Status epilepticus
Encyclopedia
Status epilepticus is a life-threatening condition in which the brain
is in a state of persistent seizure
. Definitions vary, but traditionally it is defined as one continuous unremitting seizure lasting longer than 5 minutes, or recurrent seizures without regaining consciousness between seizures for greater than 5 minutes. It is always considered a medical emergency
. There is some evidence that 5 minutes is sufficient to damage neurons and that seizures are unlikely to self-terminate by that time. First aid guidelines for seizures state that, as a rule, an ambulance should be called for seizures lasting longer than 5 minutes (if this is the patient's first seizure episode and there were no known precipitating factors, or if SE happens to an epileptic whose seizures were previously absent or well-controlled for a considerable time period, then that step can be taken before that point). The mortality rate of status epilepticus has the potential to be quite high (at least 20%), especially if treatment is not initiated quickly. However, with optimal neurological care, adherence to the medication regimen, and a good prognosis (no other underlying uncontrolled brain or other organic disease), the patient- even people who have been diagnosed with epilepsy- in otherwise good health can survive with minimal or no brain damage, and can decrease their risk of death and even avoid future seizures.
is a variant involving hour
, day
, or even week
-long jerking. It is a consequence of vascular disease
, tumours, or encephalitis
, and is drug-resistant.
Generalized myoclonus
is commonly seen in coma
tose patients following CPR and is seen by some as an indication of catastrophic damage to the neocortex
.
, or CPSE, and absence status epilepticus are rare forms of the condition which are marked by nonconvulsive seizures. In the case of CPSE, the seizure is confined to a small area of the brain, normally the temporal lobe. But the latter, absence status epilepticus, is marked by a generalised seizure affecting the whole brain, and an EEG is needed to differentiate between the two conditions. This results in episodes characterized by a long-lasting stupor, staring and unresponsiveness.
. Causes include:
became the first choice for SE. Even though other benzodiazepine
s such as clonazepam
were useful, diazepam was relied upon almost exclusively. This began to change in 1975 with a preliminary study on lorazepam
conducted by Waltregny and Dargent, who found that its pharmacological effects were longer lasting than those of an equal dose of diazepam. This meant it did not have to be repeatedly injected like diazepam, the effects of which would wear off 5–15 minutes later in spite of its 30-hour half-life
(due to extensive redistribution of diazepam outside the vascular compartment as diazepam is highly lipid soluble). It has also been found that patients who were first tried on diazepam were much more likely to require endotracheal tubing than patients who were first tried on phenobarbital
, phenytoin
, or lorazepam.
Today, the benzodiazepine of choice is lorazepam
for initial treatment due to its relatively long (2–8 hour) duration of action when injected, and its rapid onset of action, which is thought to be due to its high affinity for GABA receptor
s and to its low lipid
solubility
which causes it to remain in the vascular compartment
. If lorazepam is not available, or intravenous access is not possible, then diazepam should be given. Particularly in children another, increasingly popular treatment choice is buccal and intranasal midazolam
, which can be given into the side of the mouth. Sometimes, the failure of lorazepam alone is considered to be enough to classify a case of SE as refractory.
fosphenytoin
can be administered three times as fast and with far fewer injection site reactions. If these or any other hydantoin derivatives
are used, then cardiac monitoring is a must if they are administered intravenously. Because the hydantoins take 15–30 minutes to work, a benzodiazepine or barbiturate is often co-administered. Because of diazepam's short duration of action, they were often administered together anyway.
is not available in an intravenous formulation, and does not play a role in status epilepticus.
coma. The barbiturate most commonly used for this is phenobarbital
. Thiopental or pentobarbital
may also be used for that purpose if the seizures have to be stopped immediately or if the patient has already been compromised by the underlying illness or toxic/metabolic-induced seizures; however, in those situations, thiopental is the agent of choice.
The failure of phenobarbital therapy does not preclude the success of a lengthy comatose state induced by a stronger barbiturate such as secobarbital
. Such was the case for Ohori, Fujioka, and Ohta ca. 1998, when they induced a 10-month long coma (or "anesthesia" as they called it) in a 26-year-old woman suffering from refractory status epilepticus secondary to viral encephalitis
and then tapered her off the secobarbital very slowly while using zonisamide
at the same time.
is tried; sometimes it is used second after the failure of lorazepam
. This also means putting the patient on artificial ventilation. Propofol has been shown to be effective in suppressing the jerks seen in myoclonus status epilepticus, but , there have been no cases of anyone going into myoclonus status epilepticus, undergoing propofol treatment, and then not dying anyway.
in status epilepticus was first reported in 1955 by Bernhard, Boem and Hojeberg. Since then, it has been used in cases refractory to phenobarbital, diazepam, and phenytoin, and has been studied as an alternative to barbiturates and general anesthetics. Lidocaine is a sodium channel blocker and has been used where sodium channel dysfunction was suspected. However, in some studies, it was either ineffective or even harmful for most patients. The last is not so surprising in light of the fact that lidocaine has been known to cause seizures in humans and laboratory animals at doses greater than 15 µg/mL or 2–3 mg/kg.
, an NMDA antagonist drug, can be used as a last resort drug for resistant status epilepticus.
, approximately 40 cases of status epilepticus occur annually out of every 100,000 members of the population. This includes about 10-20% of all first seizures.
Brain
The brain is the center of the nervous system in all vertebrate and most invertebrate animals—only a few primitive invertebrates such as sponges, jellyfish, sea squirts and starfishes do not have one. It is located in the head, usually close to primary sensory apparatus such as vision, hearing,...
is in a state of persistent seizure
Seizure
An epileptic seizure, occasionally referred to as a fit, is defined as a transient symptom of "abnormal excessive or synchronous neuronal activity in the brain". The outward effect can be as dramatic as a wild thrashing movement or as mild as a brief loss of awareness...
. Definitions vary, but traditionally it is defined as one continuous unremitting seizure lasting longer than 5 minutes, or recurrent seizures without regaining consciousness between seizures for greater than 5 minutes. It is always considered a medical emergency
Medical emergency
A medical emergency is an injury or illness that is acute and poses an immediate risk to a person's life or long term health. These emergencies may require assistance from another person, who should ideally be suitably qualified to do so, although some of these emergencies can be dealt with by the...
. There is some evidence that 5 minutes is sufficient to damage neurons and that seizures are unlikely to self-terminate by that time. First aid guidelines for seizures state that, as a rule, an ambulance should be called for seizures lasting longer than 5 minutes (if this is the patient's first seizure episode and there were no known precipitating factors, or if SE happens to an epileptic whose seizures were previously absent or well-controlled for a considerable time period, then that step can be taken before that point). The mortality rate of status epilepticus has the potential to be quite high (at least 20%), especially if treatment is not initiated quickly. However, with optimal neurological care, adherence to the medication regimen, and a good prognosis (no other underlying uncontrolled brain or other organic disease), the patient- even people who have been diagnosed with epilepsy- in otherwise good health can survive with minimal or no brain damage, and can decrease their risk of death and even avoid future seizures.
Signs and symptoms
Status epilepticus can be divided into two categories—convulsive and nonconvulsive, the latter of which is underdiagnosed.Convulsive
Epilepsia partialis continuaEpilepsia partialis continua
Epilepsia partialis continua is a rare type of brain disorder in which a patient experiences recurrent motor epileptic seizures that are focal , and recur every few seconds or minutes for extended periods .-Presentation:During these seizures, there is repetitive focal myoclonus or Jacksonian...
is a variant involving hour
Hour
The hour is a unit of measurement of time. In modern usage, an hour comprises 60 minutes, or 3,600 seconds...
, day
Day
A day is a unit of time, commonly defined as an interval equal to 24 hours. It also can mean that portion of the full day during which a location is illuminated by the light of the sun...
, or even week
Week
A week is a time unit equal to seven days.The English word week continues an Old English wice, ultimately from a Common Germanic , from a root "turn, move, change"...
-long jerking. It is a consequence of vascular disease
Vascular disease
Vascular disease is a form of cardiovascular disease primarily affecting the blood vessels.Some conditions, such as angina and myocardial ischemia, can be considered both vascular diseases and heart diseases .Cigarette smoking is the major risk factor....
, tumours, or encephalitis
Encephalitis
Encephalitis is an acute inflammation of the brain. Encephalitis with meningitis is known as meningoencephalitis. Symptoms include headache, fever, confusion, drowsiness, and fatigue...
, and is drug-resistant.
Generalized myoclonus
Myoclonus
Myoclonus is brief, involuntary twitching of a muscle or a group of muscles. It describes a medical sign and, generally, is not a diagnosis of a disease. Brief twitches are perfectly normal. The myoclonic twitches are usually caused by sudden muscle contractions; they also can result from brief...
is commonly seen in coma
Coma
In medicine, a coma is a state of unconsciousness, lasting more than 6 hours in which a person cannot be awakened, fails to respond normally to painful stimuli, light or sound, lacks a normal sleep-wake cycle and does not initiate voluntary actions. A person in a state of coma is described as...
tose patients following CPR and is seen by some as an indication of catastrophic damage to the neocortex
Neocortex
The neocortex , also called the neopallium and isocortex , is a part of the brain of mammals. It is the outer layer of the cerebral hemispheres, and made up of six layers, labelled I to VI...
.
Nonconvulsive
Complex partial status epilepticusComplex partial status epilepticus
Complex partial status epilepticus is one of the non-convulsive forms of status epilepticus, a rare form of epilepsy defined by its recurrent nature. CPSE is characterized by seizures involving long-lasting stupor, staring and unresponsiveness...
, or CPSE, and absence status epilepticus are rare forms of the condition which are marked by nonconvulsive seizures. In the case of CPSE, the seizure is confined to a small area of the brain, normally the temporal lobe. But the latter, absence status epilepticus, is marked by a generalised seizure affecting the whole brain, and an EEG is needed to differentiate between the two conditions. This results in episodes characterized by a long-lasting stupor, staring and unresponsiveness.
Causes
Only 25 percent of people who experience seizures or status epilepticus have epilepsyEpilepsy
Epilepsy is a common chronic neurological disorder characterized by seizures. These seizures are transient signs and/or symptoms of abnormal, excessive or hypersynchronous neuronal activity in the brain.About 50 million people worldwide have epilepsy, and nearly two out of every three new cases...
. Causes include:
- StrokeStrokeA stroke, previously known medically as a cerebrovascular accident , is the rapidly developing loss of brain function due to disturbance in the blood supply to the brain. This can be due to ischemia caused by blockage , or a hemorrhage...
- Hemorrhage
- Intoxicants or adverse reactions to drugs.
- Insufficient dosageCompliance (medicine)In medicine, compliance describes the degree to which a patient correctly follows medical advice...
of a medication already prescribed to the patient. Such causes of this include:- Forgetfulness on the part of the patient in taking scheduled doses, or failure to take doses at the scheduled times
- Taking medicine at wrong times as a result of a time zoneTime zoneA time zone is a region on Earth that has a uniform standard time for legal, commercial, and social purposes. In order for the same clock time to always correspond to the same portion of the day as the Earth rotates , different places on the Earth need to have different clock times...
change while traveling - Dislike of the medication or its side effectsAdverse effectIn medicine, an adverse effect is a harmful and undesired effect resulting from a medication or other intervention such as surgery.An adverse effect may be termed a "side effect", when judged to be secondary to a main or therapeutic effect. If it results from an unsuitable or incorrect dosage or...
- Sudden withdrawal from a seizure medicationAnticonvulsantThe anticonvulsants are a diverse group of pharmaceuticals used in the treatment of epileptic seizures. Anticonvulsants are also increasingly being used in the treatment of bipolar disorder, since many seem to act as mood stabilizers, and in the treatment of neuropathic pain. The goal of an...
. Such causes include:- Sudden lack of access to medication due to unexpected circumstances
- Lack of ability of patient to communicate medication needs to others, leading to absence of doses
- Physician's decision to discontinue medication
- Consumption of alcoholic beverageAlcoholic beverageAn alcoholic beverage is a drink containing ethanol, commonly known as alcohol. Alcoholic beverages are divided into three general classes: beers, wines, and spirits. They are legally consumed in most countries, and over 100 countries have laws regulating their production, sale, and consumption...
s while on an anticonvulsant, or alcohol withdrawal. - DietingDietingDieting is the practice of eating food in a regulated fashion to achieve or maintain a controlled weight. In most cases dieting is used in combination with physical exercise to lose weight in those who are overweight or obese. Some athletes, however, follow a diet to gain weight...
or fastingFastingFasting is primarily the act of willingly abstaining from some or all food, drink, or both, for a period of time. An absolute fast is normally defined as abstinence from all food and liquid for a defined period, usually a single day , or several days. Other fasts may be only partially restrictive,...
while on an anticonvulsant - Starting on a new medication that reduces the effectiveness of the anticonvulsant]
- Developing a resistanceDrug resistanceDrug resistance is the reduction in effectiveness of a drug such as an antimicrobial or an antineoplastic in curing a disease or condition. When the drug is not intended to kill or inhibit a pathogen, then the term is equivalent to dosage failure or drug tolerance. More commonly, the term is used...
to an anticonvulsant already being used - GastroenteritisGastroenteritisGastroenteritis is marked by severe inflammation of the gastrointestinal tract involving both the stomach and small intestine resulting in acute diarrhea and vomiting. It can be transferred by contact with contaminated food and water...
while on an anticonvulsant. This is because the digestive system may force outVomitingVomiting is the forceful expulsion of the contents of one's stomach through the mouth and sometimes the nose...
the anticonvulsant, thereby rendering the body with a lack of protection. - Developing a new, unrelated condition in which seizures are coincidentally also a symptom, but are not controlled by an anticonvulsant already used
- MetabolicMetabolismMetabolism is the set of chemical reactions that happen in the cells of living organisms to sustain life. These processes allow organisms to grow and reproduce, maintain their structures, and respond to their environments. Metabolism is usually divided into two categories...
disturbances—such as affected kidney and liver
Treatments
Benzodiazepines
Shortly after it was introduced in 1963, diazepamDiazepam
Diazepam , first marketed as Valium by Hoffmann-La Roche is a benzodiazepine drug. Diazepam is also marketed in Australia as Antenex. It is commonly used for treating anxiety, insomnia, seizures including status epilepticus, muscle spasms , restless legs syndrome, alcohol withdrawal,...
became the first choice for SE. Even though other benzodiazepine
Benzodiazepine
A benzodiazepine is a psychoactive drug whose core chemical structure is the fusion of a benzene ring and a diazepine ring...
s such as clonazepam
Clonazepam
Clonazepamis a benzodiazepine drug having anxiolytic, anticonvulsant, muscle relaxant, and hypnotic properties. It is marketed by Roche under the trade name Klonopin in the United States and Rivotril in Australia, Brazil, Canada and Europe...
were useful, diazepam was relied upon almost exclusively. This began to change in 1975 with a preliminary study on lorazepam
Lorazepam
Lorazepam is a high-potency short-to-intermediate-acting 3-hydroxy benzodiazepine drug that has all five intrinsic benzodiazepine effects: anxiolytic, amnesic, sedative/hypnotic, anticonvulsant, antiemetic and muscle relaxant...
conducted by Waltregny and Dargent, who found that its pharmacological effects were longer lasting than those of an equal dose of diazepam. This meant it did not have to be repeatedly injected like diazepam, the effects of which would wear off 5–15 minutes later in spite of its 30-hour half-life
Half-life
Half-life, abbreviated t½, is the period of time it takes for the amount of a substance undergoing decay to decrease by half. The name was originally used to describe a characteristic of unstable atoms , but it may apply to any quantity which follows a set-rate decay.The original term, dating to...
(due to extensive redistribution of diazepam outside the vascular compartment as diazepam is highly lipid soluble). It has also been found that patients who were first tried on diazepam were much more likely to require endotracheal tubing than patients who were first tried on phenobarbital
Phenobarbital
Phenobarbital or phenobarbitone is a barbiturate, first marketed as Luminal by Friedr. Bayer et comp. It is the most widely used anticonvulsant worldwide, and the oldest still commonly used. It also has sedative and hypnotic properties but, as with other barbiturates, has been superseded by the...
, phenytoin
Phenytoin
Phenytoin sodium is a commonly used antiepileptic. Phenytoin acts to suppress the abnormal brain activity seen in seizure by reducing electrical conductance among brain cells by stabilizing the inactive state of voltage-gated sodium channels...
, or lorazepam.
Today, the benzodiazepine of choice is lorazepam
Lorazepam
Lorazepam is a high-potency short-to-intermediate-acting 3-hydroxy benzodiazepine drug that has all five intrinsic benzodiazepine effects: anxiolytic, amnesic, sedative/hypnotic, anticonvulsant, antiemetic and muscle relaxant...
for initial treatment due to its relatively long (2–8 hour) duration of action when injected, and its rapid onset of action, which is thought to be due to its high affinity for GABA receptor
GABA receptor
The GABA receptors are a class of receptors that respond to the neurotransmitter gamma-aminobutyric acid , the chief inhibitory neurotransmitter in the vertebrate central nervous system...
s and to its low lipid
Lipid
Lipids constitute a broad group of naturally occurring molecules that include fats, waxes, sterols, fat-soluble vitamins , monoglycerides, diglycerides, triglycerides, phospholipids, and others...
solubility
Solubility
Solubility is the property of a solid, liquid, or gaseous chemical substance called solute to dissolve in a solid, liquid, or gaseous solvent to form a homogeneous solution of the solute in the solvent. The solubility of a substance fundamentally depends on the used solvent as well as on...
which causes it to remain in the vascular compartment
Compartment (pharmacokinetics)
In pharmacokinetics, a compartment is a defined volume of body fluids. It is distinguished from anatomic compartments, which are bounded by fasciae...
. If lorazepam is not available, or intravenous access is not possible, then diazepam should be given. Particularly in children another, increasingly popular treatment choice is buccal and intranasal midazolam
Midazolam
Midazolam is a short-acting drug in the benzodiazepine class developed by Hoffmann-La Roche in the 1970s. The drug is used for treatment of acute seizures, moderate to severe insomnia, and for inducing sedation and amnesia before medical procedures. It possesses profoundly potent anxiolytic,...
, which can be given into the side of the mouth. Sometimes, the failure of lorazepam alone is considered to be enough to classify a case of SE as refractory.
Phenytoin and fosphenytoin
Phenytoin was once another first-line therapy, although the prodrugProdrug
A prodrug is a pharmacological substance administered in an inactive form. Once administered, the prodrug is metabolised in vivo into an active metabolite, a process termed bioactivation. The rationale behind the use of a prodrug is generally for absorption, distribution, metabolism, and...
fosphenytoin
Fosphenytoin
Fosphenytoin is a water-soluble phenytoin prodrug used only in hospitals for the treatment of epileptic seizures....
can be administered three times as fast and with far fewer injection site reactions. If these or any other hydantoin derivatives
Hydantoin
Hydantoin, which is also known as glycolylurea, is a heterocyclic organic compound that can be thought of as a cyclic "double-condensation reaction" product of glycolic acid and urea...
are used, then cardiac monitoring is a must if they are administered intravenously. Because the hydantoins take 15–30 minutes to work, a benzodiazepine or barbiturate is often co-administered. Because of diazepam's short duration of action, they were often administered together anyway.
Carbamazepine and valproate
Valproate is available to be given intravenously, and may be used for status epilepticus. CarbamazepineCarbamazepine
Carbamazepine is an anticonvulsant and mood-stabilizing drug used primarily in the treatment of epilepsy and bipolar disorder, as well as trigeminal neuralgia...
is not available in an intravenous formulation, and does not play a role in status epilepticus.
Barbiturates
Before the benzodiazepines were invented, there were the barbiturates, which are still used today if benzodiazepines or the hydantoins are not an option. These are used to induce a barbituricBarbiturate
Barbiturates are drugs that act as central nervous system depressants, and can therefore produce a wide spectrum of effects, from mild sedation to total anesthesia. They are also effective as anxiolytics, as hypnotics, and as anticonvulsants...
coma. The barbiturate most commonly used for this is phenobarbital
Phenobarbital
Phenobarbital or phenobarbitone is a barbiturate, first marketed as Luminal by Friedr. Bayer et comp. It is the most widely used anticonvulsant worldwide, and the oldest still commonly used. It also has sedative and hypnotic properties but, as with other barbiturates, has been superseded by the...
. Thiopental or pentobarbital
Pentobarbital
Pentobarbital is a short-acting barbiturate that was first synthesized in 1928. Pentobarbital is available as both a free acid and a sodium salt, the former of which is only slightly soluble in water and ethanol....
may also be used for that purpose if the seizures have to be stopped immediately or if the patient has already been compromised by the underlying illness or toxic/metabolic-induced seizures; however, in those situations, thiopental is the agent of choice.
The failure of phenobarbital therapy does not preclude the success of a lengthy comatose state induced by a stronger barbiturate such as secobarbital
Secobarbital
Secobarbital sodium is a barbiturate derivative drug that was first synthesized in 1928 in Germany. It possesses anaesthetic, anticonvulsant, sedative and hypnotic properties...
. Such was the case for Ohori, Fujioka, and Ohta ca. 1998, when they induced a 10-month long coma (or "anesthesia" as they called it) in a 26-year-old woman suffering from refractory status epilepticus secondary to viral encephalitis
Encephalitis
Encephalitis is an acute inflammation of the brain. Encephalitis with meningitis is known as meningoencephalitis. Symptoms include headache, fever, confusion, drowsiness, and fatigue...
and then tapered her off the secobarbital very slowly while using zonisamide
Zonisamide
Zonisamide is a sulfonamide anticonvulsant approved for use as an adjunctive therapy in adults with partial-onset seizures for adults; infantile spasm, mixed seizure types of Lennox-Gastaut syndrome, myoclonic, and generalized tonic clonic seizure.-History:...
at the same time.
General anesthetics
If this proves ineffective or if barbiturates cannot be used for some reason, then a general anesthetic such as propofolPropofol
Propofol is a short-acting, intravenously administered hypnotic agent. Its uses include the induction and maintenance of general anesthesia, sedation for mechanically ventilated adults, and procedural sedation. Propofol is also commonly used in veterinary medicine...
is tried; sometimes it is used second after the failure of lorazepam
Lorazepam
Lorazepam is a high-potency short-to-intermediate-acting 3-hydroxy benzodiazepine drug that has all five intrinsic benzodiazepine effects: anxiolytic, amnesic, sedative/hypnotic, anticonvulsant, antiemetic and muscle relaxant...
. This also means putting the patient on artificial ventilation. Propofol has been shown to be effective in suppressing the jerks seen in myoclonus status epilepticus, but , there have been no cases of anyone going into myoclonus status epilepticus, undergoing propofol treatment, and then not dying anyway.
Lidocaine
The use of lidocaineLidocaine
Lidocaine , Xylocaine, or lignocaine is a common local anesthetic and antiarrhythmic drug. Lidocaine is used topically to relieve itching, burning and pain from skin inflammations, injected as a dental anesthetic or as a local anesthetic for minor surgery.- History :Lidocaine, the first amino...
in status epilepticus was first reported in 1955 by Bernhard, Boem and Hojeberg. Since then, it has been used in cases refractory to phenobarbital, diazepam, and phenytoin, and has been studied as an alternative to barbiturates and general anesthetics. Lidocaine is a sodium channel blocker and has been used where sodium channel dysfunction was suspected. However, in some studies, it was either ineffective or even harmful for most patients. The last is not so surprising in light of the fact that lidocaine has been known to cause seizures in humans and laboratory animals at doses greater than 15 µg/mL or 2–3 mg/kg.
Ketamine
KetamineKetamine
Ketamine is a drug used in human and veterinary medicine. Its hydrochloride salt is sold as Ketanest, Ketaset, and Ketalar. Pharmacologically, ketamine is classified as an NMDA receptor antagonist...
, an NMDA antagonist drug, can be used as a last resort drug for resistant status epilepticus.
Prognosis
About one in five people, a total of 42,000 annually in the United States, will die within 30 days of having an initial status epilepticus seizure. The great majority of these people have an underlying brain condition causing their status seizure such as brain tumor, brain infection, brain trauma or stroke. However, people with diagnosed epilepsy who have a status seizure also have an increased risk of death if their condition is not stabilized quickly, their medication and sleep regimen adapted and adhered to, and stress and other stimulant (seizure trigger) levels controlled.Epidemiology
In the United StatesUnited States
The United States of America is a federal constitutional republic comprising fifty states and a federal district...
, approximately 40 cases of status epilepticus occur annually out of every 100,000 members of the population. This includes about 10-20% of all first seizures.