1) Definizione del paziente e della storia
Anno di nascita : 1928
Peso: 60 Statura: 1,65
Anamnesi patologica prossima Episodio di perdita di coscienza. Successiva ripresa lenta con disartria regredita spontaneamente e disorientamento temporo-spaziale.
Possibile episodio ictale/stato post critico.
TC encefalo: no lesioni acute
EEG: attività temporale sinistra
Sodiemia: 129 mmol/L
Glucosio: 123 mg/dL
Anamnesi patologica remota Ipertensione arteriosa. Da 15 aa crisi parziali e secondaria generalizzazione. Severe varicoflebiti croniche degli arti inferiori.
Anamnesi fisiologica pensionato. Buon movimento giornaliero, in media 1/2 km die. Riduzione negli ultimi mesi per algie agli arti inferiori e incertezza nella deambulazione. Dieta tipica mediterranea.
In tal modo la sequenza temporale degli eventi è chiara e il legame con l'età è istintivo.
2) Le basi molecolari degli eventi descritti, tenendo conto di tutti i sintomi ed utilizzando i link alle informazioni pertinenti
Mild chronic hyponatremia (120-132 mEq/L) may be underestimated from a clinical point of view, because no symptoms are evident when using approximate clinical criteria. Despite this, when it's individuated, clinicians usually treat it with water restriction or sodium implementation in diet, but if the normalization of serum sodium it's not achieved, there's a propensity to tolerate mild stable hyponatremia as it's often considered clinically non significant.
This study conducted on 122 elderly patients with mild chronic hyponatremia, apparently asymptomatic, highlights that it's not as innocent as it seems.
It indicates that falls in hyponatriemic patients are four time more likely than controls (21% versus 5%), and the risk is almost the same between mild (19% with 130-132 mEq/L), moderate (20% with 121-123 mEq/L) and more severe hyponatremia (22% with 115/117 mEq/L). To gain information about the pathogenesis of the falls, different gait and attention tests were administered to the hyponatremic group and to the control-normonatremic one. These tests showed an impairment in both compared to the control patients, highlighting in hyponatremic patients unsteadiness of the gait and lack of attention with an increased error rate. These neurologic manifestation can be linked to a greater risk of bone fractures, but also with an higher probability of errors during the daily routine (e.g. being confused about medications, leaving the door open..).These neurological signs were .
The pathogenesis of the unsteadiness of the gait and the lack of attention was linked to a slowed conduction in nerves due to hyponatremia. A lower gradient of sodium generates a weaker sodium current during nerve depolarization, so nerve conduction slows down.
Moreover nerves are one of the most susceptible tissues to a reduced uptake of nutrients from blood. They totally depend on oxigen and glucose to produce the ATP they need to make continuous depolarizations and transduce signals. So the extracellular sodium concentration is central in nerve impulse generation.
Hyponatremia and Seizures
Low serum sodium 's been associated with seizures.
The glucose transport inside the cell mediated by SGLT 1 and 2, depends on the sodium gradient. The extracellular sodium concentration can be affected by different conditions, such as the use of some drugs.
- Oxcarbazepine and carbamazepine frequently induce hyponatremia, acting like ADH on kidney.
The Oxcarbazepine-induced SIADH isn't associated with significant elevation in ADH plasma concentration, but seems to be referred to the Oxcarbazepine itself. This drug can directly modulate reabsorption of water acting on renal tubular cells with an antidiuretic effect, determining sometimes hyponatremia (incidence ranges from 2% to 40%, depending on the population studied). Different risk factors have been associated with an increased susceptibility to hyponatremia, including age >50 years and the concomitant use of medications associated with hyponatremia. Removing the precipitating factors or discontinuance of the oxcarbamazepine therapy are key elements for the therapy.
Can oxcarbazepine and carbamazepine-induced hyponatremia affect the effectiveness of these drugs?
Hyponatremic seizure associated with oxcarbazepine. 2003
Hyponatremia-induced seizure during carbamazepine treatment. 2007
- Very rarely, some ACEIs (ACE inhibitors) can induce hyponatremia.
In most patients treated with ACEIs, serum sodium concentrations remain unchanged. However, in a subgroup of patients ACEIs can cause severe symptomatic hyponatraemia. Why? Its genesis probably is multifactorial, but we can point the attention on some risk factors. One is . With normal aging, the sistem regulating water and sodium homeostasis can be more suceptible to various natremia changes determined by drugs o ilnesses. This is beceause as other ions asymmetries, also the gradient of sodium required a good energy production to be well maintained. Having sufficient ATP for the Na-K ATPase means pumping outside Na efficiently and being capable of rapid responses to enviromental changes. Other risk factors are or presence of (such as hypokalemia, GERD, urinary tract infection, type 2 diabetes, hyperlipidemia). All these risk factors are important for sure, but they are all focused on the patient. What happens if we concentrate our attention on the instead? This category of drugs cointains a large number of molecules with similar farmacological properties, but not exactly the same. Indeed, if we look at the lipophilicity of ACEIs we find some differences from one to another. Fosinopril is one of the ACEIs that has the highest lipophfilicy, so it can easily cross the blood-brain-barrier (BBB), instead enalapril and lisinopril are more hydrophilic and so less capable of overcoming the BBB. If we look at literature on Quertle , an interesting fact is that we find just few reports about ACEIs induced hyponatremia, and most of them regard the hydrophilic ACEIs just as enalapril and lisinopril. So this may support an intriguing hypotesis for the uncommon ACEIs induced hyponatremia.
The AG II present in the CNS has different actions, one of these is inducing the release of ADH , lowering sodium concentration.
ACEIs that pass through the BBB reduce AG II production also in the CNS, preventing the rise of ADH. ACEIs that don't pass through the BBB reduce only peripheral conversion of AG I to AG II. The resulting increased level of angiotensin I may cross the blood–brain barrier serving as the substrate for increased production of angiotensin II through the central renin–angiotensin system, determining hyponatriemia. As a low dose of drug blocks the peripheral ACE more than the brain one, probably also the dose of the ACEI plays a key role. It's important to underline that different authors say that AG II can't overcome the BBB, so probabily AG I can't too. But we don’t exactly know if a diffusion of AGII is possible from the areas of the brain without the BBB. The importance of this mechanism is not about the hyponatremia induced by some hydrophilic ACEIs, that is an infrequent event, but is about the possible connection between the peripheral RAS and the brain RAS . Are they completely independent o there's some link between them? May the anatomic regions without the BBB have a role in this process? What are the differences on the ACE inhibition among ACEIs?
Brain ACE and seizures
The presence of ACE (enzime converting angiotensin I to angiotensin II) in the central nervous system is well documented, but little is known about the possible interaction of this enzime with seizures susceptibility.
- High levels of ACE in temporal lobe epilepsy (TLE). 2012
This study of on ACE D/I polymorphisms highlight a significant higher number of patients suffering from TLE with the DD genotype. The D form leads to higher expression levels of ACE and carriers of the ACE II genotype have plasma levels half that of DD subjects. This observation may suggest that there’s a potential link between seizures and ACE.
- Use of ACE-inhibitors can potentiate anticonvulsant effect of different drugs, such as carbamazepine e lamotrigine. 2010. This effect is related to a interaction, since the concentration of those antiepilectic drugs remained unchanged with the administration of ACEIs. A greater effect is found with more lipophilic ACEIs (such as fosinopril), which can easier overcome the blood-brain-barrier and inhibit brain ACE. This suggests that the positive effect of ACEIs on seizures is mediated at a brain level.
What’s the link between ACE and seizures?
To make a complex pathway easy let's discuss the simplest Blocking ACE means lowering the production of AG II (angiotensin II). So, what are the functions of AG II in the brain? First of all, AG II is a potent vasoconstrictor. If we agree that the brain has no energy deposit but little, and it totally depends on the nutrients carried by blood flow, a reduction in perfusion due to AG II-mediated vasoconstriction means increased probability of suffering for central nervous system (CNS), that may sometimes respond with migraine and sometimes with seizures if other risk conditions are associated, such as endothelium dysfunction or damage.
So, blocking brain ACE may have a potential role in improving blood flow through a relaxation of brain vessels, ultimately reducing seizures susceptibility.
ACEIs are also used in stroke prevention. In fact ACE metabolizes not only AG I, but bradykinin too, an important vasolrelaxant.
Carbamazepine, one of the most commonly used drugs in the treatment of epilepsy is a direct inhibitor of ACE. 2012
3) Eventuali proposte di terapia, volta al ripristino delle condizioni ottimali