Postictal state

=Symptoms=

Jerome Engel defines the postictal state as “manifestations of seizure-induced reversible alterations in neuronal function but not structure.” cite book
last = Engel
first = Jerome Jr.
authorlink = Engel
title = Seizures and Epilepsy
publisher = F.A. Davis Company
location = Philadelphia
date = 1989
isbn = 0-8036-3201-0 ] 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.” Citation
last1 = Fisher | first1 = RS
author1-link = Fisher
last2 = Schachter | first2 = SC
author2-link = Schachter
title = The Postictal State: A Neglected Entity in the Management of Epilepsy.
journal = Epilepsy & Behavior
volume = 1
pages = 52-59
year = 2000 ] 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. Citation
last1 = Fisher | first1 = RS
author1-link = Fisher
last2 = Schachter | first2 = SC
author2-link = Schachter
title = The Postictal State: A Neglected Entity in the Management of Epilepsy.
journal = Epilepsy & Behavior
volume = 1
pages = 52-59
year = 2000 ] Depression is also very common after a seizure. There are social and psychological reasons for depression immediately following a seizure, but it is also believed that there are biological causes as well, perhaps the result of changing neurotransmitter systems, as discussed later in this paper.

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. Citation
last1 = Fisher | first1 = RS
author1-link = Fisher
last2 = Schachter | first2 = SC
author2-link = Schachter
title = The Postictal State: A Neglected Entity in the Management of Epilepsy.
journal = Epilepsy & Behavior
volume = 1
pages = 52-59
year = 2000 ] TP can also cause anterograde amnesia if the seizure included the bilateral hippocampi, and aphasia if the seizures began in the language-dominant hemisphere.cite book
last = Engel
first = Jerome Jr.
authorlink = Engel
title = Seizures and Epilepsy
publisher = F.A. Davis Company
location = Philadelphia
date = 1989
isbn = 0-8036-3201-0 ] 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. Citation
last1 = Fisher | first1 = RS
author1-link = Fisher
last2 = Schachter | first2 = SC
author2-link = Schachter
title = The Postictal State: A Neglected Entity in the Management of Epilepsy.
journal = Epilepsy & Behavior
volume = 1
pages = 52-59
year = 2000 ]

Postictal psychosis (PP) is a rare but serious complication following seizures, characterized by auditory and visual hallucinations, delusions, paranoia, affective change, and aggression. Interestingly, the onset of PP doesn’t begin until hours or days after the seizure has ended. 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 (mean, 9-10 days). This psychosis is treatable with standard antipsychotic drugs, and stops when the patient no longer experiences seizures. Citation
last1 = Devinsky | first1 = O
author1-link = Devinsky
title = Postictal Psychosis: Common, Dangerous, and Treatable
journal = Epilepsy Currents
volume = 8
issue = 2
pages = 31-34
year = 2008 ]

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. Citation
last1 = Fisher | first1 = RS
author1-link = Fisher
last2 = Schachter | first2 = SC
author2-link = Schachter
title = The Postictal State: A Neglected Entity in the Management of Epilepsy.
journal = Epilepsy & Behavior
volume = 1
pages = 52-59
year = 2000 ] 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.” Citation
last1 = Fisher | first1 = RS
author1-link = Fisher
last2 = Schachter | first2 = SC
author2-link = Schachter
title = The Postictal State: A Neglected Entity in the Management of Epilepsy.
journal = Epilepsy & Behavior
volume = 1
pages = 52-59
year = 2000 ]

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 following a seizure is not decreased. Neurons of the brain fire normally when stimulated, even after long periods of status epilepticus. Citation
last1 = Fisher | first1 = RS
author1-link = Fisher
last2 = Schachter | first2 = SC
author2-link = Schachter
title = The Postictal State: A Neglected Entity in the Management of Epilepsy.
journal = Epilepsy & Behavior
volume = 1
pages = 52-59
year = 2000 ] 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 axon 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. Citation
last1 = Fisher | first1 = RS
author1-link = Fisher
last2 = Schachter | first2 = SC
author2-link = Schachter
title = The Postictal State: A Neglected Entity in the Management of Epilepsy.
journal = Epilepsy & Behavior
volume = 1
pages = 52-59
year = 2000 ]

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 catalepsy. 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. Citation
last1 = Fisher | first1 = RS
author1-link = Fisher
last2 = Schachter | first2 = SC
author2-link = Schachter
title = The Postictal State: A Neglected Entity in the Management of Epilepsy.
journal = Epilepsy & Behavior
volume = 1
pages = 52-59
year = 2000 ] 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. Citation
last1 = Hammers | first1 = A
author1-link = Hammers
last2 = Asselin | first2 = MC
last3 = Hinz | first3 = R
last4 = Kitchen | first4 = I
last5 = Brooks | first5 = DJ
last6 = Duncan | first6 = JS
last7 = Koepp | first7 = MJ
title = Upregulation of opioid receptor binding following spontaneous epileptic seizures
journal = Brain
volume = 130
pages = 1009-1016
year = 2007
url = http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=8270930 ] 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. Citation
last1 = Fisher | first1 = RS
author1-link = Fisher
last2 = Schachter | first2 = SC
author2-link = Schachter
title = The Postictal State: A Neglected Entity in the Management of Epilepsy.
journal = Epilepsy & Behavior
volume = 1
pages = 52-59
year = 2000 ]

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 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). cite book
last = Engel
first = Jerome Jr.
authorlink = Engel
title = Seizures and Epilepsy
publisher = F.A. Davis Company
location = Philadelphia
date = 1989
isbn = 0-8036-3201-0 ]

Leftover inhibitory signals are he 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. Citation
last1 = Fisher | first1 = RS
author1-link = Fisher
last2 = Schachter | first2 = SC
author2-link = Schachter
title = The Postictal State: A Neglected Entity in the Management of Epilepsy.
journal = Epilepsy & Behavior
volume = 1
pages = 52-59
year = 2000 ] 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.” Citation
last1 = Fisher | first1 = RS
author1-link = Fisher
last2 = Schachter | first2 = SC
author2-link = Schachter
title = The Postictal State: A Neglected Entity in the Management of Epilepsy.
journal = Epilepsy & Behavior
volume = 1
pages = 52-59
year = 2000 ] 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 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. Citation
last1 = Hosokawa | first1 = C
author1-link = Hosokawa
last2 = | first2 = Peter
last3 = Borwein | first3 = Jonathan…
title = Regional Cerebral Blood Flow and Glucose Utilization in Spontaneously Epileptic EL Mice
journal = Journal of Nuclear Medicine
volume = 38
pages = 613-616
year = 1997
url = http://jnm.snmjournals.org/cgi/reprint/38/4/613 ] 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.

Treatments

Observing neuropeptide transcription levels during and after seizures provides a window into how the brain responds to seizures. Some neuropeptides (such as galanin, 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 using 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. Citation
last1 = Wilson | first1 = DN
author1-link = Wilson
last2 = Chung | first2 = H
last3 = Elliott | first3 = RC
last4 = Bremer | first4 = E
last5 = George | first5 = D
last6 = Koh | first6 = S
title = Microarray Analysis of Postictal Transcriptional Regulation of Neuropeptide
journal = Journal of Molecular Neuroscience
volume = 25
pages = 285-297
year = 2005
url = http://www.springerlink.com/content/a25512306211217r/ ] 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. cite book
last = Engel
first = Jerome Jr.
authorlink = Engel
title = Seizures and Epilepsy
publisher = F.A. Davis Company
location = Philadelphia
date = 1989
isbn = 0-8036-3201-0 ] Also, administering exogenous TRH, has been shown to improve postictal cognition in humans, as measured with neuropsychological tests. Citation
last1 = Khan | first1 = A
author1-link = Khan (name)
last2 = Mirolo | first2 = MH
last3 = Claypoole | first3 = K
last4 = Bhang | first4 = J
last5 = Cox | first5 = G
last6 = Horita | first6 = A
last7 = Tucker | first1 = G
title = Effects of low-dose TRH on cognitive deficits in the ECT postictal state
journal = American Journal of Psychiatry
volume = 151
issue = 11
pages = 1694-1696
year = 1994
url = http://ajp.psychiatryonline.org/cgi/reprint/151/11/1694 ] 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). cite book
last = Engel
first = Jerome Jr.
authorlink = Engel
title = Seizures and Epilepsy
publisher = F.A. Davis Company
location = Philadelphia
date = 1989
isbn = 0-8036-3201-0 ] 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.

Conclusion

There are few explanations for what could cause the long lasting symptoms of the postictal state, with patients complaining of difficulty thinking clearly and loss of short-term memory function for hours and even days. The cellular and molecular changes hypothesized to take place following a seizure would only have effects lasting for minutes. Todd’s paresis can last for 24 or 48 hours, and reversible neurological defects (typically short term memory) can last for months, suggesting that more permanent changes in neuron structure may take place following seizures. It should be noted that most patients do not display any long term neurological defects following seizures, and seizures are not believed to be damaging to the brain. It is possible in the small fraction of patients that do experience short term memory loss for weeks or months following a seizure, structural changes may take place that are eventually compensated for structurally or functionally, causing symptoms to eventually disappear.

References

1. cite book
last = Engel
first = Jerome Jr.
authorlink = Engel
title = Seizures and Epilepsy
publisher = F.A. Davis Company
location = Philadelphia
date = 1989
isbn = 0-8036-3201-0

2. Citation
last1 = Devinsky | first1 = O
author1-link = Devinsky
title = Postictal Psychosis: Common, Dangerous, and Treatable
journal = Epilepsy Currents
volume = 8
issue = 2
pages = 31-34
year = 2008

3. Citation
last1 = Fisher | first1 = RS
author1-link = Fisher
last2 = Schachter | first2 = SC
author2-link = Schachter
title = The Postictal State: A Neglected Entity in the Management of Epilepsy.
journal = Epilepsy & Behavior
volume = 1
pages = 52-59
year = 2000

4. Citation
last1 = Hammers | first1 = A
author1-link = Hammers
last2 = Asselin | first2 = MC
last3 = Hinz | first3 = R
last4 = Kitchen | first4 = I
last5 = Brooks | first5 = DJ
last6 = Duncan | first6 = JS
last7 = Koepp | first7 = MJ
title = Upregulation of opioid receptor binding following spontaneous epileptic seizures
journal = Brain
volume = 130
pages = 1009-1016
year = 2007
url = http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=8270930

5. Citation
last1 = Hosokawa | first1 = C
author1-link = Hosokawa
last2 = | first2 = Peter
last3 = Borwein | first3 = Jonathan…
title = Regional Cerebral Blood Flow and Glucose Utilization in Spontaneously Epileptic EL Mice
journal = Journal of Nuclear Medicine
volume = 38
pages = 613-616
year = 1997
url = http://jnm.snmjournals.org/cgi/reprint/38/4/613

6. Citation
last1 = Khan | first1 = A
author1-link = Khan (name)
last2 = Mirolo | first2 = MH
last3 = Claypoole | first3 = K
last4 = Bhang | first4 = J
last5 = Cox | first5 = G
last6 = Horita | first6 = A
last7 = Tucker | first1 = G
title = Effects of low-dose TRH on cognitive deficits in the ECT postictal state
journal = American Journal of Psychiatry
volume = 151
issue = 11
pages = 1694-1696
year = 1994
url = http://ajp.psychiatryonline.org/cgi/reprint/151/11/1694

7. Citation
last1 = Wilson | first1 = DN
author1-link = Wilson
last2 = Chung | first2 = H
last3 = Elliott | first3 = RC
last4 = Bremer | first4 = E
last5 = George | first5 = D
last6 = Koh | first6 = S
title = Microarray Analysis of Postictal Transcriptional Regulation of Neuropeptide
journal = Journal of Molecular Neuroscience
volume = 25
pages = 285-297
year = 2005
url = http://www.springerlink.com/content/a25512306211217r/