Postictal state
Encyclopedia
The postictal state is the altered state of consciousness
that a person enters after experiencing a seizure
. It usually lasts between 5 and 30 minutes, but sometimes longer in the case of larger or more severe seizures and is characterized by drowsiness, confusion
, nausea
, hypertension
, headache
or migraine
and other disorienting symptoms. Additionally, emergence from this period is often accompanied by amnesia or other memory defects. It is during this period that the brain
recovers from the trauma of the seizure.
While the postictal period is considered to be the period shortly after a seizure where the brain is still recovering from the seizure, the ictal
period is considered to be the seizure itself, and the interictal period to be the period between seizures, when brain activity is more normal.
-induced reversible alterations in neuronal function but not structure.” Following a seizure it is common to experience feelings of exhaustion, both mental and physical, that can last for a day or two. Patients’ most common complaint after a seizure is an inability to think clearly, specifically “poor attention
and concentration
, poor short term memory, decreased verbal and interactive skills, and a variety of cognitive defects specific to individuals.” This collection of symptoms is known as the postictal state, though the word postictal means nothing more than “after the seizure”.
Postictal migraines are a major complaint among epilepsy
patients, and can have a variety of etiologies. One possible cause of these migraines is high intracranial pressure resulting from postictal cerebral edema
. At times, patients may be unaware that they had a seizure, and the characteristic migraine is their only clue. Depression
is also very common after a seizure.
Other symptoms associated with the postictal state are less common. Todd's paresis
(TP) is a temporary regional loss of function in whatever region just experienced the seizure, and its manifestation depends on where the seizure was located. Loss of motor function is most common, and can range from weakness to full paralysis. About 6% of patients who had tonic-clonic seizures experienced TP afterward, with loss of motor function sometimes accompanied with temporary numbness, blindness, or deafness. TP can also cause anterograde amnesia
if the seizure included the bilateral hippocampi, and aphasia
if the seizures began in the language-dominant hemisphere. Symptoms typically lasts about 15 hours, but can last as long as 36 hours, and the clinician must resolve whether the loss of motor function is due to TP or ischemia
.
Postictal psychosis (PP) is a rare but serious complication following seizures, characterized by auditory and visual hallucinations, delusions, paranoia
, affective change, and aggression
. Following the conclusion of the seizure, the patient feels the typical confusion and lethargy of the postictal state, and then gradually recovers to a normal state. This is called the lucid phase. In patients who experience PP, the lucid phase usually lasts between 2 hours and a week (usually more than 6 hours) before psychosis sets in. In about 12-50% of seizure patients, the lucid phase is followed by a period of psychosis that can last for 12 hours to more than 3 months (the mean is 9–10 days). This psychosis is treatable with standard antipsychotic drugs, and stops when the patient no longer experiences seizures.
Postictal bliss (PB) is also reported following seizures. This has been described as a highly blissful feeling associated with the emergence from amnesia.
Some of these postictal symptoms are almost always present for a period of a few hours to a day or two. In fact, confusion and lack of responsiveness after a seizure is so common and expected that if a patient doesn’t show these symptoms after a seizure, it can be a signal to clinicians that the event may not be an actual seizure at all. Usually such false seizures are instead related to syncope
or have a psychogenic origin. The postictal state can also be useful for the clinician when determining the focus of the seizure. Decreased verbal memory (short term) tends to result from a seizure in the dominant hemisphere, whereas seizures in the nondominant hemisphere tend to manifest with decreased visual memory. Inability to read suggests seizure foci in the language areas of the speech-dominant hemisphere, and “after a seizure semivoluntary events as mundane as nose wiping tend to be done with the hand ipsilateral to the seizure focus.”
Individuals in a postictal state may also be susceptible to alcohol abuse
.
While it might seem that the neurons become “exhausted” after the near-constant firing involved in a seizure, the ability of the neuron to carry an action potential
following a seizure is not decreased. Neurons of the brain fire normally when stimulated, even after long periods of status epilepticus
. Furthermore, the sodium gradient that allows the axon potential to be propagated is so large in comparison to the tiny number of ions that are let through each channel with each signal that it is highly unlikely that this gradient could be ‘used up’ by high activity during a seizure. Instead, there are four major hypotheses regarding what cellular and molecular mechanisms could cause the observed postictal systems: neurotransmitter depletion, changes in receptor concentration, active inhibition, and cerebral bloodflow changes. It is likely that these may in fact interact or more than one theory may contribute to postictal symptoms.
terminal and then exocytosed into the synaptic cleft in order to propagate the signal to the next neuron. While neurotransmitters are not typically a limiting factor in neuronal signaling rates, it is possible that with extensive firing during seizures neurotransmitters could be used up faster than new ones could be synthesized in the nucleus and transported down the axon. There is currently no direct evidence for neurotransmitter depletion following seizures.
. Administering the opiate antagonist naloxone
immediately reverses this state, providing evidence that increased responsiveness or concentration of the opiate receptors may be occurring during seizures and may be partially responsible for the weariness humans experience following a seizure. When humans were given naloxone in-between seizures, researchers observed increased activity on their EEGs, suggesting that opioid receptors may also be upregulated during human seizures. To provide direct evidence for this, Hammers et al. did positron emission tomography
(PET) scanning of radiolabelled ligands before, during, and after spontaneous seizures in humans. They found that opioid receptors were upregulated in the regions near the focus of the seizure during the ictal phase, gradually returning to baseline availability during the postictal phase. Hammers notes that cerebral bloodflow after a seizure can not account for the increase in PET activity observed. Regional bloodflow can increase by as much as 70-80% after seizures but normalizes after 30 minutes. The shortest postictal interval in their study was 90 minutes and none of the patients had seizures during the scanning. It has been predicted that a decrease in opioid activity following a seizure could cause withdrawal symptoms, contributing to postictal depression. The opioid receptor connection with mitigating seizures has been disputed, and opioids have been found to have different functions in different regions of the brain, having both proconvulsive and anticonvulsive effects.
It is possible that seizures cease spontaneously, but it is much more probable that some changes in the brain create inhibitory signals that serve to tamp down the overactive neurons and effectively end the seizure. Opioid
peptides have been shown to be involved in the postictal state and are at times anticonvulsive, and adenosine has also been implicated as a molecule potentially involved in terminating seizures. Evidence for the theory of active inhibition lies in the postictal refractory period
, a period of weeks or even months following a series of seizures in which seizures cannot be induced (using animal models and a technique called kindling
, in which seizures are induced with repeated electrical stimulation).
Leftover inhibitory signals are the most likely explanation for why there would be a period in which the threshold for provoking a second seizure is high, and lowered excitability may also explain some of the postictal symptoms. Inhibitory signals could be through GABA receptors (both fast and slow IPSPs), calcium-activated potassium receptors (which give rise to afterhyperpolarization
), hyperpolarizing pumps, or other changes in ion channels or signal receptors. These changes would likely have a residual effect for a short time after successfully ending the high activity of neurons, perhaps actively inhibiting normal firing during the after the seizure has ended. However, most of these changes would be expected to last for seconds (in the case of IPSP and AHP) or maybe minutes (in the case of hyperpolarized pumps), but cannot account for the fog that lasts for hours after a seizure.
While not an example of active inhibition, acidosis
of the blood could aid in ending the seizure and also depress neuron firing following its conclusion. As muscles contract during tonic-clonic seizures they outpace oxygen supplies and go into anaerobic respiration
. With continued contractions under anaerobic conditions, the cells undergo lactic acidosis, or the production of lactic acid as a metabolic byproduct. This acidifies the blood (higher H+ concentration, lower pH), which has many impacts on the brain. For one, “hydrogen ions compete with other ions at the ion channel associated with N-methyl-d-aspartate (NMDA
). This competition may partially attenuate NMDA receptor and channel mediated hyperexcitability after seizures.” It is unlikely that these effects would be long-lasting, but by decreasing the effectiveness of NMDA-type glutamate receptors , high H+ concentrations could increase the threshold needed to excite the cell, inhibiting the seizure and potentially slowing neuronal signaling after the event.
Cerebral autoregulation
typically ensures that the correct amount of blood reaches the various regions of the brain to match the activity of the cells in that region. In other words, perfusion typically matches metabolism in all organs, but especially in the brain, which gets the highest priority. However, following a seizure it has been shown that sometimes cerebral blood flow is not proportionate to metabolism. While cerebral blood flow didn’t change in the mouse hippocampus (the foci of seizures in this model) during or after seizures, increases in relative glucose uptake were observed in the region during the ictal and early postictal periods. Animal models are difficult for this type of study because each type of seizure model produces a unique pattern of perfusion and metabolism. Thus, in different models of epilepsy, researchers have had differing results as to whether or not metabolism and perfusion become uncoupled. Hosokawa’s model used EL mice, in which seizures begin in the hippocampus
and present similarly to the behaviors observed in human epileptic patients. If humans show similar uncoupling of perfusion and metabolism, this would result in hypoperfusion in the affected area, a possible explanation for the confusion and ‘fog’ patients experience following a seizure. It is possible that these changes in blood flow could be a result of poor autoregulation following a seizure, or it could in fact be yet another factor involved in stopping seizures.
, thyrotropin releasing hormone (TRH), neuropeptide Y
, somatostatin
, and cortistatin
) are believed to have anticonvulsant and neuroprotective properties. In accordance with this perceived function, mouse studies have used microarrays to show that transcription of these genes is increased many-fold following a seizure. The number of transcripts of these molecules typically peaks around 24 hours following the seizure, but can remain statistically significantly above normal levels for up to 72 hours.
Wilson observed a higher magnitude of increase in adult rats compared to immature rats, which is of note particularly because young mice have a much shorter postictal refractory period. Also, administering exogenous TRH, has been shown to improve postictal cognition in humans, as measured with neuropsychological tests. This evidence further suggests a natural role for these molecules in ending and/or recovering from seizures, and may give rise to pharmaceuticals that mitigate postictal symptoms in the future.
In support of the opioid theory of the postictal state, pretreatment of rats with morphine
increased postictal symptoms and pretreatment with naloxone decreased postictal symptoms (as measured by the presence of EEG slow waves, increase in EEG spike activity, decreased memory, affective pain response, and explosive motor behavior). However, it is believed that opioid peptides serve a very useful purpose in ending the seizures, so pretreating humans with naloxone would put the patient at risk of status epilepticus. Naloxone may, however, prove a useful treatment for improving symptoms after seizures have ended. It is not known if this would also put the patient at risk of another seizure in the near future as a result of shortening the postictal refractory period.
Altered state of consciousness
An altered state of consciousness , also named altered state of mind, is any condition which is significantly different from a normal waking beta wave state. The expression was used as early as 1966 by Arnold M. Ludwig and brought into common usage from 1969 by Charles Tart: it describes induced...
that a person enters after experiencing a 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...
. It usually lasts between 5 and 30 minutes, but sometimes longer in the case of larger or more severe seizures and is characterized by drowsiness, confusion
ConFusion
ConFusion is an annual science fiction convention organized by the Stilyagi Air Corps and its parent organization, the Ann Arbor Science Fiction Association. Commonly, it is held the third weekend of January. It is the oldest science fiction convention in Michigan, a regional, general SF con...
, nausea
Nausea
Nausea , is a sensation of unease and discomfort in the upper stomach with an involuntary urge to vomit. It often, but not always, precedes vomiting...
, hypertension
Hypertension
Hypertension or high blood pressure is a cardiac chronic medical condition in which the systemic arterial blood pressure is elevated. What that means is that the heart is having to work harder than it should to pump the blood around the body. Blood pressure involves two measurements, systolic and...
, headache
Headache
A headache or cephalalgia is pain anywhere in the region of the head or neck. It can be a symptom of a number of different conditions of the head and neck. The brain tissue itself is not sensitive to pain because it lacks pain receptors. Rather, the pain is caused by disturbance of the...
or migraine
Migraine
Migraine is a chronic neurological disorder characterized by moderate to severe headaches, and nausea...
and other disorienting symptoms. Additionally, emergence from this period is often accompanied by amnesia or other memory defects. It is during this period that the brain
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,...
recovers from the trauma of the seizure.
While the postictal period is considered to be the period shortly after a seizure where the brain is still recovering from the seizure, the ictal
Ictal
Ictal refers to a physiologic state or event such as a seizure, stroke or headache. The word originates from the Latin ictus, meaning a blow or a stroke...
period is considered to be the seizure itself, and the interictal period to be the period between seizures, when brain activity is more normal.
Symptoms
Jerome Engel defines the postictal state as “manifestations of seizureSeizure
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...
-induced reversible alterations in neuronal function but not structure.” Following a seizure it is common to experience feelings of exhaustion, both mental and physical, that can last for a day or two. Patients’ most common complaint after a seizure is an inability to think clearly, specifically “poor attention
Attention
Attention is the cognitive process of paying attention to one aspect of the environment while ignoring others. Attention is one of the most intensely studied topics within psychology and cognitive neuroscience....
and concentration
Concentration
In chemistry, concentration is defined as the abundance of a constituent divided by the total volume of a mixture. Four types can be distinguished: mass concentration, molar concentration, number concentration, and volume concentration...
, poor short term memory, decreased verbal and interactive skills, and a variety of cognitive defects specific to individuals.” This collection of symptoms is known as the postictal state, though the word postictal means nothing more than “after the seizure”.
Postictal migraines are a major complaint among epilepsy
Epilepsy
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...
patients, and can have a variety of etiologies. One possible cause of these migraines is high intracranial pressure resulting from postictal cerebral edema
Cerebral edema
Cerebral edema or cerebral œdema is an excess accumulation of water in the intracellular or extracellular spaces of the brain.-Vasogenic:Due to a breakdown of tight endothelial junctions which make up the blood-brain barrier...
. At times, patients may be unaware that they had a seizure, and the characteristic migraine is their only clue. Depression
Depression (mood)
Depression is a state of low mood and aversion to activity that can affect a person's thoughts, behaviour, feelings and physical well-being. Depressed people may feel sad, anxious, empty, hopeless, helpless, worthless, guilty, irritable, or restless...
is also very common after a seizure.
Other symptoms associated with the postictal state are less common. Todd's paresis
Todd's paresis
Todd's paresis or Todd's paralysis is focal weakness in a part of the body after a seizure. This weakness typically affects appendages and is localized to either the left or right side of the body. It usually subsides completely within 48 hours...
(TP) is a temporary regional loss of function in whatever region just experienced the seizure, and its manifestation depends on where the seizure was located. Loss of motor function is most common, and can range from weakness to full paralysis. About 6% of patients who had tonic-clonic seizures experienced TP afterward, with loss of motor function sometimes accompanied with temporary numbness, blindness, or deafness. TP can also cause anterograde amnesia
Anterograde amnesia
Anterograde amnesia is a loss of the ability to create new memories after the event that caused the amnesia, leading to a partial or complete inability to recall the recent past, while long-term memories from before the event remain intact. This is in contrast to retrograde amnesia, where memories...
if the seizure included the bilateral hippocampi, and aphasia
Aphasia
Aphasia is an impairment of language ability. This class of language disorder ranges from having difficulty remembering words to being completely unable to speak, read, or write....
if the seizures began in the language-dominant hemisphere. Symptoms typically lasts about 15 hours, but can last as long as 36 hours, and the clinician must resolve whether the loss of motor function is due to TP or ischemia
Ischemia
In medicine, ischemia is a restriction in blood supply, generally due to factors in the blood vessels, with resultant damage or dysfunction of tissue. It may also be spelled ischaemia or ischæmia...
.
Postictal psychosis (PP) is a rare but serious complication following seizures, characterized by auditory and visual hallucinations, delusions, paranoia
Paranoia
Paranoia [] is a thought process believed to be heavily influenced by anxiety or fear, often to the point of irrationality and delusion. Paranoid thinking typically includes persecutory beliefs, or beliefs of conspiracy concerning a perceived threat towards oneself...
, affective change, and aggression
Aggression
In psychology, as well as other social and behavioral sciences, aggression refers to behavior between members of the same species that is intended to cause humiliation, pain, or harm. Ferguson and Beaver defined aggressive behavior as "Behavior which is intended to increase the social dominance of...
. Following the conclusion of the seizure, the patient feels the typical confusion and lethargy of the postictal state, and then gradually recovers to a normal state. This is called the lucid phase. In patients who experience PP, the lucid phase usually lasts between 2 hours and a week (usually more than 6 hours) before psychosis sets in. In about 12-50% of seizure patients, the lucid phase is followed by a period of psychosis that can last for 12 hours to more than 3 months (the mean is 9–10 days). This psychosis is treatable with standard antipsychotic drugs, and stops when the patient no longer experiences seizures.
Postictal bliss (PB) is also reported following seizures. This has been described as a highly blissful feeling associated with the emergence from amnesia.
Some of these postictal symptoms are almost always present for a period of a few hours to a day or two. In fact, confusion and lack of responsiveness after a seizure is so common and expected that if a patient doesn’t show these symptoms after a seizure, it can be a signal to clinicians that the event may not be an actual seizure at all. Usually such false seizures are instead related to syncope
Syncope (medicine)
Syncope , the medical term for fainting, is precisely defined as a transient loss of consciousness and postural tone characterized by rapid onset, short duration, and spontaneous recovery due to global cerebral hypoperfusion that most often results from hypotension.Many forms of syncope are...
or have a psychogenic origin. The postictal state can also be useful for the clinician when determining the focus of the seizure. Decreased verbal memory (short term) tends to result from a seizure in the dominant hemisphere, whereas seizures in the nondominant hemisphere tend to manifest with decreased visual memory. Inability to read suggests seizure foci in the language areas of the speech-dominant hemisphere, and “after a seizure semivoluntary events as mundane as nose wiping tend to be done with the hand ipsilateral to the seizure focus.”
Individuals in a postictal state may also be susceptible to alcohol abuse
Alcohol abuse
Alcohol abuse, as described in the DSM-IV, is a psychiatric diagnosis describing the recurring use of alcoholic beverages despite negative consequences. Alcohol abuse eventually progresses to alcoholism, a condition in which an individual becomes dependent on alcoholic beverages in order to avoid...
.
Causes
While it might seem that the neurons become “exhausted” after the near-constant firing involved in a seizure, the ability of the neuron to carry an action potential
Action potential
In physiology, an action potential is a short-lasting event in which the electrical membrane potential of a cell rapidly rises and falls, following a consistent trajectory. Action potentials occur in several types of animal cells, called excitable cells, which include neurons, muscle cells, and...
following a seizure is not decreased. Neurons of the brain fire normally when stimulated, even after long periods of status epilepticus
Status epilepticus
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...
. Furthermore, the sodium gradient that allows the axon potential to be propagated is so large in comparison to the tiny number of ions that are let through each channel with each signal that it is highly unlikely that this gradient could be ‘used up’ by high activity during a seizure. Instead, there are four major hypotheses regarding what cellular and molecular mechanisms could cause the observed postictal systems: neurotransmitter depletion, changes in receptor concentration, active inhibition, and cerebral bloodflow changes. It is likely that these may in fact interact or more than one theory may contribute to postictal symptoms.
Neurotransmitter depletion
Neurotransmitters must be present in the axonAxon
An axon is a long, slender projection of a nerve cell, or neuron, that conducts electrical impulses away from the neuron's cell body or soma....
terminal and then exocytosed into the synaptic cleft in order to propagate the signal to the next neuron. While neurotransmitters are not typically a limiting factor in neuronal signaling rates, it is possible that with extensive firing during seizures neurotransmitters could be used up faster than new ones could be synthesized in the nucleus and transported down the axon. There is currently no direct evidence for neurotransmitter depletion following seizures.
Changes in receptor concentration
In studies that stimulate seizures by subjecting rats to electroshock, seizures are followed by unconsciousness and slow waves on an electroencephalogram (EEG), signs of postictal catalepsyCatalepsy
Catalepsy is also a term used by hypnotists to refer to the state of making a hypnotised subject's arm, leg or back rigid. "Arm catalepsy" is often a pre-hypnotic test performed prior to an induction into a full trance.-Causes:...
. Administering the opiate antagonist naloxone
Naloxone
Naloxone is an opioid antagonist drug developed by Sankyo in the 1960s. Naloxone is a drug used to counter the effects of opiate overdose, for example heroin or morphine overdose. Naloxone is specifically used to counteract life-threatening depression of the central nervous system and respiratory...
immediately reverses this state, providing evidence that increased responsiveness or concentration of the opiate receptors may be occurring during seizures and may be partially responsible for the weariness humans experience following a seizure. When humans were given naloxone in-between seizures, researchers observed increased activity on their EEGs, suggesting that opioid receptors may also be upregulated during human seizures. To provide direct evidence for this, Hammers et al. did positron emission tomography
Positron emission tomography
Positron emission tomography is nuclear medicine imaging technique that produces a three-dimensional image or picture of functional processes in the body. The system detects pairs of gamma rays emitted indirectly by a positron-emitting radionuclide , which is introduced into the body on a...
(PET) scanning of radiolabelled ligands before, during, and after spontaneous seizures in humans. They found that opioid receptors were upregulated in the regions near the focus of the seizure during the ictal phase, gradually returning to baseline availability during the postictal phase. Hammers notes that cerebral bloodflow after a seizure can not account for the increase in PET activity observed. Regional bloodflow can increase by as much as 70-80% after seizures but normalizes after 30 minutes. The shortest postictal interval in their study was 90 minutes and none of the patients had seizures during the scanning. It has been predicted that a decrease in opioid activity following a seizure could cause withdrawal symptoms, contributing to postictal depression. The opioid receptor connection with mitigating seizures has been disputed, and opioids have been found to have different functions in different regions of the brain, having both proconvulsive and anticonvulsive effects.
Active inhibition
It is possible that seizures cease spontaneously, but it is much more probable that some changes in the brain create inhibitory signals that serve to tamp down the overactive neurons and effectively end the seizure. Opioid
Opioid
An opioid is a psychoactive chemical that works by binding to opioid receptors, which are found principally in the central and peripheral nervous system and the gastrointestinal tract...
peptides have been shown to be involved in the postictal state and are at times anticonvulsive, and adenosine has also been implicated as a molecule potentially involved in terminating seizures. Evidence for the theory of active inhibition lies in the postictal refractory period
Refractory period
In physiology, a refractory period is a period of time during which an organ or cell is incapable of repeating a particular action, or the amount of time it takes for an excitable membrane to be ready for a second stimulus once it returns to its resting state following an excitation...
, a period of weeks or even months following a series of seizures in which seizures cannot be induced (using animal models and a technique called kindling
Kindling
Kindling is a term to describe small pieces of wood and twigs used to start a fire.Kindling may also refer to:* Kindling, a 1915 film directed by Cecil B...
, in which seizures are induced with repeated electrical stimulation).
Leftover inhibitory signals are the most likely explanation for why there would be a period in which the threshold for provoking a second seizure is high, and lowered excitability may also explain some of the postictal symptoms. Inhibitory signals could be through GABA receptors (both fast and slow IPSPs), calcium-activated potassium receptors (which give rise to afterhyperpolarization
Afterhyperpolarization
Afterhyperpolarization or AHP describes the hyperpolarization phase of a neuron's action potential where the cell's membrane potential falls below the normal resting potential. This is also commonly referred to as an action potential's undershoot phase...
), hyperpolarizing pumps, or other changes in ion channels or signal receptors. These changes would likely have a residual effect for a short time after successfully ending the high activity of neurons, perhaps actively inhibiting normal firing during the after the seizure has ended. However, most of these changes would be expected to last for seconds (in the case of IPSP and AHP) or maybe minutes (in the case of hyperpolarized pumps), but cannot account for the fog that lasts for hours after a seizure.
While not an example of active inhibition, acidosis
Acidosis
Acidosis is an increased acidity in the blood and other body tissue . If not further qualified, it usually refers to acidity of the blood plasma....
of the blood could aid in ending the seizure and also depress neuron firing following its conclusion. As muscles contract during tonic-clonic seizures they outpace oxygen supplies and go into anaerobic respiration
Anaerobic respiration
Anaerobic respiration is a form of respiration using electron acceptors other than oxygen. Although oxygen is not used as the final electron acceptor, the process still uses a respiratory electron transport chain; it is respiration without oxygen...
. With continued contractions under anaerobic conditions, the cells undergo lactic acidosis, or the production of lactic acid as a metabolic byproduct. This acidifies the blood (higher H+ concentration, lower pH), which has many impacts on the brain. For one, “hydrogen ions compete with other ions at the ion channel associated with N-methyl-d-aspartate (NMDA
NMDA
N-Methyl-D-aspartic acid or N-Methyl-D-aspartate is an amino acid derivative which acts as a specific agonist at the NMDA receptor mimicking the action of glutamate, the neurotransmitter which normally acts at that receptor...
). This competition may partially attenuate NMDA receptor and channel mediated hyperexcitability after seizures.” It is unlikely that these effects would be long-lasting, but by decreasing the effectiveness of NMDA-type glutamate receptors , high H+ concentrations could increase the threshold needed to excite the cell, inhibiting the seizure and potentially slowing neuronal signaling after the event.
Cerebral bloodflow changes
Cerebral autoregulation
Autoregulation
Autoregulation is a process within many biological systems, resulting from some internal adaptive mechanism that works to adjust the systems response to stimuli. While most systems of the body show some degree of autoregulation, it is most clearly observed in the kidney, the heart, and the brain...
typically ensures that the correct amount of blood reaches the various regions of the brain to match the activity of the cells in that region. In other words, perfusion typically matches metabolism in all organs, but especially in the brain, which gets the highest priority. However, following a seizure it has been shown that sometimes cerebral blood flow is not proportionate to metabolism. While cerebral blood flow didn’t change in the mouse hippocampus (the foci of seizures in this model) during or after seizures, increases in relative glucose uptake were observed in the region during the ictal and early postictal periods. Animal models are difficult for this type of study because each type of seizure model produces a unique pattern of perfusion and metabolism. Thus, in different models of epilepsy, researchers have had differing results as to whether or not metabolism and perfusion become uncoupled. Hosokawa’s model used EL mice, in which seizures begin in the hippocampus
Hippocampus
The hippocampus is a major component of the brains of humans and other vertebrates. It belongs to the limbic system and plays important roles in the consolidation of information from short-term memory to long-term memory and spatial navigation. Humans and other mammals have two hippocampi, one in...
and present similarly to the behaviors observed in human epileptic patients. If humans show similar uncoupling of perfusion and metabolism, this would result in hypoperfusion in the affected area, a possible explanation for the confusion and ‘fog’ patients experience following a seizure. It is possible that these changes in blood flow could be a result of poor autoregulation following a seizure, or it could in fact be yet another factor involved in stopping seizures.
Treatments
Observing neuropeptide transcription levels during and after seizures provides a window into how the brain responds to seizures. Some neuropeptides (such as galaninGalanin
Galanin is a neuropeptide encoded by the GAL gene, that is widely expressed in the brain, spinal cord, and gut of humans as well as other mammals. Galanin signaling occurs through three G protein-coupled receptors....
, thyrotropin releasing hormone (TRH), neuropeptide Y
Neuropeptide Y
Neuropeptide Y is a 36-amino acid peptide neurotransmitter found in the brain and autonomic nervous system."NPY has been associated with a number of physiologic processes in the brain, including the regulation of energy balance, memory and learning, and epilepsy." The main effect is increased food...
, somatostatin
Somatostatin
Somatostatin is a peptide hormone that regulates the endocrine system and affects neurotransmission and cell proliferation via interaction with G-protein-coupled somatostatin receptors and inhibition of the release of numerous secondary hormones.Somatostatin...
, and cortistatin
Cortistatin (neuropeptide)
Precortistatin is a protein that in humans is encoded by the CORT gene. The 105 amino acid residue human precortistatin in turn is cleaved into cortistatin-17 and cortistatin-29. Cortistatin-17 is the only active peptide derived from the precursor...
) are believed to have anticonvulsant and neuroprotective properties. In accordance with this perceived function, mouse studies have used microarrays to show that transcription of these genes is increased many-fold following a seizure. The number of transcripts of these molecules typically peaks around 24 hours following the seizure, but can remain statistically significantly above normal levels for up to 72 hours.
Wilson observed a higher magnitude of increase in adult rats compared to immature rats, which is of note particularly because young mice have a much shorter postictal refractory period. Also, administering exogenous TRH, has been shown to improve postictal cognition in humans, as measured with neuropsychological tests. This evidence further suggests a natural role for these molecules in ending and/or recovering from seizures, and may give rise to pharmaceuticals that mitigate postictal symptoms in the future.
In support of the opioid theory of the postictal state, pretreatment of rats with morphine
Morphine
Morphine is a potent opiate analgesic medication and is considered to be the prototypical opioid. It was first isolated in 1804 by Friedrich Sertürner, first distributed by same in 1817, and first commercially sold by Merck in 1827, which at the time was a single small chemists' shop. It was more...
increased postictal symptoms and pretreatment with naloxone decreased postictal symptoms (as measured by the presence of EEG slow waves, increase in EEG spike activity, decreased memory, affective pain response, and explosive motor behavior). However, it is believed that opioid peptides serve a very useful purpose in ending the seizures, so pretreating humans with naloxone would put the patient at risk of status epilepticus. Naloxone may, however, prove a useful treatment for improving symptoms after seizures have ended. It is not known if this would also put the patient at risk of another seizure in the near future as a result of shortening the postictal refractory period.