Author(s): Rani Haley Lindberg, Devin Wells MDOriginally published: August 7, 2012 Last updated: April 5, 2016
Seizure is the transient onset of paroxysmal events due to abnormal electrical activity within the brain as a result of excessive or synchronous neuronal activity.1
- Acute symptomatic seizures: seizures resulting from acute central nervous system (CNS) insult including but not limited to metabolic, toxic, structural, infectious, or inflammatory insults.2
- Unprovoked seizures: seizures that occur in the absence of active CNS insult or beyond the time interval estimated for acute seizures.2
- Seizures can be focal (with or without dyscognitive features) or generalized. Generalized seizures include absence, tonic-clonic, atonic, and myotonic seizures.
- Status epilepticus denotes that the seizure is prolonged or immediately recurrent without return of consciousness.
Epilepsy is a brain disorder in which there is a chronic underlying CNS disorder resulting in unprovoked, recurring seizures
Seizure precipitants include but are not limited to the following:
- Traumatic brain injury
- Hypoxic-ischemic events in the brain
- Intracranial hemorrhage
- Infection of the central nervous system
- Metabolic disorder
- Congenital abnormalities of the brain
- Neurodegenerative disorders
- Drug withdrawal or intoxication
- Brain tumors/mass lesions
- Primary or idiopathic epilepsy (unknown cause)
While seizures can be unprovoked, in some cases they may be triggered by factors such as fatigue, sleep deprivation, or flickering lights.
Epidemiology including risk factors and primary prevention
According to the World Health Organization 2015 update, there are approximately 50 million people world-wide who are living with epilepsy: a prevalence of 4 to 10 per 1000 people. Around 5% of the population will have at least 1 seizure within their lifespan.3 Incidence of neonatal seizures is 1-1.2% of live births. Younger children are at a higher risk if they have congenital, genetic, or developmental conditions; in adults, neoplastic, vascular, and degenerative etiologies are more common. The highest incidence of epilepsy occurs at the extremes of life. Men are at higher risk than women for epilepsy.
Focal seizures are the most common seizure type, yet generalized seizures are more common in children. Seizures developing 1 week post-TBI occurs in 14-53% of the moderate to severe TBI survivors. 50% of TBI survivors with penetrating brain injuries develop epilepsy. In individuals aged 15 to 24, TBI is the leading cause of epilepsy.
An impairment of the biochemical processes at the neurotransmitter and ion channel level causes hyperexcitability and neuronal hypersynchrony. Seizures are a result of this abnormal and excessive neuronal activity because of an imbalance between excitatory and inhibitory forces within the brain.
The primary excitatory neurotransmitter in the brain is glutamate, and the primary inhibitory neurotransmitter is gamma-aminobutyric acid (GABA). Antiepileptic drugs (AEDs) facilitate neuronal inhibition and/or reduce excitation.
Disease progression including natural history, disease phases or stages, disease trajectory (clinical features and presentation over time)
Individuals in whom the sole cause of a seizure is a correctable condition, for example a metabolic disturbance without an underlying structural lesion, are rarely at risk for future epilepsy or recurrent seizures in the absence of recurrence of the condition.
The risk of seizure recurrence in someone with an unprovoked or idiopathic initial seizure is estimated to be 30-70% in the first 12 months, depending on seizure type and etiology. Abnormal neurologic exam, postictal paralysis, abnormal electroencephalogram (EEG), and strong family history of seizures increase the risk of seizure recurrence.
Approximately 60-70% of individuals whose seizures are completely controlled can eventually discontinue antiepileptic therapy.
Specific secondary or associated conditions and complications
Consequences and complications associated with seizures and epilepsy include but are not limited to:
- Impairment of consciousness
- Physical injuries during the event
- Anoxic injury to the brain
- Learning disabilities
- Memory loss
- Language deficits
- Impaired self-esteem
- Mood disorders (e.g., anxiety, depression, adjustment disorders)
- Loss of independence and limitations in participation, including specific work activities and driving.
Side effects of AEDs are common and include osteoporosis, weight gain, negative cognitive impairments, nausea, sedation, and/or ataxia.
2. essentials of assessment
A comprehensive history is necessary to confirm seizure activity, to characterize the seizure, and to identify risk factors for seizure. An accurate description of surrounding events, including witness interview, helps identify sources that elicit seizures, the presence of any aura, and ictal and postictal behaviors.
- Aura may include abnormal smell or taste, deja vu feeling, or an intense feeling that a seizure is imminent.
- Patients or witnesses may report: generalized convulsions, repetitive movements, staring spells, visual or auditory disturbances, or dysesthesias
History should also include a comprehensive review of medications, alcohol or drug use/abuse, family history, and thorough medical history, including history of head trauma, stroke, neurodegenerative diseases, and intracranial infections. In patients with confirmed epilepsy, history should assess seizure control and the functional/social impact of seizures.
Differential diagnosis includes but is not limited to transient ischemic attacks, vaso-vagal/syncopal episodes, delirium, migraine headaches, movement disorders, and psychological factors.
A careful neurologic examination in the interictal period, including assessment of cortical function and mental status, is essential. Presence of TBI or other premorbid neurological disorder can mask signs and symptoms of seizure. Thus, observation for subtle clues and symptoms is essential to seizure diagnosis.
The physical manifestation of a seizure is dependent on its classification:
- Generalized tonic-clonic seizures: Abrupt onset with loss of consciousness; generalized muscle rigidity, followed by jerking/twitching movements. Often followed by a postictal phase characterized by deep sleep with deep respirations and gradual awakening accompanied by a headache.
- Focal seizures with dyscognitive features (complex partial seizures): altered consciousness without loss of consciousness often associated with repetitive behaviors or automatisms (lip smacking, snapping fingers, facial grimacing). The postictal phase includes confusion, somnolence, and headaches.
- Absence seizures (typically occurs during childhood): staring spell with impaired consciousness; during is typically 5-10 seconds.
- Subclinical seizures: abnormal electroencephalographic activity without physically symptoms or signs.
The physical exam should be comprehensive to assist in searching for an underlying cause of seizure, such as infection or a systemic disorder.
Depending on the cause and duration of the seizure, there can be subsequent impairments in mobility, self-care, behavior, cognition, mood, self-esteem, learning abilities, and speech/language. In mesial temporal sclerosis, the most commonly diagnosed focal structural abnormality in patients with epilepsy, associated neuropsychiatric impairments may include decreased memory, cognition, depression, anxiety, and psychiatric comorbidities.
Laboratory tests include:
- Comprehensive metabolic panel including sodium, glucose, calcium, magnesium, renal and liver function levels
- Hematology studies
- Toxicology screens
- Serum prolactin level (elevated post seizure, must be drawn within 1 hour of the event)
- Lumbar puncture is indicated if there is suspicion of a central neurologic infectious process
Neuroimaging studies are typically indicated for evaluation of the brain structure. Magnetic resonance imaging (MRI) is preferred over computerized tomography (CT)11, given that it facilitates better identification of structural causes of epilepsy, such as mesial temporal sclerosis, cortical dysplasia, brain tumors, vascular malformations, TBI, cerebral infarction/hemorrhages, and infectious process.
An epilepsy protocol for the MRI should be performed, which would ideally include the following:
- Standard T1-weighted images.
- T2-weighted fast spin-echo sequences.
- Gradient echo (T2) sequences.
- Fluid-attenuated inversion recovery sequences.
- Three-dimensional (3D) volume acquisition sequences with high definition of the gray-white junction; 3D fast spoiled gradient recalled echo acquisition at the steady state.
Functional imaging techniques such as positron emission tomography (PET), single-photon emission computerized tomography (SPECT), functional magnetic resonance imaging (fMRI), and magnetic resonance spectroscopy (MRS) are helpful in localizing/mapping epileptic foci and can aide in surgical management of epilepsy.
Supplemental assessment tools
EEG is an essential diagnostic tool when evaluating seizures. Epileptiform abnormalities usually increase the likelihood that the patient will experience another seizure over the next 2 years. EEG abnormalities can be nonspecific and a normal EEG does not rule out epilepsy. Long-term video EEGs are helpful in recording multiple seizures. Epileptiform discharges are associated with epilepsy, while nonepileptiform abnormalities are nonspecific EEG abnormalities that do not support the diagnosis of epilepsy.
Neuropsychological testing can be used in nonoperative or postoperative epilepsy patients to assess level of cognitive functioning. Results can assist with recommendations for vocational and cognitive rehabilitation.
Early predictions of outcomes
In individuals with TBI resulting in loss of consciousness or amnesia lasting less than thirty minutes (mild injury), there is a 0.5% cumulative five-year probability of seizures. In moderate injury, or loss of consciousness for 30 minutes to 24 hours or skull fracture, there is a 1.2% probability and for severe injuries (loss of consciousness or amnesia >24hours, cerebral contusion, SDH) there is a 10% probability.13
In hospitalized TBI patients with initial GCS of 13 to 15, the 2 year incidence of epilepsy is 8%. For GCS 3 to 8, the 2 year incidence is 16.8%.12
Refractory epilepsy requiring multiple medications is more likely in those with focal seizures due to underlying structural abnormalities, multiple seizure types, or comorbid developmental delays.
Seizures can be triggered by environmental factors such as loud noises and flashing lights.
Environmental safety considerations include avoiding heights/climbing activities, scuba diving, and swimming alone.
Social role and social support system
Seizures and epilepsy can significantly impact functional independence, learning abilities, employability, insurability/financial resources, self-esteem, mood, ability to drive or operate heavy equipment, and vocational skills.
Support systems should provide resources within the home and the community to provide these patients, families, and support network with education, and counseling about seizure triggers, physical and psychosocial consequences of seizures, and coping with seizure/epilepsy diagnosis.
States differ in their requirements for reporting seizure/epilepsy diagnoses to the Office of Driver Services. Physicians should be knowledgeable of their local state law and regulations regarding drivers with an active history of epilepsy.4
3. rehabilitation management and treatments
Available or current treatment guidelines
The following are recommendations for seizure prophylaxis with antiepileptic drugs (AEDs) in patients with TBI:5
- Immediate seizures (within first 24 hours) post-TBI do not require any additional prophylaxis after 7 days.
- Early seizures (between days 1 and 7) post-TBI should be treated for at least 24 months with AEDs, unless there was a casual time-limited intracranial abnormality (hydrocephalus, active hemorrhage, or infectious process). Early seizures are associated with a higher incidence of intracranial bleeding. Incidence of early seizures post-TBI decreases significantly with seizure prophylaxis the first 7 days post-TBI.
- Late seizures (after 7 days) post TBI should be treated for at least 24 months.
- Any seizure post-TBI that is considered status epilepticus, requires treatment with AEDs for at least 12-24 months.6
- Individuals with frequent seizures during the first year post-trauma are less likely to have seizure remission.7
Recommendations for seizure prophylaxis for newly diagnosed brain tumors:8
- Anticonvulsant medications are not proven effective in preventing initial seizures. Because of a lack of efficacy and potential side effects, prophylactic anticonvulsants should not be routinely used in patients with newly diagnosed brain tumors.
- In patients with brain tumors who have not had a seizure, tapering and discontinuing anticonvulsants after the first postoperative week is appropriate, particularly in those patients who are medically stable and who are experiencing anticonvulsant-related side effects.
At different disease stages
- Initial seizure: Treat acute underlying cause (metabolic derangements, alcohol and drug withdrawal, intracranial hemorrhages, infectious process, hypoxic events, drug toxicity). If there is strong evidence of an epileptogenic focus, then AED treatment should be initiated.
- Initiate an AED after 2 or more unprovoked seizures.
- Choice of AED should take into consideration drug effectiveness for the seizure type, potential adverse effects including neurological/cognitive impairments, medication interactions, comorbid medical conditions, age and sex (pregnancy risk), lifestyle, cost, and patient preferences.
- Monotherapy is preferred. 10-15%of people need two AEDs to control seizure activity. Up to 80% of patients can become seizure free on AED treatment.
- First-line antiepileptic drugs include:
- Generalized tonic-clonic seizures: valproic acid or lamotrigine
- Focal seizures: carbamazepine, lamotrigine, or phenytoin
- Absence seizures: valproic acid or ethosuximide for absence seizures
- Routine follow up of patients on AEDs should include AED serum level, blood counts, albumin level (for phenytoin), and hepatic and renal function monitoring.
- After a seizure-free period of 2-4 years, it is reasonable to consider discontinuation of AEDs. Tapering should be performed slowly; there is no well-defined accepted tapering schedule. It should be done over a 2-3 month period at minimum.
- Treatment for seizures resistant to AEDs include: Vagal nerve stimulators or surgical procedures9 such as anteromedial temporal resection, corpus callosotomy, functional hemispherectomy (hemispherotomy), and multiple subpial transection.
- Status epilepticus: Benzodiazepines are the first line of treatment followed by phenytoin, barbiturates, and propofol.
Coordination of care
Medical care should be coordinated with measures to address psychosocial consequences. Treatment team should include primary care physician, neurologist, physiatrist, neurosurgeon, psychiatry/psychology, physical therapy, occupation therapy, speech therapy, and vocational therapist.
Emerging and unique interventions include transcranial magnetic stimulation and deep brain stimulation and are discussed below.
4. cutting edge/emerging and unique concepts and practice
Cutting edge concepts and practice
Up to one third of patients do not have a response to current AED’s and therapies. 19
Clobazam is a benzodiazepine which is used for treatment of various types of epilepsy, though only approved for Lennox-Gastuat syndrome in the United States. It has less sedating effects that other benzodiazepines and has high safety profile and efficacy in refractory epilepsy. 17
Deep brain stimulation (DBS) is a newer area of study that is useful in treating pharmacologically refractory epilepsy.10 Stimulation of the anterior nuclei of the thalamus (ANT) has been shown to be useful in adjunctive treatment of refractory epilepsy; the FDA approved DBS in the ANT as treatment for severe and refractory partial-onset seizures. Other deep brain areas, such as the subthalamic nucleus, caudate nucleus, cerebellum, are being studies as it relates to DBS. More well-controlled, larger studies are needed for other deep brain structures.
Transcranial magnetic stimulation (TMS) is another area being studies for improvement in refractory cases of epilepsy. Low-frequency high intensity repetitive TMS has a significant antiepileptic effect when delivered to epileptogenic areas of the brain and can also reduce interictal epileptic discharge improving psychological conditions in patients.15
Responsive neurostimulator (RNS) is a device that when implanted in the cortical or subcortical epileptogenic areas of the brain detects abnormal activity and delivers electrical stimulation to inhibit seizures prior to the onset of symptoms. Clinical trials are ongoing currently, but data supports the RNS device as a therapy option for refractory partial seizures.16
Other treatment options that are being explored include Synchrotron radiation and lactate dehydrogenase inhibition.18,19
5. gaps in the evidence-based knowledge
Gaps in the evidence-based knowledge
Although there are multiple resources providing recommendations regarding prophylaxis for seizures/epilepsy in high risk populations such as patients with CNS pathology, there are limited references providing a consensus to develop evidence-based guidelines for prevention and treatment.
- Fisher RS, van Emde Boas W, Blume W, et al. Epileptic seizures and epilepsy: definitions proposed by the International League Against Epilepsy (ILAE) and the International Bureau for Epilepsy (IBE). Epilepsia. 2005 Apr. 46(4):470-2.
- Beghi E, Carpio A, Forsgren L, et al. Recommendation for a definition of acute symptomatic seizure. Epilepsia. 2010;51:671-675.
- Moran NF, Poole K, Bell G, et al. Epilepsy in the United Kingdom: seizure frequency and severity, anti-epileptic drug utilization and impact on life in 1652 people with epilepsy. Seizure. 2004;13:425-433.
- Shareef YS, McKinnon JH, Gauthier SM, Noe KH, Sirven JI, Drazkowski JF. Counseling for driving restrictions in epilepsy and other causes of temporary impairment of consciousness: how are we doing? Epilepsy Behav. 2009;14:550-552.
- Temkin NR. Risk factors for posttraumatic seizures in adults. Epilepsia. 2003;44 Suppl 10:18-20.
- Christensen J, Pedersen MG, Pedersen CB, Sidenius P, Olsen J, Vestergaard M. Long-term risk of epilepsy after traumatic brain injury in children and young adults: a population-based cohort study. Lancet. 2009;373:1105-1110.
- Emanuelson I, Uvebrant P. Occurence of epilepsy during first 10 years after traumatic brain injury acquired in childhood up to the age of 18 years in the south western Swedish population-based series. Brain Inj. 2009;23:612-616.1. 64p.
- Kerrigan S, Grant R. Antiepileptic drugs for treating seizures in adults with brain tumors. Cochrane Database Syst Rev. 2011 Aug 10;(8):CD008586.
- Wyllie E, Comair YG, Kotagal P, Bulacio J, Bingaman W, Ruggieri P. Seizure outcome after epilepsy surgery in children and adolescents. Ann Neurol. 1998;44:740-748.
- Wakerley B, Schweder P, Green A, Aziz T. Possible seizure suppression via deep brain stimulation of the thalamic ventralis oralis posterior nucleus. J Clin Neurosci. 2011;18:972-973.
- Salmenpera TM, Duncan JS. Imaging in epilepsy. Journal of Neurol Neurosurg Psychiatry. 2005(76): iii2-iii10.
- EnglanderJ, Bushnik T, et al. Analyzing risk factors for late posttraumatic seizures: a prospective, multicenter investigation. Arch Phys Med Rehabil. 2003; 84 (3): 365
- Annegers JF, Hauser WA, et al. A population-based study of seizures after traumatic brain injuries. N Engl J Med. 1998;338 (1): 20
- SANTE Trial of Deep Brain Stimulation in Epilepsy Published; FDA Panel Recommends Approval in Close Vote. Medscape. Mar 19, 2010
- Sun W, Mao W, et al. Low-frequency repetitive transcranial magnetic stimulation for the treatment of refractory partial epilepsy: A controlled clinical Study. Epilepsia 2012; 53: 1782-1789
- Bergey G, Morrell M, et al. Long-term treatment with responsive brain stimulation in adults with refractory partial seizures. Neurology. 2015; 84: 810-817
- Gauthier A, Mattson R. Clobazan: A safe, efficacious, and newly rediscovered therapeutic for epilepsy. CNS Neuroscience & Therapeutics; 2015; 21: 543-548.
- Romanelli P, Bravin A, et al. New radiosurgical paradigms to treat epilepsy using synchrotron radiation. Epilepsy Toward the Next Decade. 2014; 231-236
- Rho J, Inhibition of Lactate Dehydrogenase to Treat Epilepsy. N Engl J Med. 2015; 373:187-189
- Sada N, Lee S, Katsu T, Otsuki T, Inoue T. Epilepsy treatment: targeting LDH enzymes with a stiripentol analog to treat epilepsy. Science 2015;347:1362-1367