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| **Laboratory tests:** Physicians may request a blood sample from patients to look into whether they may have a genetic condition, toxin, or infection leading to the onset of the seizures (Mayo Clinic, 2017). The blood test can also help to determine if the seizures are merely a byproduct of another disease, such as diabetes. | **Laboratory tests:** Physicians may request a blood sample from patients to look into whether they may have a genetic condition, toxin, or infection leading to the onset of the seizures (Mayo Clinic, 2017). The blood test can also help to determine if the seizures are merely a byproduct of another disease, such as diabetes. | ||
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| + | ====== The Action Potential ====== | ||
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| + | A quick review of the normal transmission of the action potential aids in understanding the pathophysiology behind ictogenesis, or the production of a seizure. The resting potential in a neuron that is not firing is -70 millivolts (mV). A higher concentration of sodium (Na+) is found outside the cell, and a higher concentration of potassium (K+) is found inside the cell (Stafstrom, 1998). | ||
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| + | Once stimulated, the action potential is an “all-or-none” event. Depolarization occurs as there is an influx of Na+ ions through voltage-gated ion channels (Stafstrom, 1998). The membrane potential at the end of the depolarization stage is +30 mV, at which point K+ ions exit the cell. After repolarization, the membrane reaches a stage of hyperpolarization (Stafstrom, 1998). This stage is dependent of intracellular calcium (Ca2+) levels and is mediated by the action of the Ca2+-dependent K+ channels. These channels regulate the refractory period so that the cell cannot generate another action potential. After the production of one action potential is complete, the cell then enters the refractory period, which restores the normal balance of intracellular and extracellular ions (Stafstrom, 1998). | ||
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| + | ====== Synaptic Transmission ====== | ||
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| + | As action potentials arrive at the end of the axon, the influx of Ca2+ prompts vesicles to release one of two neurotransmitters: glutamate or gamma-amino butyric acid, or GABA. In an inhibitory post-synaptic potential (IPSP), GABA is released into the synapse (Stafstrom, 1998). GABA receptors activate chloride channels. Influx of Cl- ions increases the negative charge of the neuron which results in hyperpolarization, thus inhibiting the passage of the action potential. In an excitatory post-synaptic potential (EPSP), glutamate is released into the synapse (Stafstrom, 1998). Glutamate binds to one of its many receptors on the post-synaptic terminal, which activates another ion channel. Depending on the type of receptor activated, Na+, Mg2+, or Ca2+ may enter the cell and initiate a depolarization event (Stafstrom, 1998). | ||
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| ====== Etiology ====== | ====== Etiology ====== | ||
| - | **ENTER HERE YUMNA** | + | Etiology underlying epilepsy is categorized into three main types: idiopathic, remote symptomatic, and cryptogenic (Berg et al., 1999). |
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| + | Idiopathic epilepsy contributes to 40% of the diagnoses (Engelborghs et al., 2000). Patients show no neurological abnormalities but have a strong genetic predisposition for the disorder (Berg et al., 1999). The most common examples include benign rolandic epilepsy, juvenile myoclonic epilepsy, and childhood absence epilepsy. Underlying genetic bases for idiopathic epilepsy are not very well understood because of the polygenic nature of its inheritance (Engelborghs et al., 2000). Although there is very little literature on humans with absence epilepsy, studies conducted on rat models have demonstrated an autosomal dominant mode of inheritance of one main gene, the WAG/Rij strain, along with significant interactions of a few other genes (Renier & Coenen, 2000). Various replications of this study have been conducted and literature reviews claim that these studies are validated with similar patterns of inheritance seen in patients with absence epilepsy (Coenen & Van Luijtelaar, 2003). Underlying changes in the biochemical microenvironment can also play a role in the etiology of epilepsy. These include increase in glutamate levels, decrease in GABA, and in some cases, blockage of the Na+-K+ pump (Engelborghs et al., 2000). Genetic alterations in T-type calcium channels have been associated with most generalized epilepsy syndromes, including childhood absence epilepsy (Stafstrom & Rho, 2016). | ||
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| + | Remote symptomatic epilepsy is less common and has no known genetic bases. This type of epilepsy is characterized by the presence of a neurological abnormality, a history of brain injury, or comorbidities with other disorders. Patients are diagnosed with symptomatic epilepsy if they have had more than one sporadic, unprovoked seizure (Berg et al., 1999). Symptomatic mechanisms may be caused by a process known as “kindling” (Engelborghs et al., 2000). Kindling refers to the process of permanently decreasing the threshold potential for normal neuronal transmission. This causes the membrane to depolarize at a lower potential charge and may lead to structural and functional changes in glutamatergic synapses (Engelborghs et al., 2000). | ||
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| + | Finally, some types of epilepsy have no known causes or underlying mechanisms and these are known as cryptogenic (Berg et al., 1999). | ||
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| ====== Pathophysiology ====== | ====== Pathophysiology ====== | ||
| - | **ENTER HERE YUMNA** | + | The pathophysiology of epilepsy is characterized by two distinct but related hallmarks: hyperexcitability and hypersynchrony. Hyperexcitability is when a neuron abnormally responds to incoming excitatory stimuli and fires multiple discharges at once instead of just one (Stafstrom, 1998). Hypersynchrony is when a large number of neighboring neurons discharge into one neuron simultaneously. Epilepsy is the result of a combination of both these characteristics (Stafstrom, 1998). |
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| + | The main distinguishing factor of a seizure from a normal depolarization event can be seen in an EEG. Normally, excitation and inhibition are balanced and when neurons are not needed, they are silent (Stafstrom, 1998). Normal brain activity is low-voltage and desynchronized. If neurons start firing discharges at an abnormal rate, this classifies as a paroxysmal depolarization shift (PDS) and can be seen in an EEG as a “spike” of electrical activity. This is known as the interictal state (Stafstrom, 1998). In the ictal state, there is a flood of repeated EEG spikes which may continue for several second and can last up to a few minutes (Stafstrom, 1998). | ||
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| + | ====== Ictogenesis ====== | ||
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| + | Abnormal excitation of neurons may be attributed to a combination of factors. In the axonal membrane, there may be an abnormally large amount of K+ ions outside the cell, which switches around the normal concentration gradient (Stafstrom, 1998). After depolarization, there will be no efflux of K+ and Na+ would remain within the cell. The cell membrane will then remain in a state of depolarization, during which an abnormal number of action potentials will discharge within one large depolarization event (Stafstrom, 1998). This shift in depolarization is what characterizes the PDS, depicted in the EEG as the interictal spike. In some cases, the PDS is followed by a state of “post-PDS hyperpolarization” during which the cell may temporarily hyperpolarize (Stafstrom, 1998). However, if the PDS progresses, it leads to the barrage of synchronized neuronal firing characteristic of the ictal state (Stafstrom, 1998). | ||
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| + | Another factor that characterizes a seizure is when the action potential reaches the end of the axon. Due to the presence of genetically altered T-type calcium, a large number of Ca2+ enters the cell, which induces the release of a large amount of neurotransmitters into the synapse. Epileptic neurons also tend to have chronically elevated Ca2+ levels inside the cell to begin with (Stafstrom & Rho, 2016). This, in combination with the excess of glutamate and low GABA levels, leads to overstimulation and depolarization of a multitude of surrounding neurons (Engelborghs et al., 2000). All components of normal neurotransmission are intricately linked together in a delicate balance of electric potential within the brain. A disruption in any one of these checkpoints can have a devastating domino effect which may lead to the production of an epileptic seizure. | ||
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| + | In childhood absence epilepsy, these events take place in thalamocortical circuitry. Specific pathogenesis of an absence seizure results from the effects of a few abnormalities listed previously (Stafstrom & Rho, 2016). Namely, the T-type Ca2+ channels are altered, so that they are activated by smaller membrane depolarizations. Changes in other subtypes of channels that play a role in normal transmission of potentials in the thalamus are also seen in this type of epilepsy. Other synaptic influences include antagonists of GABA and agonists of glutamate (Stafstrom & Rho, 2016). | ||
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| + | ====== Susceptibility of the Immature Brain ====== | ||
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| + | Seizure incidence is highest in the early years of life and in some cases, especially childhood absence epilepsy, the disorder seems to disappear right after puberty. This is a result of multiple physiological factors that contribute to increased susceptibility (Stafstrom & Rho, 2016). | ||
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| + | - Ion channels that mediate depolarization events usually develop earlier than those that are responsible for repolarization. In conjuncture with this, excitatory neurotransmitters are produced earlier in development than inhibitory neurotransmitters (Stafstrom & Rho, 2016). | ||
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| + | - Early in development, GABA actually induces an excitatory effect rather than an inhibitory effect (Stafstrom & Rho, 2016). | ||
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| + | - There are more synapses found in the immature brain than the mature one. This increases the amount of fast-acting electrical signals to be transmitted that may facilitate the production of seizures (Stafstrom & Rho, 2016). | ||
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| + | These are just some examples that may increase a child’s susceptibility to developing epilepsy. Each of these factors alters the brain’s delicate balance of excitation and inhibition, in the favor of excitation (Stafstrom & Rho, 2016). | ||
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| ====== Prognosis and Prevention ====== | ====== Prognosis and Prevention ====== | ||
| - | **ENTER HERE KRITIKA** | + | Overall, the remission rate for CAE is 80% by early puberty, although these rates vary widely. Approximately, 11-18% of children who have CAE develop tonic-clonic seizures, which begin at puberty. If the child has tonic-clonic seizures as well as absence seizures, these are less likely to go away. However, they are usually easy to control. |
| + | Early treatment to the anti-epileptic drugs may contribute to the permanent disappearance of the seizures. Drugs may be discontinued if a child has been seizure free for two-three years, but early discontinuation may trigger seizures. | ||
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| + | A study conducted by Wirrell et al found that, in a study size of 81 children, forty-seven (65%) were in remission at the time of follow-up, which was 20.4 years on average. 17% of this population were taking AEDs but continued to have seizures, while 13% were taking AEDs and 15% had progressed to juvenile myoclonic epilepsy (JME). This ecidence suggests that when AEDs are taken, chances of remission into adulthood are high. | ||
| + | Of 81 children with CAE, 72 (89%) were contacted for follow-up. Mean age at seizure onset was 5.7 years (range, 1 to 14 years) and at follow-up was 20.4 years (range, 12 to 31 years). Forty-seven (65%) were in remission. Twelve others (17%) were not taking AEDs but continued to have seizures. Thirteen (18%) were taking AEDs; five were seizure-free over the last year (in four of these a trial without AEDs had previously failed). Fifteen percent of the total cohort had progressed to juvenile myoclonic epilepsy (JME). Multiple clinical and EEG factors were examined as predictors of outcome. Factors predicting no remission (p < 0.05) included cognitive difficulties at diagnosis, absence status prior to or during AED treatment, development of generalized tonic clonic or myoclonic seizures after onset of AEDs, abnormal background on initial EEG, and family history of generalized seizures in first-degree relatives. | ||
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| + | Furthermore, in a retrospective analysis of a cohort of 163 patients, 64 of which had CAE, were followed for a duration of 25.8 years. It was found that 58% of patients with CAE were in remission, and had been seizure free for a period of at least two years. | ||
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| - | For patients who refuse pharmacological treatment, a Ketogenic diet, special high fat, low-carbohydrate diet, is available as an alternative regimen to control and manage seizures. **(KRITIKA ADD STUFF HERE)** | + | For patients who refuse pharmacological treatment, a Ketogenic diet, special high fat, low-carbohydrate diet, is available as an alternative regimen to control and manage seizures. The ketogenic diet may prove to be beneficial in comparison to the antiepileptic drugs. Studies find that approximately 50% reduction in the frequency of seizures. In a recent study of 317 Chinese children, 35.0%, 26.2%, and 18.6% children showed >50% seizure reduction at three, six, and 12 months, respectively. Furthermore, in a systematic review conducted by Keene et al, with a total collective population of 972, an average of 15.6% of the patients had become seizure-free at the 6-month mark, and 33.0% had more than 50% reduction in seizure frequency after incorporating the ketogenic diet. |
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| ====== References ====== | ====== References ====== | ||
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| + | Berg, A. T., Shinnar, S., Levy, S. R., & Testa, F. M. (1999). Newly diagnosed epilepsy in children: presentation at diagnosis. Epilepsia, 40(4), 445-452. | ||
| Buchhalter, J. (2011). Treatment of Childhood Absence Epilepsy—An Evidence-Based Answer at Last!. //Epilepsy Currents//, 11(1), 12-15. | Buchhalter, J. (2011). Treatment of Childhood Absence Epilepsy—An Evidence-Based Answer at Last!. //Epilepsy Currents//, 11(1), 12-15. | ||
| + | Coenen, A. M. L., & Van Luijtelaar, E. L. J. M. (2003). Genetic animal models for absence epilepsy: a review of the WAG/Rij strain of rats. Behavior genetics, 33(6), 635-655. | ||
| Crunelli, V., & Leresche, N. (2002). Childhood absence epilepsy: genes, channels, neurons andnetworks. //Nature Reviews Neuroscience//, 3(5), 371-382. | Crunelli, V., & Leresche, N. (2002). Childhood absence epilepsy: genes, channels, neurons andnetworks. //Nature Reviews Neuroscience//, 3(5), 371-382. | ||
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| Donner, E. J. (2010). Absence Seizures. about kid’s health. Retrieved January 24, 2017 from, http://www.aboutkidshealth.ca/En/ResourceCentres/Epilepsy/UnderstandingEpilepsyDia gnosis/TypesofSeizures/Pages/Absence-Seizures.aspx | Donner, E. J. (2010). Absence Seizures. about kid’s health. Retrieved January 24, 2017 from, http://www.aboutkidshealth.ca/En/ResourceCentres/Epilepsy/UnderstandingEpilepsyDia gnosis/TypesofSeizures/Pages/Absence-Seizures.aspx | ||
| + | Engelborghs, S., D’hooge, R., & De Deyn, P. P. (2000). Pathophysiology of epilepsy. Acta neurologica belgica, 100(4), 201-213. | ||
| Epilepsy. (2013, May 31). Mayo Clinic. Retrieved January 21, 2017, from http://www.mayoclinic.org/diseases-conditions/epilepsy/basics/definition/CON-20033721?p=1 | Epilepsy. (2013, May 31). Mayo Clinic. Retrieved January 21, 2017, from http://www.mayoclinic.org/diseases-conditions/epilepsy/basics/definition/CON-20033721?p=1 | ||
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| Pillai, J. & Sperling, M. R. (2006). Interictal EEG and the Diagnosis of Epilepsy. //Epilepsia//. 47 (s1), 14-22. | Pillai, J. & Sperling, M. R. (2006). Interictal EEG and the Diagnosis of Epilepsy. //Epilepsia//. 47 (s1), 14-22. | ||
| + | Renier, W. O., & Coenen, A. M. L. (2000). Human absence epilepsy: the WAG/Rij rat as a model. Neuroscience Research Communications, 26(3), 181-191. | ||
| Sander, J. W. (2003). The epidemiology of epilepsy revisited.// Current opinion in neurology//, 16(2), 165-170. | Sander, J. W. (2003). The epidemiology of epilepsy revisited.// Current opinion in neurology//, 16(2), 165-170. | ||
| + | Stafstrom, C. E. (1998). Back to Basics: The Pathophysiology of Epileptic Seizures: A Primer For Pediatricians. Pediatrics in Review, 19 (10). | ||
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| + | Stafstrom, C. E., Rho, J. M. (2016). Pathophysiology of seizures and epilepsy. URL: https://www.uptodate.com/contents/pathophysiology-of-seizures-and-epilepsy | ||
| What Is Epilepsy? (2014, January). Epilepsy Foundation. Retrieved January 21, 2017, http://www.epilepsy.com/learn/epilepsy-101/what-epilepsy | What Is Epilepsy? (2014, January). Epilepsy Foundation. Retrieved January 21, 2017, http://www.epilepsy.com/learn/epilepsy-101/what-epilepsy | ||
