Seizures and Epilepsy

Disease/ Disorder

A 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.^1,2

Epilepsy is a brain disorder in which there is a chronic underlying CNS disorder resulting in unprovoked, recurring seizures. The International League Against Epilepsy further defines epilepsy as a disease of the brain defined by any of the following: 2 unprovoked seizures greater than 24 hours apart, one unprovoked seizure and a high probability of further seizures over the next 10 years, and/or diagnosis of an epilepsy syndrome.^1,3

As we are unable to cover the expansive breadth of information related to seizures and epilepsy, this text will focus on general recommendations for evaluation and treatment with a focus on provoked seizures due to acquired brain injury.

Etiology

Seizure precipitants include but are not limited to the following:

In the case of unprovoked and provoked seizures, events may be triggered by factors such as fatigue, sleep deprivation, or flickering lights.¹

Epidemiology including risk factors and primary prevention

Epilepsy

According to the World Health Organization 2019 update, there are approximately 50 million people worldwide living with epilepsy: a prevalence of 4 to 10 per 1000 people. Up to 10% of the population will have at least 1 seizure within their lifetime.³ The highest incidence of epilepsy occurs at the extremes of life. Incidence of neonatal seizures is 1-1.2% of live births. In individuals aged 15 to 24, TBI is the leading cause of epilepsy.

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. 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. In critically ill patients with TBI, up to half of reported seizures are subclinical.^4,5

Brain tumor related seizures

Seizures are a common in brain tumor patients. 15-30% of patients may present with seizure as an initial symptom and up to 60% of patients diagnosed with tumor will experience brain tumor related epilepsy. ⁶

Post-stroke seizures

Seizures following a stroke are more likely to occur during the first 24 hours after stroke onset and are more common with hemorrhagic than ischemic etiology. Incidence of early seizure following stroke varies in literature but is estimated to occur in less than 10% of patients with ischemic stroke and approximately 15% of patients with hemorrhagic stroke. Incidence in the literature for late seizures varies significantly, with some studies reporting seizures in up to 2/3 of patients. ^4,7

Post Traumatic Seizure (PTS) and Post Traumatic Epilepsy (PTE)

Seizures can occur at any time following traumatic brain injury and are categorized based on time frame:

Cumulative incidence varies widely; over 50% of TBI survivors may report seizure at some point following injury. Incidence varies by severity and intracranial pathology with the highest noted in penetrating injuries. Need for neurosurgical procedure also increases risk of subsequent seizure. ⁸

Incidence of new onset seizure is highest in the first year after injury. 82% of individuals who develop late posttraumatic seizures do so within the first 2-years post-injury with an incidence of 8% in patients with mild TBI (GCS 13-15)  and 16.8% in patients with severe TBI (GCS 3-8). ⁸

In addition to TBI severity (as based on GCS), loss of consciousness has also been associated with some risk of developing PTS. 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 (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 >24 hours, cerebral contusion, SDH) there is a 10% probability.

Patho-anatomy/physiology

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

Increasing evidence shows a link between epilepsy and psychiatric conditions, especially depression and anxiety. ³

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
• Fatigue
• Mood disorders (e.g., anxiety, depression, adjustment disorders)
• Loss of independence and limitations in participation, including specific work activities and driving.
• Sudden unexpected death in epilepsy (SUDEP)

Side effects of AEDs are common and include blood dyscrasias, osteoporosis, weight gain, negative cognitive impairments, nausea, sedation, and/or ataxia.

Essentials of Assessment

History

A comprehensive history is necessary to confirm seizure activity, characterize the seizure, and 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/postictal behaviors.²

• 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
• To better categorize seizure, information should be gathered on focal versus generalized onset; awareness versus nonaware during episode; motor versus nonmotor manifestations

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.

Physical examination

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: ^2,3

• 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.
• Focal seizures without dyscognitive features (simple partial seizures): person is aware of self and environment during the seizure, even if immobile
• 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.
• Physical exam findings of seizure associated trauma or pathology: evidence of head trauma/healed trauma, tongue/mouth lacerations or bite injuries, meningeal signs, papilledema, etc.

The physical exam should be comprehensive to assist in searching for an underlying cause of seizure, such as infection or a systemic disorder.

Functional assessment

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 studies

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

Imaging

Neuroimaging studies are typically indicated for evaluation of the brain structures. Noncontrast Head CT is recommended in the emergent setting for patients presenting with a seizure to guide appropriate management, especially in those with abnormal neurological examination, predisposing history, or focal seizure onset. ⁹

While CT Head imaging is most sensitive for hemorrhage, Magnetic resonance imaging (MRI) 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 processes.

An epilepsy protocol for the MRI should be performed, which would ideally include the following: ^9–11

• 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. ¹¹

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 non-specific, 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

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.

In post-traumatic epilepsy specifically immediate (within 24 hours post-injury) seizures are considered transient and do not contribute to risk of post-traumatic epilepsy. A seizure occurring after the 24 hour mark following injury increases risk of developing late post-traumatic seizures. ^5,8,12  Prophylactic treatment of seizures may reduce the incidence of early post-traumatic seizures (occurring 24 hours to 7 days post-injury) but has no impact on late seizures (occurring > 1 week following injury) or on mortality following traumatic brain injury.

Environmental

While uncommon (4-7% of all epilepsy diagnoses), seizures can be reflexive and triggered by environmental factors such as loud noises and flashing lights More commonly, environmental stress, sleep deprivation, alcohol, or hormonal fluctuations associated with menstrual cycles can also trigger a seizure.¹³

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.

Professional Issues

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.¹⁴

Rehabilitation Management and Treatments

Available or current treatment guidelines

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. ⁵

Monotherapy is preferred. 10-15% of people need two AEDs to control seizure activity.

First-line antiepileptic drugs include:¹⁵

• Generalized tonic-clonic seizures: Levetiracetam, Valproate, Lamotrigine
• Focal seizures: Carbamazepine, Oxcarbazepine, Lamotrigine, Lacosamide
• Absence seizures: Ethosuximide, Valproate

Status epilepticus: Benzodiazepines are the first line of treatment followed by phenytoin, barbiturates, and propofol. Recent literature supports the use of Levetiracetam and Valproate as well. ¹⁶

Routine follow up of patients on AEDs should include AED serum level, blood counts, albumin level (for phenytoin), and hepatic and renal function monitoring.

Up to one third of patients do not have a response to current AEDs and therapies. ¹⁷Treatment for seizures resistant to AEDs include: Vagal nerve stimulators or surgical procedures¹⁸ such as anteromedial temporal resection, corpus callosotomy, functional hemispherectomy (hemispherotomy), and multiple subpial transection.

The following are recommendations for prophylaxis/treatment of seizures in commonly encountered diagnoses in the rehabilitation setting:

•  TBI:^5,19
  • Patients with severe injury should be placed on seizure prophylaxis for 7 days following injury.
  • Medications options for prophylaxis include Levetiracetam, Phenytoin, and Valproate. Phenytoin has been shown helpful in reducing early but not late seizures after TBI. Levetiracetam is increasingly being used for seizure prophylaxis post trauma due to its favorable side effect profile. ²⁰
  • 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.²¹
  • 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.¹²
• Brain tumors ^6,22
  • Anticonvulsant medications are not proven effective in preventing initial seizures, thus prophylactic use should not be routinely used in patients with newly diagnosed brain tumors. If an AED has been started, taper and discontinue anticonvulsants after the first postoperative week, particularly in those patients who are medically stable and who are experiencing anticonvulsant-related side effects.
  • Anticonvulsant medications are indicated for brain tumor patients who have had at least one seizure. There is no current consensus on length of treatment, though AEDs can be considered for taper once seizure-free for 12-24 months and/or following tumor removal.
• Stroke ^4,7,23
  • Current guidelines from the American heart association, recommend against the use of prophylactic antiseizure medication in both ischemic and hemorrhagic stroke. Despite this, AED use has increased during the acute hospital course likely due to limited large scale randomized controlled trials and concern for increased seizure risk among specific subgroups of hemorrhagic stroke patients, such as those with subarachnoid hemorrhage.

At different disease stages

New onset/acute:

• 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, AED treatment should be initiated.
• Initiate an AED after 2 or more unprovoked seizures.

Chronic/Following Prolonged treatment:

• 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.²¹

Coordination of care

Support patients to participate more actively in managing their 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/unique Interventions

Deep brain stimulation (DBS) is a newer area of study that is useful in treating pharmacologically refractory epilepsy. 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.^24–26 Other deep brain areas, such as the hippocampus, subthalamic nucleus, caudate nucleus, and cerebellum, are being studied as potential DBS targets. ²⁴

Transcranial magnetic stimulation (TMS) is another area being studied for treatment 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 discharges thus improving psychological conditions in patients. Further studies are needed to develop a standard protocol including frequency of dosing.²⁷

Cutting Edge/ Emerging and Unique Concepts and Practice

Trend toward alternative and complimentary medicine including medical marijuana, essential oils, and cannabidiol. Limited literature has suggested benefit especially in refractory seizures or for patients in which titration of AEDs are limited due to adverse effects. However, there is currently paucity of randomized control trials and limited federal regulation. Some compounds have the potential to lower seizure threshold and potentiate seizure, thus routine use for seizure treatment cannot be recommended at this time.^3,28,29

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.³⁰

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.³¹

Other treatment options that are being explored include Synchrotron radiation and lactate dehydrogenase inhibition.^17,32

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. Global initiatives aim to provide more information about prevention as well as novel targets for treatment of epilepsy.

References

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3. Epilepsy: A Public Health Imperative.; 2019. Accessed November 8, 2020. https://www.who.int/mental_health/neurology/epilepsy/report_2019/en/
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9. Bernasconi A, Cendes F, Theodore WH, et al. Recommendations for the use of structural magnetic resonance imaging in the care of patients with epilepsy: A consensus report from the International League Against Epilepsy Neuroimaging Task Force. Epilepsia. 2019;60(6):1054-1068. doi:10.1111/epi.15612
10. Salmenpera TM. Imaging in epilepsy. J Neurol Neurosurg Psychiatry. 2005;76(suppl_3):iii2-iii10. doi:10.1136/jnnp.2005.075135
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21. Randomised study of antiepileptic drug withdrawal in patients in remission. Medical Research Council Antiepileptic Drug Withdrawal Study Group. Lancet Lond Engl. 1991;337(8751):1175-1180.
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26. Fisher R, Salanova V, Witt T, et al. Electrical stimulation of the anterior nucleus of thalamus for treatment of refractory epilepsy: Deep Brain Stimulation of Anterior Thalamus for Epilepsy. Epilepsia. 2010;51(5):899-908. doi:10.1111/j.1528-1167.2010.02536.x
27. Mishra A, Maiti R, Mishra BR, Jena M, Srinivasan A. Effect of Repetitive Transcranial Magnetic Stimulation on Seizure Frequency and Epileptiform Discharges in Drug-Resistant Epilepsy: A Meta-Analysis. J Clin Neurol Seoul Korea. 2020;16(1):9-18. doi:10.3988/jcn.2020.16.1.9
28. Bahr TA, Rodriguez D, Beaumont C, Allred K. The Effects of Various Essential Oils on Epilepsy and Acute Seizure: A Systematic Review. Evid-Based Complement Altern Med ECAM. 2019;2019:6216745. doi:10.1155/2019/6216745
29. Alexis Arzimanoglou, Ulrich Brandl, J Helen Cross, et al. Epilepsy and Cannabidiol: A guide to treatment. Epileptic Disord. 2020;22(1). doi:10.1684/epd.2020.1141
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Original Version of the Topic:

Tamara Zagustin, MD. Seizures and epilepsy. Published 8/7/2012

Previous Revision(s) of the Topic:

Rani Haley Lindberg, Devin Wells MD. Seizures and epilepsy. Published 4/5/2016

Author Disclosures

Rani Haley Lindberg, MD
Nothing to Disclose

Lindsay Mohney, DO
Nothing to Disclose