Research progress on biological markers and risk factors for sudden epilepsy death

Epilepsy is a common neurological disorder, and spontaneous seizures in patients with epilepsy are characterized by

Sudden epileptic death is the unexpected, non-traumatic and non-drowning death of a person with epilepsy who has no evidence of seizures and whose autopsy does not reveal a clear structural or toxicological cause of death

The exact pathogenesis of sudden epilepsy death is not clear, but current research suggests that respiratory, cardiac and autonomic dysfunction, cerebral wakefulness inhibition and other mechanisms are involved in the occurrence of sudden epilepsy death, and age, seizure type, unreasonable anti-epileptic drug treatment regimen, genetic background, etc.

1 Biological markers and risk factors for sudden epilepsy death associated with respiratory dysfunction

1.

Both clinical and animal studies have shown that respiratory dysfunction during seizures is one of the important mechanisms for the occurrence of

The MORTEMUS study confirmed that the clinical manifestations of sudden epilepsy death are highly consistent, beginning with generalized tonic-clonic seizures, followed by short-term acceleration of respiratory rate and tachycardia, followed by apnea, which eventually leads to cardiac arrest

Apnea always precedes cardiac arrest, suggesting that respiratory dysfunction is a major driver

In addition, seizure-induced dysfunction of the brainstem region responsible for initiating respiratory motor signals, may be another mechanism

The occurrence of central respiratory disturbances is associated with epilepsy and seizure types, and a retrospective study of 312 patients with focal epilepsy and their 148 generalized tonic-clonic seizures found that 36.

Brainstem serotonin also plays a key role in seizures and is associated

Therefore, the brainstem 5⁃serotonin content, the number of serotonin transporters, and the expression levels of somatostatin, glycopeptide, tryptophan hydroxylase and neurokinin 1 receptors can be used as biological markers of sudden epilepsy death, and since 5⁃serotonin cannot pass through the blood-brain barrier, we need to be cautious about

1.

In addition to central apnea, airway obstruction may be another risk factor

The specific mechanism of decreased lung function due to brain injury after a seizure is unclear and may be related

However, it is still unclear

1.

In patients with Dravet syndrome caused by mutations in the SCN1A gene, severe periennial respiratory dysfunction can be observed, including abnormal respiratory rhythms and prolonged hypopnea
.
In a mouse model of Dravet syndrome caused by a mutation in the SCN1A gene, mice exhibited abnormalities in respiratory function and status, including hypoventilation, apnea, hypercapnia and decreased ventilation response
.
KCNA1 gene deletion mice, manifested by spontaneous seizures and progressive respiratory dysfunction
that worsens as animals age.
The findings based on animal modelling studies are similar to those observed in the MORTEMUS study in which respiratory dysfunction precedes
cardiac dysfunction.

Total exon sequencing of epilepticogenic brain tissue surgically removed before death in 8 patients who died of sudden epileptic death found that these patients showed variations in opioid-like, γ⁃aminobutyric acid and glutamate neurotransmitter genes, as well as genes associated with arrhythmias, suggesting that sudden epileptic death may involve both central transmitter transmission and cardiac rhythm gene variations, and that abnormal transmitter transmission may cause apnea by affecting the medullary lamellar respiratory control center, causing or exacerbating arrhythmias and eventually developing sudden epileptic death
。 However, the study was unable to draw a definitive conclusion about the relationship between any one of the independent genetic variants and the risk of sudden epilepsy death, and further large-scale multicenter studies and more accurate predictions were needed in the future
.

2 Biological markers and risk factors for sudden epilepsy death associated with cardiac and autonomic dysfunction

Cardiac dysfunction is often considered one of
the important mechanisms by which sudden epileptic death occurs.
A decrease in oxygen saturation below 90% during a seizure leads to changes in the QT interval on the ECG, suggesting that cardiac dysfunction found in cases of sudden epileptic death may be due
to respiratory depression.
In Dravet syndrome, mutations in the sodium channel gene SCN1A suggest that sudden epileptic death may have originated in the heart
.
However, there are also studies that show that sudden epileptic death in Dravet syndrome is related to
respiratory dysfunction.
Whether the key initiating mechanism of sudden epilepsy death is respiratory dysfunction, cardiac dysfunction, or both, remains controversial
.

Autonomic dysfunction and cardiac dysfunction, the role of the two in the occurrence of sudden epilepsy death penetrates each other and is difficult to separate
.
Each seizure can increase sympathetic and parasympathetic nerve activity by about 10 times, and seizures not only cause arrhythmias such as tachycardia, atrial fibrillation, supraventricular tachycardia, and atrioventricular block, but also cause a decrease
in heart rate variability.
On the other hand, autonomic dysfunction affects cardiac output, leading to a decrease in cerebral blood flow, which is beneficial for the termination of seizures, so arrhythmias caused by seizures may not be life-threatening
due to the spontaneous termination of seizures.

Decreased heart rate variability and early repolarization are important predictors of sudden death in patients with heart disease
.
Myers et al.
observed lower
heart rate variability in patients with sudden epilepsy death with sodium channel mutations when awake.
Other studies have confirmed that patients with epilepsy do have decreased heart rate variability, particularly those with temporal lobe epilepsy or drug-resistant epilepsy, but there is no significant correlation with the sudden epilepsy death ⁃7 scale score
.
Heart rate variability may reflect autonomic function, but there is still a lack of evidence that this biological marker predicts the risk
of sudden epileptic death.
An early repolarization study of 354 patients with epilepsy showed that patients with epilepsy had a significantly higher
probability of ST segment downward movement and lower arm lead J-wave amplitude abnormalities.
Heart rate variability and early repolarization may be potential biological markers for determining the risk of sudden epilepsy death
.

Cardiomyocyte hypertrophy and myocardial fibrosis are often observed in patients with sudden epilepsy death, so cardiac changes are also considered potential biological markers
of sudden epileptic death.
Studies comparing the biomarkers of cardiac ultrasound associated with the risk of sudden cardiac death in patients with temporal lobe epilepsy without cardiovascular history and the general population, and found that patients with temporal lobe epilepsy without cardiovascular history showed significantly increased left ventricular pressure, left atrial volume, and echocardiography biological marker levels
.

However, another study compared the cardiological features of 25 patients with sudden epileptic death, 285 non-epileptic patients with sudden death due to arrhythmias, and 104 patients with traumatic death, and concluded that the cardiac changes in patients with sudden epilepsy death were similar to those in patients with traumatic death, and that the severity was significantly lower than that of non-epileptic patients with
sudden arrhythmia death.
Whether cardiac changes are potential biological markers of sudden epilepsy death require more clinical research to confirm
.

Although arrhythmias during sudden seizures of epilepsy appear to be a self-termination event, it is unclear whether patients with sudden epilepsy death pericontemplative cardiac arrest, bradycardia, or non-persistent ventricular tachycardia increase the risk of
sudden epileptic death.
There is a correlation between these seizures that may trigger arrhythmias and prolonged persistent hypoxemia compared with epilepsy patients with epilepsy who do not develop arrhythmias during the periconvalsive
period.
Abnormal regulation of blood pressure during seizures may also increase the risk
of sudden epilepsy death.

Recent studies on pressure reflex sensitivity in patients with epilepsy have concluded that the sensitivity to pressure reflexes in patients with focal seizures has increased or not changed accordingly, and that the sensitivity of pressure reflexes in patients with generalized tonic-clonic seizures has decreased significantly
, as well as post-seizure pressure reflex sensitivity.
Suggests that seizures cause transient changes in cardiovascular homeostasis, and that specific seizure types or abnormal firing of specific cortex may cause abnormal fluctuations in blood pressure, leading to sudden cardiac death
.
Therefore, arrhythmias during the periennial period of sudden epilepsy death and changes in the sensitivity of the pressure reflex of seizures may be risk factors
for the occurrence of sudden epileptic death.

3 Biological markers and risk factors for sudden epilepsy death associated with arousal dysfunction

Arousal dysfunction after a seizure is involved in the occurrence
of sudden epileptic death.
Under normal circumstances, the body's arousal behavior after the increase in serum carbon dioxide concentration is considered an important protective mechanism
of the body.
When epilepsy occurs, the ascending arousal system located in the brainstem can be suppressed by self-conducting seizures and systemic reactions caused by seizures, resulting in loss of consciousness and disruption of the corresponding protective feedback mechanism, resulting in disorders
of the cardiopulmonary and autonomic nervous systems.
Generalized EEG suppression after a generalized tonic-clonic seizure is also strongly associated
with severe hypoxemia and arrhythmias.

Although the link between sudden epileptic death and generalized EEG suppression after systemic tonic-clonic seizures is controversial, it has been found that all patients with sudden epileptic death have generalized EEG suppression after a seizure and arrhythmias after apnea, and almost all patients have no autonomous activity during generalized EEG suppression after a systemic tonic-clonic seizure or do not respond to external stimuli, which is not conducive to awakening and postural changes, When generalized tonic-clonic seizures occur during sleep or when oxygen is not given early in time, the risk of generalized EEG suppression after systemic tonicclonic seizures increases
significantly.
These findings suggest that generalized EEG suppression after a systemic tonic-clonic seizure is a potential risk factor
for sudden epilepsy death.

4 Other biological markers and risk factors for sudden epilepsy death

A video study analyzed brainstem volume and heart rate variability in 18 patients with focal epilepsy, and found a correlation between excessive reduction of periductal gray matter and bulbar autonomic nucleus volume and heart rate variability, suggesting a direct link
between epilepsy-related brainstem volume changes and cardiac autonomic control.
Changes in brainstem volume may be a risk factor
for sudden epilepsy death.

Another MRI study compared cortical thickness in patients with extensive EEG suppression after a seizure, and reduced
cortical thickness in patients with generalized EEG suppression after a generalized tonic-clonic seizure in patients with generalized electroencephalostatic after a generalized tonic-clonic seizure 。 Functional connectivity in patients with temporal lobe epilepsy at low risk of sudden death and high risk of sudden death was compared with resting functional MRI, with significantly reduced connections between the thalamus, brainstem, anterior cingulate gyrus, shell nucleus, and amygdala in the low-risk group, and a chronic increase
in connections between the medial/orbitofrontal cortex, insula lobe, hippocampus, amygdala, corpus callosum cortex, brainstem, thalamus, caudal nucleus, and shell nucleus.
Therefore, changes in brainstem volume, regional cortex thinning, and decreased functional connections suggested by magnetic resonance imaging may be risk factors
for sudden epilepsy death.

In addition, existing studies have shown that the risk factors for sudden epilepsy death also include the young age of epilepsy, the long course of epilepsy, systemic tonic-clonic seizures, nocturnal seizures, refractory epilepsy and unreasonable anti-epileptic drug treatment options
.

5 Prevention of risk factors for sudden epilepsy death

Seizure control is central to the effective prevention of sudden epileptic death, and it is important to actively avoid seizure triggers, develop personalized antiepileptic drug treatment plans, and improve patient treatment adherence
.
For some patients with drug-refractory epilepsy, surgical resection may be an option
.
After surgical treatment of epilepsy patients, the incidence of sudden epilepsy death decreased from 6.
3 to 9.
3 thousand people/year to 1.
8 to 4.
0 thousand people/year, and postoperative mortality was closely
related to whether postoperative epilepsy was well controlled.

For drug-refractory epilepsy that is not suitable for surgical treatment, palliative care modalities such as vagus nerve stimulators (VNS), deep brain stimulators (DBS), and responsive nerve stimulation (RNS) may
be used.
At the same time, measures such as night monitoring/listening to epilepsy patients, timely identification of patients' seizure status, changing patients' positions, preventing airway obstruction, and giving cardiopulmonary resuscitation are of great significance
to save patients' lives.

6 Summary

Sudden epileptic death is the main cause of epilepsy death, the specific mechanism is not fully understood, and the death of patients mainly occurs after a generalized tonic-clonic seizure, which may be related
to respiratory, cardiac, autonomic, and arousal disorders at the time of epilepsy.

Sudden epilepsy death is the result of a combination of factors, and epidemiological studies and large-sample multicenter clinical trials can help identify risk factors and guide patients to actively avoid risk factors to control epilepsy
.
Exploring the pathogenesis of sudden epilepsy death and finding biological markers, guiding drug treatment plans and formulating plans to avoid sudden epilepsy death are beneficial to improving the quality of life of patients with epilepsy and preventing and reducing the occurrence
of sudden epilepsy death.

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