Sudden unexpected death in epilepsy | |
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Specialty | Neurology |
Sudden unexpected death in epilepsy (SUDEP) is a fatal complication of epilepsy. [1] It is defined as the sudden and unexpected, non-traumatic and non-drowning death of a person with epilepsy, without a toxicological or anatomical cause of death detected during the post-mortem examination. [2] [3]
While the mechanisms underlying SUDEP are still poorly understood, it is possibly the most common cause of death as a result of complications from epilepsy, accounting for between 7.5 and 17% of all epilepsy-related deaths [2] and 50% of all deaths in refractory epilepsy. [4] [5] The causes of SUDEP seem to be multifactorial [2] and include respiratory, cardiac and cerebral factors as well as the severity of epilepsy and seizures. [5] Proposed pathophysiological mechanisms include seizure-induced cardiac and respiratory arrests. [4]
Among epileptics, SUDEP occurs in about 1 in 1,000 adults and 1 in 4,500 children annually. [6] Rates of death as a result of prolonged seizures (status epilepticus) are not classified as SUDEP. [7]
The overarching term SUDEP can be subdivided into four different categories: Definite, Probably, Possible, and Unlikely. [8]
Consistent risk factors include:
Genetic mutations have been identified that increase a person's risk for SUDEP (some are discussed below), but ultimately their genetic risk is determined by the function of multiple genes that is not yet well understood. Overlap is seen between these ion channel genes and the different sudden death disorders, including SUDEP, [11] SIDS, [12] sudden unexpected death (SUD), [13] and sudden unexplained death in childhood (SUDC). [14] Many of the genes are involved in long QT syndrome.
The mechanisms underlying SUDEP are not well understood but probably involve several pathophysiological mechanisms and circumstances. The most commonly involved are seizure-induced hypoventilation and cardiac arrhythmias, but different mechanisms may be involved in different individuals, and more than one mechanism may be involved in any one individual. [16]
Currently, the most effective strategy to protect against SUDEP in childhood epilepsy is seizure control, but this approach is not completely effective and is particularly challenging in cases of intractable epilepsy. The lack of generally recognized clinical recommendations available are a reflection of the dearth of data on the effectiveness of any particular clinical strategy, [16] but based on present evidence, the following may be relevant:
Epilepsy is a group of non-communicable neurological disorders characterized by recurrent epileptic seizures. An epileptic seizure is the clinical manifestation of an abnormal, excessive, purposeless and synchronized electrical discharge in the brain cells called neurons. The occurrence of two or more unprovoked seizures defines epilepsy. The occurrence of just one seizure may warrant the definition in a more clinical usage where recurrence may be able to be prejudged. Epileptic seizures can vary from brief and nearly undetectable periods to long periods of vigorous shaking due to abnormal electrical activity in the brain. These episodes can result in physical injuries, either directly such as broken bones or through causing accidents. In epilepsy, seizures tend to recur and may have no immediate underlying cause. Isolated seizures that are provoked by a specific cause such as poisoning are not deemed to represent epilepsy. People with epilepsy may be treated differently in various areas of the world and experience varying degrees of social stigma due to the alarming nature of their symptoms.
An epileptic seizure, informally known as a seizure, is a period of symptoms due to abnormally excessive or synchronous neuronal activity in the brain. Outward effects vary from uncontrolled shaking movements involving much of the body with loss of consciousness, to shaking movements involving only part of the body with variable levels of consciousness, to a subtle momentary loss of awareness. Most of the time these episodes last less than two minutes and it takes some time to return to normal. Loss of bladder control may occur.
Anticonvulsants are a diverse group of pharmacological agents used in the treatment of epileptic seizures. Anticonvulsants are also increasingly being used in the treatment of bipolar disorder and borderline personality disorder, since many seem to act as mood stabilizers, and for the treatment of neuropathic pain. Anticonvulsants suppress the excessive rapid firing of neurons during seizures. Anticonvulsants also prevent the spread of the seizure within the brain.
Tuberous sclerosis complex (TSC) is a rare multisystem autosomal dominant genetic disease that causes non-cancerous tumours to grow in the brain and on other vital organs such as the kidneys, heart, liver, eyes, lungs and skin. A combination of symptoms may include seizures, intellectual disability, developmental delay, behavioral problems, skin abnormalities, lung disease, and kidney disease.
Lennox–Gastaut syndrome (LGS) is a complex, rare, and severe childhood-onset epilepsy syndrome. It is characterized by multiple and concurrent seizure types including tonic seizure, cognitive dysfunction, and slow spike waves on electroencephalogram (EEG), which are very abnormal. Typically, it presents in children aged 3–5 years and most of the time persists into adulthood with slight changes in the electroclinical phenotype. It has been associated with perinatal injuries, congenital infections, brain malformations, brain tumors, genetic disorders such as tuberous sclerosis and numerous gene mutations. Sometimes LGS is observed after infantile epileptic spasm syndrome. The prognosis for LGS is marked by a 5% mortality in childhood and persistent seizures into adulthood.
Dravet syndrome (DS), previously known as severe myoclonic epilepsy of infancy (SMEI), is an autosomal dominant genetic disorder which causes a catastrophic form of epilepsy, with prolonged seizures that are often triggered by hot temperatures or fever. It is very difficult to treat with anticonvulsant medications. It often begins before one year of age, with six months being the age that seizures, characterized by prolonged convulsions and triggered by fever, usually begin.
Benign familial neonatal seizures (BFNS), formerly called benign familial neonatal convulsions (BFNC), is a rare autosomal dominant inherited form of seizures. This condition manifests in newborns as episodes of clonic and/or apneic seizures with asymptomatic periods in between. Characteristically, seizure activity spontaneously ends during infancy and does not affect childhood development. However, some studies have reported that a minority of children with BFNS consequently develop intellectual disability. Additionally, BFNS increases lifetime susceptibility to seizures as approximately 14% of those afflicted go on to develop epilepsy later in life. There are three known genetic causes of BFNE, two being the voltage-gated potassium channels KCNQ2 (BFNC1) and KCNQ3 (BFNC2) and the third being a chromosomal inversion (BFNC3). There is no obvious correlation between most of the known mutations and clinical variability seen in BFNE.
Juvenile myoclonic epilepsy (JME), also known as Janz syndrome or impulsive petit mal, is a form of hereditary, idiopathic generalized epilepsy, representing 5–10% of all epilepsy cases. Typically it first presents between the ages of 12 and 18 with myoclonic seizures. These events typically occur after awakening from sleep, during the evening or when sleep-deprived. JME is also characterized by generalized tonic–clonic seizures, and a minority of patients have absence seizures. It was first described by Théodore Herpin in 1857. Understanding of the genetics of JME has been rapidly evolving since the 1990s, and over 20 chromosomal loci and multiple genes have been identified. Given the genetic and clinical heterogeneity of JME some authors have suggested that it should be thought of as a spectrum disorder.
Geschwind syndrome, also known as Gastaut-Geschwind, is a group of behavioral phenomena evident in some people with temporal lobe epilepsy. It is named for one of the first individuals to categorize the symptoms, Norman Geschwind, who published prolifically on the topic from 1973 to 1984. There is controversy surrounding whether it is a true neuropsychiatric disorder. Temporal lobe epilepsy causes chronic, mild, interictal changes in personality, which slowly intensify over time. Geschwind syndrome includes five primary changes; hypergraphia, hyperreligiosity, atypical sexuality, circumstantiality, and intensified mental life. Not all symptoms must be present for a diagnosis. Only some people with epilepsy or temporal lobe epilepsy show features of Geschwind syndrome.
Spike-and-wave is a pattern of the electroencephalogram (EEG) typically observed during epileptic seizures. A spike-and-wave discharge is a regular, symmetrical, generalized EEG pattern seen particularly during absence epilepsy, also known as ‘petit mal’ epilepsy. The basic mechanisms underlying these patterns are complex and involve part of the cerebral cortex, the thalamocortical network, and intrinsic neuronal mechanisms.
Benign Rolandic epilepsy or self-limited epilepsy with centrotemporal spikes is the most common epilepsy syndrome in childhood. Most children will outgrow the syndrome, hence the label benign. The seizures, sometimes referred to as sylvian seizures, start around the central sulcus of the brain.
Sleep-related hypermotor epilepsy (SHE), previously known as nocturnal frontal lobe epilepsy, is a form of focal epilepsy characterized by seizures which arise during sleep. The seizures are most typically characterized by complex motor behaviors. It is a relatively uncommon form of epilepsy that constitutes approximately 9-13% of cases. This disorder is associated with cognitive impairment in at least half of patients as well as excessive daytime sleepiness due to poor sleep quality. This disorder is sometimes misdiagnosed as a non-epileptic sleep disorder. There are many potential causes of SHE including genetic, acquired injuries and structural abnormalities.
Epilepsy-intellectual disability in females also known as PCDH19 gene-related epilepsy or epileptic encephalopathy, early infantile, 9 (EIEE9), is a rare type of epilepsy that affects predominately females and is characterized by clusters of brief seizures, which start in infancy or early childhood, and is occasionally accompanied by varying degrees of cognitive impairment. The striking pattern of onset seizures at a young age, genetic testing and laboratory results, potential developmental delays or developmental regression and associated disorders, eases diagnosis.
Febrile infection-related epilepsy syndrome (FIRES), is onset of severe seizures following a febrile illness in someone who was previously healthy. The seizures may initially be focal; however, often become tonic-clonic. Complications often include intellectual disability, behavioral problems, and ongoing seizures.
People with epilepsy may be classified into different syndromes based on specific clinical features. These features include the age at which seizures begin, the seizure types, and EEG findings, among others. Identifying an epilepsy syndrome is useful as it helps determine the underlying causes as well as deciding what anti-seizure medication should be tried. Epilepsy syndromes are more commonly diagnosed in infants and children. Some examples of epilepsy syndromes include benign rolandic epilepsy, childhood absence epilepsy and juvenile myoclonic epilepsy. Severe syndromes with diffuse brain dysfunction caused, at least partly, by some aspect of epilepsy, are also referred to as epileptic encephalopathies. These are associated with frequent seizures that are resistant to treatment and severe cognitive dysfunction, for instance Lennox-Gastaut syndrome and West syndrome.
Carl L. Faingold is an American neuroscientist who is a Distinguished Professor in the Department of Pharmacology of Southern Illinois University School of Medicine in Springfield, Illinois; he is a founding faculty member of both the department and the School of Medicine. He has had an extensive career as a medical and graduate student educator as well as a researcher into brain mechanisms. He is a specialist in the actions of drugs on brain activity at the level of the single neuron as it relates to networks of neurons in awake behaving animals.
Drug-resistant epilepsy (DRE), also known as refractory epilepsy, intractable epilepsy, or pharmacoresistant epilepsy, is diagnosed following a failure of adequate trials of two tolerated and appropriately chosen and used antiepileptic drugs (AEDs) to achieve sustained seizure freedom. The probability that the next medication will achieve seizure freedom drops with every failed AED. For example, after two failed AEDs, the probability that the third will achieve seizure freedom is around 4%. Drug-resistant epilepsy is commonly diagnosed after several years of uncontrolled seizures, however, in most cases, it is evident much earlier. Approximately 30% of people with epilepsy have a drug-resistant form.
Lori L. Isom is an American pharmacologist, an elected Fellow of the American Association for the Advancement of Science, and a member of the National Academy of Medicine.
Computational models in epilepsy mainly focus on describing an electrophysiological manifestation associated with epilepsy called seizures. For this purpose, computational neurosciences use differential equations to reproduce the temporal evolution of the signals recorded experimentally. A book published in 2008, Computational Neuroscience in Epilepsy,. summarizes different works done up to this time. The goals of using its models are diverse, from prediction to comprehension of underlying mechanisms.
Malignant migrating partial seizures of infancy (MMPSI) is a rare epileptic syndrome that onsets before 6 months of age, commonly in the first few weeks of life. Once seizures start, the site of seizure activity repeatedly migrates from one area of the brain to another, with few periods of remission in between. These seizures are 'focal' (updated term for 'partial'), meaning they do not affect both sides of the brain at the same time. These continuous seizures cause damage to the brain, hence the descriptor 'malignant.'