) against MES-induced seizures in mice. In addition, acute adverse effects of acetone-AEDs combinations were assessed in the chimney test (motor performance) and passive avoidance task (long-term memory). Pharmacokinetic interactions between acetone and AEDs were also studied in the mouse brain tissue. RESULTS: Acetone (5 or 7.5 mmol/kg, intraperitoneally [i.p.]) enhanced the anticonvulsant activity of CBZ, LTG, PB, and VPA against MES-induced seizures; effects of OXC, PHT, and TPM were not changed. Acetone (7.5 mmol/kg) did not enhance the acute adverse-effect profiles of the studied AEDs. Acetone (5 or 7.5 mmol/kg, i.p.) did not affect total brain concentrations of the studied AEDs. In contrast, VPA, CBZ, LTG, OXC, and TPM significantly decreased the concentration of free acetone in the brain; PB and PHT had no effect. CONCLUSIONS: Acetone enhances the anticonvulsant effects of several AEDs such as VPA, CBZ, LTG, and PB without affecting their pharmacokinetic and side-effect profiles.