Perinatal Stroke Presenting As HIE: Practical Diagnostic And Management Challenges

BACKGROUND: 

While therapeutic hypothermia is accepted as a standard of care for improving neurological outcomes for HIE patients, evidence of its benefits for neonatal stroke is lacking. Neurological presentations of HIE and neonatal stroke can be difficult to distinguish. Our observational analysis of neonatal stroke infants highlights challenges in distinguishing between the two groups and reaching an early definitive diagnosis to inform appropriate treatment. This analysis attempts to quantify whether antenatal sentinel events, clinical presentation, CFM, and cranial ultrasound help distinguish between the two groups and whether perinatal factors influence early diagnosis and management. 

METHODS: 

A retrospective cohort study of term neonates >37 weeks gestation born between May 2011 and April 2020 at a specialized NICU network in the East of England with a principal diagnosis of neonatal stroke. A total of 16 patients were identified of which 8 had been cooled for an initial clinical diagnosis of HIE, and retrospective MRI diagnosis of neonatal stroke. MRI brain injury scores (1a to 3) were based on the National Institute of Child Health and Human Development Neonatal Research Network classification. 

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RESULTS: 

15 infants had middle cerebral artery infarction, and one infant had cerebral sinus thrombosis. Of the 8 cooled infants, only 3 (37%) of cooled infants fulfilled both Toby A and B criteria. Infants who received therapeutic hypothermia were more likely to present with early-onset seizures (5/8) than infants who were not cooled (1/8) (p=0.019).  The CFM showed unilateral seizure activity in 14/16 (87.5%) of infants. Only 1 infant with underlying venous infarction presented with bilateral seizure activity. The background trace was normal in 8 (50%) of infants. There was no correlation between seizure burden and background trace. Cooled infants were more likely to present with abnormal neurology at birth but had a lower seizure burden and MRI injury score than non-cooled infants although this did not reach statistical significance. Cranial ultrasound findings were absent or non-specific. 

CONCLUSION:

Infants with neonatal stroke who present with early seizures are more likely to receive therapeutic hypothermia despite failure to fulfill both Toby A and B criteria. Early suspicion to inform management can be obtained more effectively from CFM while cranial ultrasound findings are generally non-specific. A normal CFM background or unilateral abnormal background with unilateral seizure activity is highly suggestive of neonatal stroke. Evidence of the effectiveness and indication of therapeutic hypothermia in this setting is still lacking. The new BAPM framework for HIE with the inclusion of the CFM in the selection of infants who undergo therapeutic cooling will likely decrease the incidence of infants with neonatal stroke receiving therapeutic hypothermia. Future research in understanding the effectiveness of therapeutic hypothermia on neurological outcomes in neonatal stroke is needed.

The Neuroprotective Properties of Cistanche:

Cistanche is a traditional Chinese medicinal herb that has been used for centuries to treat various diseases such as infertility, impotence, constipation, and aging-related disorders. In recent years, Cistanche has attracted the attention of researchers due to its neuroprotective effect. Cistanche contains various bioactive compounds such as phenylethanoid glycosides, iridoids, lignans, and polysaccharides, which have been reported to possess multiple pharmacological properties, including anti-inflammatory, antioxidative, and anti-apoptotic effects. This article aims to review the neuroprotective mechanism of Cistanche and provide insight into its therapeutic potential for neurodegenerative diseases.

Cistanche can modulate the immune system by enhancing the activity of natural killer cells and promoting the production of cytokines such as IFN-γ, TNF-α, and IL-2, which have neuroprotective effects (Ma et al., 2014). Cistanche can also scavenge free radicals and inhibit lipid peroxidation, thus attenuating oxidative stress-induced neuronal damage (Chen et al., 2018). 

The main bioactive compounds in Cistanche are phenylethanoid glycosides, which have been shown to exert neuroprotective effects. For example, acteoside, a phenylethanoid glycoside isolated from Cistanche, protects against neurotoxicity induced by β-amyloid (Aβ) and glutamate in cultured hippocampal neurons (Yi et al., 2013).

Several other phenylethanoid glycosides have been reported to have neuroprotective effects. For instance, echinacoside prevents neuronal apoptosis and attenuates hippocampal injury induced by cerebral ischemia-reperfusion in rats (Zhang et al., 2013). Similarly, salidroside, another phenylethanoid glycoside, protects dopaminergic neurons from rotenone-induced toxicity in a rat model of Parkinson's disease (Wang et al., 2016).

The Role of Cistanche Polysaccharides in Neuroprotection:

Cistanche polysaccharides are another class of bioactive compounds in Cistanche that have been reported to have neuroprotective effects. For instance, Cistanche polysaccharides protect against apoptosis induced by Aβ and H2O2 in cultured PC12 cells (Wang et al., 2015).

Moreover, Cistanche polysaccharides can enhance the expression of brain-derived neurotrophic factor (BDNF) in cultured neurons and in the hippocampus of rats treated with scopolamine. This drug impairs learning and memory (Liu et al., 2015). BDNF is a neurotrophic factor that plays a critical role in neuronal survival, differentiation, and plasticity.

Cistanche polysaccharides can also activate the PI3K/Akt signaling pathway, which phosphorylates and activates the downstream effector glycogen synthase kinase 3β (GSK-3β), a key enzyme involved in neuronal survival and synaptic plasticity (Zhou et al., 2018). Inhibition of GSK-3β activity can prevent neuronal damage and enhance cognitive function in animal models of Alzheimer's disease (AD) (Llorens-Martín et al., 2014).

The Mechanism of Cistanche's Neuroprotective Effect:

Recent studies have revealed the mechanism underlying the neuroprotective effect of Cistanche. Cistanche can activate the Nrf2/ARE signaling pathway, which is a critical pathway for cellular defense against oxidative stress and inflammation (Zeng et al., 2020). Upon activation, Nrf2 translocates to the nucleus and binds to the antioxidant response element (ARE) in the promoter region of target genes, such as heme oxygenase-1 (HO-1), NAD(P)H: quinone oxidoreductase 1 (NQO1), and glutathione S-transferase (GST).

These genes encode enzymes involved in antioxidant defense, xenobiotic metabolism, and inflammatory response. Activation of the Nrf2/ARE pathway can upregulate the expression of these enzymes and protect neurons from oxidative stress-induced damage and inflammation-induced injury (Cui et al., 2019).

Cistanche can also inhibit the activation of microglia, which are immune cells in the brain that play a critical role in neuroinflammation. Upon activation, microglia can release pro-inflammatory cytokines, such as TNF-α, IL-1β, and IL-6, and reactive oxygen species (ROS) that can damage neurons and exacerbate neurodegeneration (Block et al., 2007).

Cistanche can suppress the activation of microglia by downregulating the expression of toll-like receptor 4 (TLR4), a receptor that mediates the activation of microglia by various stimuli, such as lipopolysaccharide (LPS) and Aβ (Yang et al., 2017). Cistanche can also suppress the activation of NLRP3 inflammasome, a multiprotein complex that initiates the maturation and secretion of IL-1β and IL-18, two pro-inflammatory cytokines involved in neuroinflammation (Jiang et al., 2020).

In conclusion, Cistanche is a promising natural product with neuroprotective effects that can mitigate oxidative stress, inflammation, and apoptosis in neurons. The underlying mechanism involves the modulation of immune cells, the scavenging of free radicals, the activation of neurotrophic factors, and the regulation of signaling pathways that control cellular metabolism, redox balance, and inflammatory response.

This review highlights the potential therapeutic application of Cistanche for neurodegenerative diseases, such as AD, Parkinson's disease, and stroke. However, further studies are needed to elucidate the pharmacokinetics and bioavailability of Cistanche in humans and to explore its synergistic effects with other drugs or supplements.