Safety and efficacy of topiramate in neonates with hypoxic ischemic encephalopathy treated with hypothermia (NeoNATI): a feasibility study

Filippi, Luca; Fiorini, Patrizio; Catarzi, Serena; Berti, Elettra; Padrini, Letizia; Landucci, Elisa; Donzelli, Gianpaolo; Bartalena, Laura; Fiorentini, Erika; Boldrini, Antonio; Giampietri, Matteo; Scaramuzzo, Rosa Teresa; Marca, Giancarlo la; Bona, Maria Luisa Della; Fiori, Simona; Tinelli, Francesca; Bancale, Ada; Guzzetta, Andrea; Cioni, Giovanni; Pisano, Tiziana; Falchi, Melania; Guerrini, Renzo

doi:10.1080/14767058.2017.1304536

Cited by 55 publications

(38 citation statements)

References 25 publications

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“…Supporting this, the anticonvulsant topiramate (Lee et al . 2000) also did not improve death or neurological disability in a small phase‐II trial in hypothermia‐treated neonates with HIE, compared with hypothermia‐treated babies alone (Filippi et al . 2018).…”

Section: The Mechanisms Of Hypothermic Neuroprotectionmentioning

confidence: 99%

A working model for hypothermic neuroprotection

Wassink

Davidson

Lear

et al. 2018

The Journal of Physiology

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Therapeutic hypothermia significantly improves survival without disability in near-term and full-term newborns with moderate to severe hypoxic-ischaemic encephalopathy. However, hypothermic neuroprotection is incomplete. The challenge now is to find ways to further improve outcomes. One major limitation to progress is that the specific mechanisms of hypothermia are only partly understood. Evidence supports the concept that therapeutic cooling suppresses multiple extracellular death signals, including intracellular pathways of apoptotic and necrotic cell death and inappropriate microglial activation. Thus, the optimal depth of induced hypothermia is that which effectively suppresses the cell death pathways after hypoxia-ischaemia, but without inhibiting recovery of the cellular environment. Thus mild hypothermia needs to be continued until the cell environment has recovered until it can actively support cell survival. This review highlights that key survival cues likely include the inter-related restoration of neuronal activity and growth factor release. This working model suggests that interventions that target overlapping mechanisms, such as anticonvulsants, are unlikely to materially augment hypothermic neuroprotection. We suggest that further improvements are most likely to be achieved with late interventions that maximise restoration of the normal cell environment after therapeutic hypothermia, such as recombinant human erythropoietin or stem cell therapy.

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Section: The Mechanisms Of Hypothermic Neuroprotectionmentioning

confidence: 99%

A working model for hypothermic neuroprotection

Wassink

Davidson

Lear

et al. 2018

The Journal of Physiology

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“…One of the most compelling benefits of TH relies on the attenuation of post-depolarization release of excitatory amino acids [20]. Recently, the use of TPM (10 mg/kg/day) for 3 days during TH in patients with moderate to severe HIE did not reduce mortality or improve neurodevelopmental outcome at 18–24 months; however, it significantly reduced seizure activity [11]. Glass et al [9] have also described the efficacy of TPM using similar doses; however, increasing the dose to 25 mg/kg/day did not increase TPM efficacy.…”

Section: Discussionmentioning

confidence: 99%

“…TPM in experimental models has displayed neuroprotective effects [8] and has been safely used in the neonatal period [9-11]. One of the most compelling benefits of TH relies on the attenuation of post-depolarization release of excitatory amino acids [20].…”

Section: Discussionmentioning

confidence: 99%

“…Pilot studies in the newborn period have described the efficacy of TPM as an antiseizure drug and suggest a synergistic action of TPM in combination with hypothermia. However, these were safety trials with a small number of patients that did not include follow-up and therefore did not provide sufficient evidence on the dose regime employed [9-11]. We hypothesized that prophylactic TPM would reduce seizure activity and as a consequence enhance neuronal survival, leading to improved outcomes.…”

Section: Introductionmentioning

confidence: 99%

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Topiramate plus Cooling for Hypoxic-Ischemic Encephalopathy: A Randomized, Controlled, Multicenter, Double-Blinded Trial

et al. 2019

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Background and Objectives: Therapeutic interventions to improve the efficacy of whole-body cooling for hypoxic-ischemic encephalopathy (HIE) are desirable. Topiramate has been effective in reducing brain damage in experimental studies. However, in the clinical setting information is limited to a small number of feasibility trials. We launched a randomized controlled double-blinded topiramate/placebo multicenter trial with the primary objective being to reduce the antiepileptic activity in cooled neonates with HIE and assess if brain damage would be reduced as a consequence. Study Design: Neonates were randomly assigned to topiramate or placebo at the initiation of hypothermia. Topiramate was administered via a nasogastric tube. Brain electric activity was continuously monitored. Topiramate pharmacokinetics, energy-related and Krebs’ cycle intermediates, and lipid peroxidation biomarkers were determined using liquid chromatography-mass spectrometry and MRI for assessing brain damage. Results: Out of 180 eligible patients 110 were randomized, 57 (51.8%) to topiramate and 53 (48.2%) to placebo. No differences in the perinatal or postnatal variables were found. The topiramate group exhibited less seizure burden in the first 24 h of hypothermia (topiramate, n = 14 [25.9%] vs. placebo, n = 22 [42%]); needed less additional medication, and had lower mortality (topiramate, n = 5 [9.2%] vs. placebo, n = 10 [19.2%]); however, these results did not achieve statistical significance. Topiramate achieved a therapeutic range in 37.5 and 75.5% of the patients at 24 and 48 h, respectively. A significant association between serum topiramate levels and seizure activity (p < 0.016) was established. No differences for oxidative stress, energy-related metabolites, or MRI were found. Conclusions: Topiramate reduced seizures in patients achieving therapeutic levels in the first hours after treatment initiation; however, they represented only a part of the study population. Our results warrant further studies with higher loading and maintenance dosing of topiramate.

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“…The results of recent clinical trials have been mixed. For example, in a phase-II trial in newborns with HIE treated with hypothermia, treatment with an anticonvulsant, topiramate (n=21), was safe, but did not improve death or neurological disability compared with cooling alone (n=23) [66]. The noble gas Xenon has significant anti-apoptotic effects via the N-methyl-D-aspartate (NMDA) receptor in piglets [67], but did not augment hypothermic neuroprotection in a small phase-II trial (n=46 for both groups) as assessed by magnetic resonance spectroscopy measures, including lactate to Nacetyl aspartate ratio in the thalamus (mean ratio: 1.09; 95% CI: 0.90-1.32) and fractional anisotropy (mean difference: -0.01; 95% CI: 0.03-0.02) in the posterior limb of the internal capsule [68].…”

Section: What Is the Potential For Add-on Therapies?mentioning

confidence: 99%

Therapeutic Hypothermia in Neonatal Hypoxic-Ischemic Encephalopathy

Wassink

Davidson

Dhillon

et al. 2019

Curr Neurol Neurosci Rep

110

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Purpose of review -therapeutic hypothermia reduces death or disability in term and near-term infants with moderate-severe hypoxic-ischemic encephalopathy. Nevertheless, many infants still survive with disability, despite hypothermia, supporting further research into ways to further improve neurologic outcomes. Recent findings -recent clinical and experimental studies have refined our understanding of the key parameters for hypothermic neuroprotection, including timing of initiation, depth, and duration of hypothermia, and subsequent rewarming rate. However, important knowledge gaps remain. There is encouraging clinical evidence from a small phase II trial that combined treatment of hypothermia with recombinant erythropoietin further reduces risk of disability but definitive studies are still needed. Summary -In conclusion, recent studies suggest that current protocols for therapeutic hypothermia are nearoptimal, and that the key to better neurodevelopmental outcomes is earlier diagnosis and initiation of hypothermia after birth. Further research is essential to find and evaluate ways to further improve outcomes after hypoxic-ischemic encephalopathy, including add-on therapies for therapeutic hypothermia and preventing pyrexia during labor and delivery.

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Safety and efficacy of topiramate in neonates with hypoxic ischemic encephalopathy treated with hypothermia (NeoNATI): a feasibility study

Abstract: Results of this pilot trial suggest that administration of TPM in newborns with HIE is safe but does not reduce the combined frequency of mortality and severe neurological disability. The role of TPM co-treatment in preventing subsequent epilepsy deserves further studies.

Cited by 55 publications

References 25 publications

A working model for hypothermic neuroprotection

A working model for hypothermic neuroprotection

Topiramate plus Cooling for Hypoxic-Ischemic Encephalopathy: A Randomized, Controlled, Multicenter, Double-Blinded Trial

Therapeutic Hypothermia in Neonatal Hypoxic-Ischemic Encephalopathy

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