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.

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.

Revision of trabeculectomy filtering blebs with mitomycin C: Long term results.

AIM: The aim of the study is to assess the outcomes of transconjunctival mitomycin C (MMC)-augmented revision in eyes with failed trabeculectomy. MATERIALS AND METHODS: This is a retrospective, noncomparative case series. One hundred and twenty-one eyes of 113 consecutive glaucoma patients with previously failed trabeculectomy who underwent transconjunctival revision with at least 12 months of follow-up were initially included in the study. The success was determined on the basis of intraocular pressure (IOP) alone. The main outcome measures were IOP, best-corrected distance visual acuity, complications, bleb appearance, lens status, visual field progression, and time between primary trabeculectomy and MMC revision. The main purpose of the study was to determine the efficacy of a single MMC-augmented needle revision. RESULTS: Mean follow-up was 2.3 years. Twelve months after revision, IOP had declined from 26.1 ± 8.4 mmHg to 14.1 ± 4.8 mmHg (P < 0.05) and remained 16.0 ± 5.6 mmHg at 24 months, 15.7 ± 5.8 mmHg at 48 months, and 15.2 ± 4.0 mmHg at 60 months. Complete success was achieved in 53% of cases, 84% achieved qualified success, and 16% were classified as failures 12 months after revision. Early complications developed in 45 of the initial 121 eyes (37.2%). CONCLUSIONS: Transconjunctival MMC-augmented revision appears to be a safe and useful tool in reducing IOP and re-establishing filtration after trabeculectomy failure. This simple procedure has a high rate of success and helps avoid other surgical interventions which are more destructive for the conjunctiva.

Effects of topical bevacizumab application on early bleb failure after trabeculectomy: observational case series.

BACKGROUND: The aim of this study was to evaluate the influence of topical bevacizumab on the formation and function of filtering blebs in eyes with early bleb failure after antiglaucoma surgery. METHODS: Of all patients who underwent mitomycin-augmented trabeculectomy for glaucoma in the Department of Ophthalmology at the Medical University in Lublin, Poland, between March 2009 and March 2010, a total of 21 eyes from 20 patients with injected filtration bleb 9.8 ± 4.7 days after surgery were included in this observational case series. All patients were treated with standard steroid therapy and topical bevacizumab 5 mg/mL five times a day for 20.9 ± 9.8 days. Patients were followed up every other day, and a full eye examination was performed 14, 30, 60, and 180 days after initiation of treatment. Blebs were evaluated for vascularity by slit-lamp examination with concomitant photographic documentation and intraocular pressure measurement. RESULTS: Elevated functional bleb with significantly reduced vascularity was present in 16 eyes, and was flat and nonfunctional in five eyes. Intraocular pressure in all eyes decreased from a mean of 26.6 ± 9.6 mmHg before surgery to 14.6 ± 7.7 mmHg and 15.8 ± 8.3 mmHg at 2 and 6 months after surgery, respectively. Filtration bleb leak was noted in three eyes while on treatment with bevacizumab. CONCLUSION: Topical application of bevacizumab might favor functional bleb formation after trabeculectomy in eyes with a high risk of failure.

Efficacy and safety of mitomycin C--augmented revisions of non-functioning filtering blebs after trabeculectomy--7 year results.

PURPOSE: To determine the efficacy and safety of mitomycin C-augmented revision in eyes after failed primary trabeculectomy failure. MATERIAL AND METHODS: Retrospective review of 40 eyes after a single MMC-augmented revision due to primary trabeculectomy failure. MAIN OUTCOME MEASURES: intraocular pressure, best corrected visual acuity, number of antiglaucoma medications, complications. RESULTS: Twelve months after revision the mean intraocular pressure declined from 24.5 +/- 6.7 mmHg to 15.4 +/- 4.4 mmHg (p < 0.05) and remained decreased at 24 months (16.33 +/- 4.2 mmHg) and at 84 months (16.75 +/- 2.8 mmHg). The therapeutic success, defined as intraocular pressure < or = 18 mmHg without medication at 12 months after revision, was achieved in seventeen eyes (42.5%). Fourteen eyes (35.0%) achieved qualified success, defined as intraocular pressure < or = 18 mmHg with antiglaucoma medication, and 9 of 40 eyes (22.5%) were classified as failures. Mean best corrected visual acuity did not change significantly after the surgery (12 month: p = 0.76, 36-48 months: p = 0.25, 72-84 months: p = 0.15). The mean number of medications was reduced from 1.2 +/- 0.8 preoperatively to 0.68 +/- 0.8 postoperatively at 12 months, to 0.78 +/- 0.49 at 24 months and the drop was statistically significantly. Early complications developed in 7 (17.5%) eyes but they resolved spontaneously. CONCLUSIONS: MMC-augmented revision appears to be a safe and useful tool in reducing intraocular pressure after trabeculectomy failure. This simple-technique procedure is successful in 42.5% of eyes for up to 24-36 months and helps protect the eye from other surgical intervention, more destructive for the conjunctiva.

Ketogenic diet increases concentrations of kynurenic acid in discrete brain structures of young and adult rats.

Targeting mechanisms that result in increased concentrations of kynurenic acid (KYNA) in the brain has been considered as a therapeutic approach for the treatment of epilepsy and certain neurodegenerative disorders. Recently, KYNA has been implicated in the effects produced by the high-fat and low-protein/carbohydrate ketogenic diet (KD) in a report demonstrating an increased production of KYNA in vitro by one of the ketone bodies, ß-hydroxybutyrate, elevated by the KD. To further explore this association, brain concentrations of KYNA were compared in young (3 weeks old) and adult (8-10 weeks old) rats that were chronically exposed to the KD and regular diet. Exposure to the KD resulted in the anticipated elevations of ß-hydroxybutyrate with accompanying decreases in glucose concentrations. In comparison to rats fed the regular diet, KYNA concentrations were significantly (p < 0.05) increased in the hippocampus (256 and 363% increase in young and adult rats, respectively) and in the striatum (381 and 191% increase in young and adult rats, respectively) in KD-fed rats. KD-induced increases in KYNA concentrations in young versus adult rats in the hippocampus and striatum were comparable (p > 0.05). Exposure to the KD had no effect on KYNA concentrations in the cortex of young and adult rats (p > 0.05). In summary, chronic exposure to the KD resulted in several-fold increases in KYNA concentrations in discrete brain structures in the rats. Thus, the relevant clinical question for further exploration is whether KD-induced increases in KYNA concentrations can translate into clinically significant improvements in neuropsychiatric diseases associated with KYNA hypofunction.

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.

Neuroprotection by acetoacetate and ß-hydroxybutyrate against NMDA-induced RGC damage in rat--possible involvement of kynurenic acid.

PURPOSE: This study investigated the effects of systemically administered lithium acetoacetate (ACA) and sodium ß-hydroxybutyrate (BHB) in a rat model of N-methyl-D-aspartate (NMDA)-induced damage of retinal ganglion cells (RGC). Additionally, the influence of ACA and BHB on kynurenic acid (KYNA) production was assessed in vitro in bovine retinal slices. METHODS: Female adult Brown-Norway rats in groups of 5-8 animals were used. ACA and BHB were administered intraperitoneally once a day for 21 consecutive days, and phosphate buffered saline (PBS) was administered to control animals. After 2 weeks, the animals received intraocular NMDA (2 µl of a 10 mM solution in PBS) or intraocular PBS as a control. On day 19, retinal ganglion cells were labeled retrogradely with hydroxystilbamidine. Two days later, RGC density (cells per mm(2)) was assessed on retinal flatmounts. Additionaly, bovine retinal slices were incubated with NMDA and ACA or BHB at concentrations of 1.0 mM and 3.0 mM, and de novo KYNA production was measured using HPLC. RESULTS: Intraperitoneal ACA (250 mg/kg) or BHB (291.2 mg/kg) significantly protected RGC against NMDA-induced neurodegeneration. De novo KYNA production in bovine retinal slices was lowered by NMDA. Both ACA and BHB at a concentration of 3.0 mM significantly reduced the effects of NMDA. CONCLUSIONS: ACA and BHB had a significant dose-dependent neuroprotective effect on RGC in a rat model of NMDA-induced RGC damage. Both ketone bodies also significantly attenuated NMDA-induced reduction of retinal KYNA production in vitro, suggesting that this mechanism may be essential for the neuroprotective effects of ACA and BHB in vivo. Our results imply that ketone bodies may represent an additional treatment option in chronic neurodegenerative disorders of the eye.