The interplay between blood sugar levels and susceptibility to seizures is especially complex. Glucose is the main energy supply of the central nervous system. The human brain accounts for only 2% of body weight but consumes about 20% of glucose-derived energy of the whole body, and cerebral metabolic requests are likely much higher in paediatric age ^{[1][2][3][4][5]}[1,2,3,4,5]. This remarkable metabolic demand is due to both neuronal workflow (generation of action and postsynaptic potentials, maintenance of ion gradients, and resting potentials) and the biosynthesis of neurotransmitters by neurons and astrocytes ^[2][3][4][2,3,4]. The grey matter utilizes a significantly greater amount of energy compared to the white matter ^[5][6][5,6], and the demand for glucose briskly increases with neuronal activation [7].

Glycogen stores in the brain are tiny and limited to astrocytes, thus the brain is reliant on a continuous intake of glucose from the systemic circulation. Glucose movements within different compartments happen through glucose transporters (GLUTs). The entry within the central nervous system is mediated by the GLUT1 subtype, which allows facilitated diffusion through the blood–brain barrier. GLUT1 also mediates glucose uptake from brain extracellular fluid into glial cells. Instead, the GLUT3 subtype lets glucose flow into neurons [2] and is much more efficient than GLUT1, insomuch as neurons are privileged with respect to glial cells in case of high metabolic demand [2].

In human cells, energy can be produced from glucose by glycolysis in the cytosol and by oxidative phosphorylation (oxphos) in mitochondria. Intracellular glucose is initially metabolized to pyruvate by glycolysis, with no request for oxygen. Thereafter, pyruvate enters the mitochondrion and undergoes oxphos, which is much more efficient than glycolysis in terms of energy production; oxphos can only be performed in aerobiosis. Pyruvate is, instead, transformed to lactate in anaerobiosis, and energy production as ATP molecules is only obtained by low-efficiency glycolysis. The healthy brain may increase both glycolysis and oxphos in order to maximize the energy supply after acute activation [8].

In epilepsy, there is a derailment of glucose catabolic pathways. Seizures greatly enhance the cerebral metabolic rate, increasing oxygen consumption, cerebral blood flow, and glucose uptake by neurons. Glucose metabolism is acutely shifted towards glycolysis and lactate production (ictal hypermetabolism), followed by a postictal decrease below baseline (postictal hypometabolism) ^[9][10][9,10]. Mitochondrial oxygen consumption also increases acutely, yet there is a net shift towards less efficient glycolysis despite aerobiotic conditions, reminiscent of the Warburg effect observed in cancer cells. Cerebral glucose availability may also be limited, because, in chronic epilepsy, GLUT transporters may be dysfunctional ^[10][11][10,11].

On the other side, the disruption of mitochondrial oxphos could be involved in epileptogenesis. Experimental oxphos inhibition results in the destabilization of hippocampal membrane potentials and provokes epileptiform activity in initially healthy male rats [12]. Neuronal excitability can also be directly affected by glycaemic levels. In the animal model, blood glucose concentrations positively correlate with susceptibility to seizures, and diabetes mellitus favours blood–brain barrier alterations during experimental epileptic seizures ^[1][13][1,13]. In humans, both hyper- and hypoglycaemic conditions have been found to exacerbate seizures ^[14][15][16][14,15,16]. As a matter of fact, glucose imbalances influence the brittle energy homeostasis of the brain. A disruption of energy availability affects the sodium–potassium pump and the resting state potential and increases intracellular calcium and reactive oxygen species that promote cell death [17]. Hyperglycaemia can directly increase neuronal excitability acting on the ATP-sensitive potassium channels of hippocampal and neocortical neurons; hypoglycaemia depresses GABA levels enhancing excitatory transmission ^[18][19][18,19].

Seizures usually improve with the control of glycaemic status in patients with type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM) [20], whereas fluctuations in blood glucose have been associated with drug-resistant epilepsy [21].

2. Hypoglycaemia

Hypoglycaemia is a condition characterised by the lowering of plasma glucose levels. In paediatric populations, hypoglycaemia is not a rare condition. Although there is no uniform cut-off, a plasma glucose level of 50 mg/dL or less has been considered sufficient to define hypoglycaemia, as many counterregulatory responses occur at this level ^[22][23][24][22,23,24]. Severe hypoglycaemia is a medical emergency presenting with neuroglycopenic (e.g., confusion, impairment of vigilance, behaviour disturbances, acute symptomatic seizures) and autonomic symptoms (e.g., diaphoresis, tachycardia, tremulousness) [25]. Acute symptomatic seizures develop with different characteristics according to the age of onset and aetiology of hypoglycaemia, and reflect aberrant neurotransmitter metabolism, cerebral blood flow, and even blood–brain barrier and microvascular function [26]. Hypoglycaemia can acutely induce the release of excitatory amino acids, such as glutamate, resulting in neuronal hyperexcitability [26], chronically reducing the availability of cerebral glycogen stored by astrocytes ^[26][27][26,27]. It can also lead to structural brain abnormalities that may persist even after the hypoglycaemia has resolved, favouring the development of neurocognitive deficits and epilepsy in the long term ^[28][29][28,29].

3. Hyperglycaemia

Hyperglycaemia can affect different age groups and be sustained by variable aetiologies. The mechanisms by which it induces seizures are largely unknown. Lowering the seizure threshold due to increased GABA metabolism, cerebrovascular dysfunction, neuronal hyperosmolarity, and dehydration can all play a role in provoking acute symptomatic seizures ^{[30][31][32][33]}[74,104,105,106].

4. Conclusions

Brain excitability and systemic metabolic balance are strictly intermingled. The energy supply to the neurons critically depends on glucose, whose fluctuations can promote immediate hyperexcitability resulting in acute symptomatic seizures. Hypoglycaemia is particularly epileptogenic, especially in newborns who have high metabolic demands, in children with neurometabolic disorders, and in those with brittle glucose homeostasis due to diabetes mellitus. An expedite recognition of hypoglycaemic symptoms prompt the investigation of the underlying cause and prevents brain damage, which in turn yield chronic epilepsy. Hyperglycaemia provokes acute symptomatic seizures less often, mostly when acute complications of diabetes mellitus ensue. Instead, diabetes mellitus is remarkably linked to chronic epilepsy and such comorbidity should be carefully investigated. Defining homogenous cut-offs in children for hypoglycaemia/hyperglycaemia-induced brain damage is complicated, and clinical observation is strikingly important. The complex interplay between glycaemia and seizure susceptibility must always be considered in the developing age, in order to optimize the care of children and prevent the development of chronic neurological conditions in young patients.