Partial Seizures☆

Partial Seizures☆ U Uysal, University of Kansas Medical Center, Kansas City, KS, USA ã 2014 Elsevier Inc. All rights reserved.

Introduction Definition Classification Consequences Associated Disorders Etiology Epidemiology Pathophysiology Signs and Symptoms Standard Therapies Animal Models References

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Introduction According to the Glossary of Ictal Semiology (Blume et al., 2001) an epileptic seizure is ‘excessive and/or hypersycnhronous, usually self-limited activity of neurons in the brain’ and a focal seizure is ‘a seizure whose initial activation of only part of one cerebral hemisphere’. Operational (practical) definition published recently as ILAE Official report describes epilepsy as a disease of brain defined by either at least two unprovoked seizures occurring >24 h apart, or one seizure and a high probability (60%) of further seizures over 10 years, or an epilepsy syndrome diagnosis (Fisher et al., 2014).

Definition Partial seizures are those that remain localized in a particular region of the brain. It is possible to have partial seizures that originate from independent seizure foci from multiple lobes and both hemispheres.

Classification According to 1981 ILAE classification partial seizures may be simple or complex. They can have different semiology and present only with motor, somatosensory or special sensory, autonomic orpsychic symptoms. Unlike complex partial seizures, simple partial seizures are not associated with alterations of consciousness. Either simple partial or complex partial seizures can evolve to generalized tonic-clonic convulsions. Especially when they originate from the medial surface of the frontal lobe, partial seizures may spread across the midline through the corpus callosum and become generalized very rapidly. Partial seizures can also be classified by the site of the onset. Thus, temporal lobe seizures originate in the neocortex of the temporal lobe or the amygdala–hippocampus complex (AHC). Extratemporal lobe neocortical seizures originate in the frontal lobe, supplementary sensory-motor cortex, parietal lobe, and occipital lobe. Both temporal lobe and extratemporal lobe seizures can have additional foci in multiple lobes and in both hemispheres (dual pathology). A recent report of the ILAE Commission on Classification and Terminology (Berg et al., 2010) revised the terminology and recommended to eliminate the terms such as complex partial or simple partial seizures but rather to use descriptors of focal seizures according to degree of impairment during seizure. The descriptors can be found in the Glossary of Ictal Semiology (Blume et al., 2001).

Consequences Partial seizures and epilepsy has significant impact on patients physical, psychological and socioeconomic well being. Additionally the standardized mortality rate for patients with epilepsy is 2–5 times higher than the general public and this is number is higher in children. Death can occur from direct epilepsy related causes such as sudden unexpected death in epilepsy (SUDEP), status ☆

Change History: August 2014. U Uysal updated the text and further readings to this entire article.

Reference Module in Biomedical Research

http://dx.doi.org/10.1016/B978-0-12-801238-3.05214-4

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epilepticus, accidents and trauma caused by seizures, medication side effects and suicide or causes related to underlying disorder. In addition, the seizures themselves can render the patient encephalopathic by damaging the brain. The damage results from the large amount of excitotoxins and lactate released in the brain as a result of the seizures. Damage to the brain results in behavioral disorders and decrease or loss of neurological function.

Associated Disorders Patients with partial seizures may have a brain tumor, cerebrovascular disease, vascular malformation of the brain, tuberous sclerosis, infections (abscesses, cycsticercosis), inherited disorders, or multiple sclerosis.

Etiology Head injury, intracranial neoplasms, meningitis, encephalitis, cerebral ischemia, cerebral infarction, gliosis, vascular malformations, and cortical dysplasias are some of the causes for partial seizures. Prolonged and frequent febrile seizures increase the risk of complex partial seizures. Medial temporal lobe sclerosis is a common cause for complex partial seizures. Some of the partial epilepsies may be primarily genetically transmitted, such as benign familial neonatal convulsions, autosomal dominant nocturnal frontal lobe epilepsy or autosomal dominant lateral temporal lobe epilepsy.

Epidemiology The prevalence of epilepsy is 0.5–1% for the general population. The incidence of partial seizures is approximately 15–35 per 100 000 person-year. Most simple partial seizures are associated with other types of seizures and less than 10% of patients have simple partial seizures exclusively.

Pathophysiology Seizures result from synchronization of abnormal rhythmic electrical activity of neurons. Lesions of the brain that disturb the membrane potentials of neuronal membranes make the neurons prone to epileptogenesis. Such lesions include ischemic cortex, blood products in contact with the cortex, gliosis, neuronal cell loss, and increased intracellular and interstitial fluid. Seizure discharges occur when there is synchrony in an adequate number of neurons with abnormal membrane potential. These discharges may produce clinical changes representing the area in which they are generated or they may produce clinical changes representing another area, to which the discharges propagate. Areas with the lowest threshold for electrical stimulation are the limbic areas and the sensory and motor cortex. Similarly, areas of the cortex that have a disproportionately large area of representation in the cortical homunculus are affected first. Mutations in genes that affect the neuronal nicotinic acetylcholine receptor alpha4 and beta2 subunit, K+ channel, voltagegated Na+-channel, and Ca2+ channel have been detected in certain genetic seizures. This suggests involvement of these channels in the pathogenesis of certain types of epilepsy (Hirose et al., 2002).

Signs and Symptoms Complex partial seizures may begin as simple partial seizures. As the seizure progresses, the patient may become less responsive, have decreased awareness of self and surroundings, have decreased ability to communicate, or be totally unable to communicate or have amnesia of the event. They may also have automatism, presenting as quasi-purposeful movements, which are often inappropriate, stereotyped, and repetitive. Tonic and dystonic movement of the limbs may occur contralateral to the seizure focus. This may be accompanied by head or eye turning ipsilateral or contralateral to the seizure focus. Complex partial seizures often last for a few minutes and may become more prolonged, leading to secondary generalization. Once the seizures have subsided, the patients may have decreased awareness, alertness and responsiveness of varying degrees from mild confusion and drowsiness to deep sleep for a while depending on the seizure type. Postictal headache is also a common symptom. Symptoms may vary depending on where the seizures originate. Temporal lobe seizures may begin with a rising epigastric sensation, feeling of deja vu, auditory or visual hallucinations, fear, or a sense of unreality. Patients may then give a stare and have motor or oral automatism and may eventually experience tonic-clonic seizures. Parietal lobe seizures may begin with an abnormal sensation such as tingling or numbness. Those originating from the occipital cortex may have visual hallucinations. Frontal lobe seizures may begin with motor automatisms or stereotyped motor activity and usually have a shorter postictal period. It may also produce tonic and dystonic arm posturing or head or eye turning contralateral to the seizure focus.

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Status epilepticus is a condition where seizure activity lasts longer than 30 min, or there is repeated seizure activity without time for full recovery of consciousness between seizures. Epilepsia partialis continua are continuous focal, simple partial seizures that are almost continuous and last for at least hours or days and occur during wakefulness and sleep. Depending on the etiology and severity of the disorder, patients may have normal neurological examination or have mental retardation, psychological disorders, aphasia, apraxia, hemiparesis, hemi-neglect, hypertonia, or hyper-reflexia.

Standard Therapies There are multiple available antiepileptic medications. Phenytoin, carbamazepine, valproic acid and phenobarbital are drugs marketed before 1990. Newer agents marketed after 1990 are gabapentin, lamotrigine, topiramate, felbamate, oxcarbazepine, tiagabine, zonisamide,lacosamide, rufinamide, tiagabine, clobazam, vigabatrin,levetiracetam, perampanel and eslicarbazepine. Carbamazepine, valproic acid, phanytoin and oxcarbazepine can be used as monotherapy for partial seizures and lamotrigine has monotherapy conversion approval by FDA. The other medications are used as add-on or adjuncts to therapy. Other treatment options are vagal nerve stimulation, deep brain stimulation and responsive neurostimulator (Browne, 1998; Dichter and Brodie, 1996; Mattson, 1998; Pellock, 1998; Porter et al., 2012; Vonck et al., 2012).

Agent name

Discussion

Phenytoin

Phenytoin inhibits the spread of seizure activity in the motor cortex, possibly by promoting the efflux of neuronal sodium, and blocks ‘T’ type channels. It also reduces the activity of brain stem centers responsible for the tonic phase of tonic-clonic seizures. Phosphorylated formulation-fosphenytoin can be administered parenterally. Side effects include death from cardiac arrest if it is administered too rapidly. Cardiac effects include atrial and ventricular conduction depression and ventricular fibrillation. Other side effects include blood dyscrasias, skin rash, and gingival hypertrophy Carbamazepine is effective in treating complex partial seizures. It blocks use-dependent sodium channels, inhibiting sustained repetitive firing, reducing polysynaptic responses, and blocking post-tetanic potentiation. It also reduces sustained high-frequency repetitive neural firing. Some side effects include drowsiness, dizziness, and blurred vision Valproic acid is thought to act by increasing brain levels of GABA and by blocking ‘T’ type channels. Side effects of this drug include thrombocytopenia, hepatotoxicity, and pancreatitis. Valproic acid may also cause tremor, nausea, somnolence, asthenia, and dizziness. It is unsafe in pregnancy Gabapentin is structurally related to GABA, although it does not appear to interact with GABA receptors. Indeed, its primary mode of action is unknown. Side effects include blurred or double vision, dizziness, drowsiness, muscle ache or pain, swelling of extremities, shakiness, and fatigue Lamotrigine stabilizes membrane potentials by inhibiting the release of glutamate and inhibiting voltage-sensitive sodium channels. Its side effects include impaired renal or hepatic functions and severe allergic drug reactions Topiramate promotes antiepileptic activity by decreasing intracortical excitability. It is reported to block sodiumchannels, to act as a gamma-aminobutyric acid type A (GABAA)-receptor agonist, and a non-N-methyl-Daspartate (NMDA)-glutamate receptor antagonist. Side effects include ataxia, drowsiness, psychomotor slowing, nausea, decreased concentration, and speech problems (Reis et al., 2002) Felbamate displays weak inhibitory effects on the GABA receptor and benzodiazepine receptor binding sites. It is also reported to be an antagonist at the glycine recognition site of NMDA receptor-ionophore complex. Its side effects include anorexia, vomiting, headache, nausea, and idiosyncratic reactions in the form of aplastic anemia and hepatotoxicity. It is typically used only when other, less toxic, medications fail to control the seizures Oxcarbazepine impairs neuronal discharges and propagation of discharges by affecting sodium and calcium channels and potassium conductance. Side effects include psychomotor slowing in children and impaired speech, concentration, and language Tiagabine is used as an add-on for complex-partial epilepsy. Its mechanism of action appears to be inhibition of GABA uptake into presynaptic neurons. Tiagabine side effects include generalized weakness Zonisamide is a sulfonamide antiepileptic with sodium and ‘T’ type channel blocking actions. It is a good adjunct therapy for partial, myoclonic, and generalized seizures. Its side effects include weight loss, somnolence, anorexia, and ataxia Levetiracetam acts by modulating inhibitory neurotransmission at GABA and glycine receptor gated currents. It is effective against partial seizures. Side effects include somnolence, leukopenia, incoordination, anxiety, depression, and psychosis Rufinamide approved in 2008 for Lennox-Gestaut Syndrome modulates voltage-dependent neuronal sodium channels, has low protein binding (34%), excreted by kidneys and has no major drug-drug interaction. However in children VPA can increase its level by 40%. It can cause somnolence, vomiting, diarrhea and pyrexia Lacosamide enchances the slow inactivation of voltage-gated sodium channels selectiveley without interfering with fast inactivation. It can cause dizziness, vomiting, diplopia, somnolenece, ataxia and headache

Carbamazepine

Valproic acid

Gabapentin

Lamotrigine Topiramate

Felbamate

Oxcarbazepine

Tiagabine Zonisamide

Levetiracetam

Rufinamide

Lacosamide

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Clobazam

Perampanel

Eslicarbazepine

Surgical treatment: lesionectomy

Surgical treatment: lobectomy Surgical treatment: multiple subpial transection

Surgical treatment: vagal nerve stimulation

Surgical treatment: deep brain stimulation

Clobazam was approved in 2011 for Lennox-Gestaut Syndrome. It is a long-acting benzodiazepine and activates GABAA receptors. It is metabolized in liver by P450 enzyme systems. Side effects include somnolenece, pyrexia, lethargy and drooling Approved by FDA in November 2012 as adjunctive therapy. It has unique mechanism of action and is a non-competitive antagonist of postsynaptic AMPA receptor. Side effects include irritability, hostility, dizziness, fatigue, weight gain and ataxia (French et al., 2012, 2013; Krauss et al., 2012, 2013) Approved in November 2013 as adjunctive therapy for partial onset seizures. Exact mechanism of action is unknown. Side effects include diplopia, dizziness, fatigue, weight gain, blurred vision, vertigo and ataxia (Gil-Nage et al., 2013) When a lesion or lesions can be identified as epileptogenic, surgical excision may be beneficial. Such lesions include tumors, vascular malformations, gliosis, or focal cortical malformation and medial temporal lobe sclerosis. Some of these lesions can be ablated by stereotactic techniques using radiofrequency current or by focus beam radiation (Arunkumar and Morris, 1998) Lobectomy may be performed when the seizure foci involves the neocortex. Temporal lobectomy is the most common of these (Apuzzo, 1991) This surgical procedure prevents synchronization of seizure discharges by interrupting horizontal inter-neuronal fibers in the cerebral cortex. Because vertical fibers and pial vessels are preserved, cortical function remains intact. This procedure can, therefore, be safely performed over the eloquent cortex and can be used as a primary procedure to treat intractable epilepsy (Patil et al., 1997) Vagal nerve stimulation is a new, relatively simple procedure, with minimal serious side effects. With the use of drug therapy, approximately 25% of patients treated with this procedure become seizure free, another 25% have 80% reduction in seizure frequency, another 25% have 50% reduction in seizure frequency, and 25% of the patients do not benefit from this approach This is a very new form of therapy. Only a neocortical implanted responsive neurostimulator received FDA approval recently. It records EEG signals through implanted subdural and/or depth electrodes and delivers responsive stimulation to stop seizure (Morrell, 2011). Other areas being targeted at the present time, include the anterior nucleus of the thalamus, centromedian nucleus of the thalamus,the subthalamic nucleus and temporal lobe. Early studies showed encouraging results but this modalities have not beed approved by FDA yet

Animal Models Limbic kindling is an animal model of temporal lobe epilepsy with a long-last epileptogenic effect (McIntyre et al., 1999). Electrical and chemical kindling can be performed. The alumina gel monkey model is used to study partial epilepsies and for examining the effect of vagal nerve stimulation on seizures (Lockard et al., 1990).

References Apuzzo MLJ (1991) Neurosurgical aspects of epilepsy. Pine Ridge, IL: American Association of Neurological Surgeons. Arunkumar G and Morris H (1998) Epilepsy update: New medical and surgical treatment options. Cleveland Clinic Journal of Medicine 65(10): 527–537. Berg AT, Berkovic SF, Brodie MJ, Buchhalter J, Cross JH, van Emde Boas W, Engel J, French J, Glauser TA, Mathern GW, Moshe´ SL, Nordli D, Plouin P, and Scheffer IE (2010) Revised terminology and concepts for organization of seizures and epilepsies: report of the ILAE Commission on Classification and Terminology, 2005–2009. Epilepsia 51(4): 676–685. Blume WT, Luder HO, Mizrahi E, Tassinari C, van Emde Boas W, and Engel J Jr (2001) Glossary of ictal semiology. Epilepsia 42: 1212–1218. Browne TR (1998) Pharmacokinectics of antiepileptic drugs. Neurology 51(5 Suppl. 4): S2–S7. Dichter MA and Brodie MJ (1996) New antiepileptic drugs. The New England Journal of Medicine 334(24): 1583–1589. Fisher RS, Acevedo C, Arzimanoglou A, Bogacs A, Cross JH, Elger CE, Engel J, et al. (2014) A practical definition of epilepsy. Epilepsia 42: 475–482. French JA, Krauss GL, Biton V, Squillacote D, Yang H, Laurenza A, Kumar D, and Rogawski MA (2012) Adjunctive perampanel for refractory partial-onset seizures: Randomized phase III study 304. Neurology 79(6): 589–596. French JA, Krauss GL, Steinhoff BJ, Squillacote D, Yang H, Kumar D, and Laurenza A (2013) Evaluation of adjunctive perampanel in patients with refractory partial-onset seizures: Results of randomized global phase III study 305. Epilepsia 54(1): 117–125. Gil-Nage A, Elger C, Ben-Menachem E, Hala´sz P, Lopes-Lima J, Gabbai AA, Nunes T, Falca˜o A, Almeida L, and da-Silva PS (2013) Efficacy and safety of eslicarbazepine acetate as add-on treatment in patients with focal-onset seizures: Integrated analysis of pooled data from double-blind phase III clinical studies. Epilepsia 54(1): 98–107. Hirose S, Okada M, Kaneko S, and Mitsudome A (2002) Molecular genetics of human familial epilepsy syndromes. Epilepsia 43(Suppl. 9): 21–25. Krauss GL, Perucca E, Ben-Menachem E, Kwan P, Shih JJ, Squillacote D, Yang H, Gee M, Zhu J, and Laurenza A (2013) Perampanel, a selective, noncompetitive a-amino-3hydroxy-5-methyl-4-isoxazolepropionic acid receptor antagonist, as adjunctive therapy for refractory partial-onset seizures: Interim results from phase III, extension study 307. Epilepsia 54(1): 126–134. Krauss GL, Serratosa JM, Villanueva V, Endziniene M, Hong Z, French J, Yang H, Squillacote D, Edwards HB, Zhu J, and Laurenza A (2012) Randomized phase III study 306: Adjunctive perampanel for refractory partial-onset seizures. Neurology 78(18): 1408–1415. Lockard JS, Congdon WC, and DuCharme LL (1990) Feasibility and safety of vagal stimulation in monkey model. Epilepsia 31(Suppl. 2): S20–S26. Mattson RH (1998) Medical management of epilepsy in adults. Neurology 51(5 Suppl. 4): S15–S20. McIntyre DC, Kelly ME, and Dufresne C (1999) FAST and SLOW amygdala kindling rat strains: Comparison of amygdala, hippocampal piriform and perirhinal cortex kindling. Epilepsy Research 35: 197–209. Morrell MJ (2011) RNS system in epilepsy study group. Responsive cortical stimulation for the treatment of medically intractable partial epilepsy. Neurology 77(13): 1295–1304. Patil A, Andrews R, and Torkelson R (1997) Treatment of intractable seizures with multilobar and BIHEMISPHERIC seizure foci. Surgical Neurology 47: 72–78.

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Pellock JM (1998) Treatment of seizures and epilepsy in children and adolescents. Neurology 51(5 Suppl. 4): S8–S14. Porter RJ, Dhir A, MacDonald RL, and Rogawski MA (2012) Mechanism of action of antiseizure drugs. Handbook of Clinical Neurology 108: 663–681. Reis J, Tergau F, Hamer HM, Muller HH, Knake S, Fritsch B, Oertel WH, and Rosenow F (2002) Topiramate selectively decreases intracortical excitability in human motor cortex. Epilepsia 43: 1149–1156. Vonck K, De Herdt V, Sprengers M, and Ben-Menachem E (2012) Neurostimulation for epilepsy. Handbook of Clinical Neurology 108: 955–970.

Relevant Websites http://www.epilepsy.org.uk/info/types.html (Epilepsy Action website) – This website is the working name for the British Epilepsy Association. The site has many useful descriptions on the various types of partial seizures.