3321 Seizures and Epilepsy CHAPTER 425

medication, and clearly understands the potential risks and benefits.

In most cases, it is preferable to reduce the dose of the drug gradually over 2–3 months. Most recurrences occur in the first 3 months

after discontinuing therapy, and patients should be advised to avoid

potentially dangerous situations such as driving or swimming during this period. Up to 20% of seizure-free patients who discontinue

antiseizure medications but then have a recurrent seizure may not

regain full control when these medications are resumed.

TREATMENT OF REFRACTORY EPILEPSY

Approximately one-third of patients with epilepsy do not respond

to treatment with a single antiseizure drug, and it becomes necessary to try a combination of drugs to control seizures. Patients

who have focal epilepsy related to an underlying structural lesion

or those with multiple seizure types and developmental delay are

particularly likely to require multiple drugs. There are currently no

clear guidelines for rational polypharmacy, although in theory, a

combination of drugs with different mechanisms of action may be

most useful. In most cases, the initial combination therapy combines first-line drugs (i.e., carbamazepine, oxcarbazepine, lamotrigine, valproic acid, levetiracetam, and phenytoin). If these drugs are

unsuccessful, then the addition of other drugs such as zonisamide,

brivaracetam, topiramate, lacosamide, or tiagabine is indicated.

Patients with myoclonic seizures resistant to valproic acid may benefit from the addition of levetiracetam, zonisamide, clonazepam, or

clobazam, and those with absence seizures may respond to a combination of valproic acid and ethosuximide. The same principles concerning the monitoring of therapeutic response, toxicity, and serum

levels for monotherapy apply to polypharmacy, and potential drug

interactions need to be recognized. If there is no improvement, a

third drug can be added while the first two are maintained. If there

is a response, the less effective or less well tolerated of the first two

drugs should be gradually withdrawn.

SURGICAL TREATMENT OF REFRACTORY EPILEPSY

Approximately 20–30% of patients with epilepsy continue to have

seizures despite efforts to find an effective combination of antiseizure drugs. For some patients with focal epilepsy, surgery can be

extremely effective in substantially reducing seizure frequency and

even providing complete seizure control. Understanding the potential

value of surgery is especially important when a patient’s seizures are

not controlled with initial treatment, as such patients often do not

respond to subsequent medication trials. Rather than submitting the

patient to years of unsuccessful medical therapy and the psychosocial

trauma and increased mortality associated with ongoing seizures, the

patient should have an efficient but relatively brief attempt at medical

therapy and then be referred for surgical evaluation.

The most common surgical procedure for patients with temporal

lobe epilepsy involves resection of the anteromedial temporal lobe

(temporal lobectomy) or a more limited removal of the underlying

hippocampus and amygdala (amygdalohippocampectomy). Focal

seizures arising from extratemporal regions may be abolished by

a focal neocortical resection with precise removal of an identified

lesion (lesionectomy). Localized neocortical resection without a clear

lesion identified on MRI is also possible when other tests (e.g., MEG,

PET, SPECT) implicate a focal cortical region as a seizure onset

zone. When the cortical region cannot be removed, multiple subpial

transection, which disrupts intracortical connections, is sometimes

used to prevent seizure spread. Hemispherectomy or multilobar

resection is useful for some patients with severe seizures due to hemispheric abnormalities such as hemimegalencephaly or other dysplastic abnormalities, and corpus callosotomy has been shown to be

effective for disabling tonic or atonic seizures, usually when they are

part of a mixed-seizure syndrome (e.g., Lennox-Gastaut syndrome).

Presurgical evaluation is designed to identify the functional

and structural basis of the patient’s seizure disorder. Inpatient

video-EEG monitoring is used to define the anatomic location of

the seizure focus and to correlate the abnormal electrophysiologic

activity with behavioral manifestations of the seizure. Routine scalp

or scalp-sphenoidal recordings and a high-resolution MRI scan

are usually sufficient for localization of the epileptogenic focus,

especially when the findings are concordant. Functional imaging

studies such as SPECT, PET, and MEG are adjunctive tests that may

help to reveal or verify the localization of an apparent epileptogenic

region. Once the presumed location of the seizure onset is identified, additional studies, including neuropsychological testing, the

intracarotid amobarbital test (Wada test), and functional MRI may

be used to assess language and memory localization and to determine the possible functional consequences of surgical removal of the

epileptogenic region. In some cases, standard noninvasive evaluation

is not sufficient to localize the seizure onset zone, and invasive electrophysiologic monitoring, such as implanted depth or subdural electrodes, is required for more definitive localization. The exact extent of

the resection to be undertaken can also be determined by performing

cortical mapping at the time of the surgical procedure, allowing for

a tailored resection. This involves electrocorticographic recordings

made with electrodes on the surface of the brain to identify the extent

of epileptiform disturbances. If the region to be resected is within

or near brain regions suspected of having sensorimotor or language

function, electrical cortical stimulation mapping is performed on

the awake patient to determine the function of cortical regions in

question in order to avoid resection of so-called eloquent cortex and

thereby minimize postsurgical deficits.

Advances in presurgical evaluation and microsurgical techniques

have led to a steady increase in the success of epilepsy surgery. Clinically significant complications of surgery are <5%, and the use of

functional mapping procedures has markedly reduced the neurologic

sequelae due to removal or sectioning of brain tissue. For example,

~70% of well-selected patients treated with temporal lobectomy will

become seizure free, and another 15–25% will have at least a 90%

reduction in seizure frequency. Marked improvement is also usually seen in patients treated with hemispherectomy for catastrophic

seizure disorders due to large hemispheric abnormalities. Postoperatively, patients generally need to remain on antiseizure drug therapy,

but the marked reduction of seizures following resective surgery can

have a very beneficial effect on quality of life. Recently, catheter-based

stereotactic laser thermal ablation has been developed as a less invasive means for destroying the seizure focus in select patients.

Not all medically refractory patients are suitable candidates for

resective surgery or laser ablation. For example, some patients have

seizures arising from more than one brain region or from a single

“eloquent” region that mediates a critical function (e.g., vision,

movement, language), such that the potential harm from removal

is unacceptably high. In these patients, implanted neurostimulation

devices that deliver electrical energy to the brain to reduce seizures

represent palliative treatment options. Vagus nerve stimulation

(VNS) involves an extracranial device that works through scheduled intermittent (“open loop”) stimulation of the left vagus nerve.

Efficacy of VNS is limited, and side effects related to recurrent

laryngeal nerve activation (e.g., hoarseness, throat pain, dyspnea) can be significant and dose-limiting. By contrast, responsive

neurostimulation (RNS) involves an implanted device connected

to two lead wires that are placed intracranially at the site(s) from

where seizures arise. The neurostimulator detects the onset of a

seizure (often before the seizure becomes clinically apparent) and

delivers electrical stimulation—typically imperceptible—directly

to the brain to reduce seizures over time, a form of “closed loop”

neurostimulation. RNS is the only device that provides chronic

EEG, which has a growing number of clinical applications, such as

quantifying the lateralization of seizures arising from both sides of

the brain, characterizing clinical spells, assessing effects of medications and other therapeutic interventions, and revealing cyclical

patterns of epileptic brain activity that may help anticipate future

events. A third modality, thalamic deep brain stimulation (DBS),

involves open loop stimulation of deep, bilateral cerebral structures,

the anterior thalamic nuclei, which are key nodes in limbic circuits

mediating certain types of seizures. Whereas precise seizure localization is necessary for RNS, it is not required for VNS or DBS.

3322 PART 13 Neurologic Disorders

Long-term clinical trials of all three neurostimulation devices

demonstrate significant reductions in frequency with outcomes

improving over time, but only a minority of patients treated with

these devices achieve seizure freedom (e.g., ~15% with RNS). Furthermore, no head-to-head device trials exist to establish relative

superiority, so choice of a device is guided by patient-specific factors and by the strengths and limitations of each technology.

■ STATUS EPILEPTICUS

Status epilepticus refers to continuous seizures or repetitive, discrete

seizures with impaired consciousness in the interictal period. Status epilepticus has numerous subtypes, including generalized convulsive status

epilepticus (GCSE) (e.g., persistent, generalized electrographic seizures,

coma, and tonic-clonic movements) and nonconvulsive status epilepticus (e.g., persistent absence seizures or focal seizures with confusion or

partially impaired consciousness, and minimal motor abnormalities).

The duration of seizure activity sufficient to meet the definition of status

epilepticus has traditionally been specified as 15–30 min. However, a

more practical definition is to consider status epilepticus as a situation in

which the duration of seizures prompts the acute use of anticonvulsant

therapy. For GCSE, this is typically when seizures last beyond 5 min.

GCSE is an emergency and must be treated immediately, because

cardiorespiratory dysfunction, hyperthermia, and metabolic derangements can develop as a consequence of prolonged seizures, and these

can lead to irreversible neuronal injury. Furthermore, CNS injury can

occur even when the patient is paralyzed with neuromuscular blockade but continues to have electrographic seizures. The most common

causes of GCSE are anticonvulsant withdrawal or noncompliance,

metabolic disturbances, drug toxicity, CNS infection, CNS tumors,

refractory epilepsy, and head trauma.

GCSE is obvious when the patient is having overt seizures. However, after 30–45 min of uninterrupted seizures, the signs may become

increasingly subtle. Patients may have mild clonic movements of only the

fingers or fine, rapid movements of the eyes. There may be paroxysmal

episodes of tachycardia, hypertension, and pupillary dilation. In such

cases, the EEG may be the only method of establishing the diagnosis.

Thus, if the patient stops having overt seizures, yet remains comatose,

an EEG should be performed to rule out ongoing status epilepticus. This

is obviously also essential when a patient with GCSE has been paralyzed

with neuromuscular blockade in the process of protecting the airway.

The first steps in the management of a patient in GCSE are to attend

to any acute cardiorespiratory problems or hyperthermia, perform a

brief medical and neurologic examination, establish venous access,

and send samples for laboratory studies to identify metabolic abnormalities. Anticonvulsant therapy should then begin without delay; a

treatment approach is shown in Fig. 425-5.

The treatment of nonconvulsive status epilepticus is thought to be

less urgent than GCSE, because the ongoing seizures are not accompanied by the severe metabolic disturbances seen with GCSE. However,

evidence suggests that nonconvulsive status epilepticus, especially that

caused by ongoing, focal seizure activity, is associated with cellular

injury in the region of the seizure focus; therefore, this condition

should be treated as promptly as possible using the general approach

described for GCSE.

BEYOND SEIZURES: OTHER

MANAGEMENT ISSUES

■ EPILEPSY COMORBIDITIES

The adverse effects of epilepsy often go beyond clinical seizures. Many

people with epilepsy feel completely normal between seizures and live

Other approaches

Surgery, VNS, RNS, rTMS,

ECT, hypothermia

Other anesthetics

Isoflurane, desflurane,

ketamine

IV MDZ 0.2 mg/kg → 0.2–0.6 mg/kg/h

and/or

IV PRO 2 mg/kg → 2–10 mg/kg/h

Focal-complex,

myoclonic or

absence SE

Generalized

convulsive or

“subtle” SE

Impending and early SE

(5–30 min)

Established and

early refractory SE

(30 min to 48 h)

Late refractory SE

(>48 h)

Further IV/PO antiseizure drug

VPA, LEV, LCM, TPM, PGB, or other

Other medications

Lidocaine, verapamil,

magnesium, ketogenic diet,

immunomodulation

IV antiseizure drug

PHT 20 mg/kg, or VPA 20–30 mg/kg,

or

LEV 20–30 mg/kg

IV benzodiazepine

LZP 0.1 mg/kg, or MDZ 0.2 mg/kg,

or

CLZ 0.015 mg/kg

PTB (THP)

5 mg/kg (1 mg/kg) → 1–5 mg/kg/h

FIGURE 425-5 Pharmacologic treatment of generalized tonic-clonic status epilepticus (SE) in adults. CLZ, clonazepam; ECT, electroconvulsive therapy; LCM,

lacosamide; LEV, levetiracetam; LZP, lorazepam; MDZ, midazolam; PGB, pregabalin; PHT, phenytoin or fosphenytoin; PRO, propofol; PTB, pentobarbital; RNS, responsive

neurostimulation; rTMS, repetitive transcranial magnetic stimulation; THP, thiopental; TPM, topiramate; VNS, vagus nerve stimulation; VPA, valproic acid. (Data from AO

Rossetti, DH Lowenstein: Management of refractory status epilepticus in adults: still more questions than answers. Lancet Neurol 10:922, 2011.)

3323 Seizures and Epilepsy CHAPTER 425

highly successful and productive lives. However, a significant proportion

of patients suffer from varying degrees of cognitive dysfunction, including psychiatric disease, and it has become increasingly clear that the

network dysfunction underlying epilepsy can have effects well beyond

the occurrence of seizures. For example, patients with seizures secondary to developmental abnormalities or acquired brain injury may have

impaired cognitive function and other neurologic deficits due to abnormal brain structure. Frequent interictal EEG abnormalities are associated

with subtle dysfunction of memory and attention. Patients with many

seizures, especially those emanating from the temporal lobe, often note

an impairment of short-term memory that may progress over time.

The psychiatric problems associated with epilepsy include depression, anxiety, and psychosis. This risk varies considerably depending

on many factors, including the etiology, frequency, and severity of

seizures and the patient’s age and previous personal or family history

of psychiatric disorder. Depression occurs in ~20% of patients, and the

incidence of suicide is higher in people with epilepsy than in the general population. Depression should be treated through counseling and/

or medication. The selective serotonin reuptake inhibitors (SSRIs) typically have minimal effect on seizures, whereas tricyclic antidepressants

may lower the seizure threshold. Anxiety can be a seizure symptom,

and anxious or psychotic behavior can occur during a postictal delirium. Postictal psychosis is a rare phenomenon that typically occurs

after a period of increased seizure frequency. There is usually a brief

lucid interval lasting up to a week, followed by days to weeks of agitated, psychotic behavior. The psychosis usually resolves spontaneously

but frequently will require short-term treatment with antipsychotic or

anxiolytic medications.

■ MORTALITY OF EPILEPSY

People with epilepsy have a risk of death that is roughly two to three

times greater than expected in a matched population without epilepsy.

Most of the increased mortality is due to the underlying etiology of

epilepsy (e.g., tumors or strokes in older adults). However, a significant number of patients die from accidents, status epilepticus, and a

syndrome known as sudden unexpected death in epilepsy (SUDEP),

which usually affects young people with convulsive seizures and tends

to occur at night. The cause of SUDEP is unknown; it may result from

brainstem-mediated effects of seizures on pulmonary, cardiac, and

arousal functions. Recent studies suggest that, in some cases, a genetic

mutation may be the cause of both epilepsy and a cardiac conduction

defect that gives rise to sudden death.

■ PSYCHOSOCIAL ISSUES

There continues to be a cultural stigma about epilepsy, although it is

slowly declining in societies with effective health education programs.

Many people with epilepsy harbor fear of progressive cognitive decline

or dying during a seizure. These issues need to be carefully addressed

by educating the patient about epilepsy and by ensuring that family

members, teachers, fellow employees, and other associates are equally

well informed. A useful source of educational material is the website

www.epilepsy.com.

■ EMPLOYMENT, DRIVING, AND OTHER ACTIVITIES

Many patients with epilepsy face difficulty in obtaining or maintaining

employment, even when their seizures are well controlled. Federal and

state legislation is designed to prevent employers from discriminating

against people with epilepsy, and patients should be encouraged to

understand and claim their legal rights. Patients in these circumstances

also benefit greatly from the assistance of health providers who act as

strong patient advocates.

Loss of driving privileges is one of the most disruptive social consequences of epilepsy. Physicians should be very clear about local

regulations concerning driving and epilepsy, because the laws vary

considerably among states and countries. In all cases, it is the physician’s responsibility to warn patients of the danger imposed on themselves and others while driving if their seizures are uncontrolled (unless

the seizures are not associated with impairment of consciousness or

motor control). In general, most states allow patients to drive after a

seizure-free interval (on or off medications) of between 3 months and

2 years.

Patients with incompletely controlled seizures must also contend

with the risk of being in other situations where an impairment of consciousness or loss of motor control could lead to major injury or death.

Thus, depending on the type and frequency of seizures, many patients

need to be instructed to avoid working at heights or with machinery or

to have someone close by for activities such as bathing and swimming.

SPECIAL ISSUES RELATED TO WOMEN

AND EPILEPSY

■ CATAMENIAL EPILEPSY

Some women experience a marked increase in seizure frequency

around the time of menses. This is believed to be mediated by either

the effects of estrogen and progesterone on neuronal excitability or

changes in antiseizure drug levels due to altered protein binding or

metabolism. Some women with epilepsy may benefit from increases

in antiseizure drug dosages during menses. Natural progestins or

intramuscular medroxyprogesterone may be of benefit to a subset of

women.

■ PREGNANCY

Most women with epilepsy who become pregnant will have an uncomplicated gestation and deliver a normal baby. However, epilepsy poses

some important risks to a pregnancy. Seizure frequency during pregnancy will remain unchanged in ~50% of women, increase in ~30%,

and decrease in ~20%. Changes in seizure frequency are attributed to

endocrine effects on the CNS, variations in antiseizure drug pharmacokinetics (such as acceleration of hepatic drug metabolism or effects

on plasma protein binding), and changes in medication compliance.

It is useful to see patients at frequent intervals during pregnancy and

monitor serum antiseizure drug levels. Measurement of the unbound

drug concentrations may be useful if there is an increase in seizure

frequency or worsening of side effects of antiseizure drugs.

The overall incidence of fetal abnormalities in children born to

mothers with epilepsy is 5–6%, compared to 2–3% in healthy women.

Part of the higher incidence is due to teratogenic effects of antiseizure

drugs, and the risk increases with the number of medications used

(e.g., 10–20% risk of malformations with three drugs) and possibly

with higher doses. A meta-analysis of published pregnancy registries

and cohorts found that the most common malformations were defects

in the cardiovascular and musculoskeletal system (1.4–1.8%). Valproic

acid is strongly associated with an increased risk of adverse fetal outcomes (7–20%). Findings from a large pregnancy registry suggest that,

other than topiramate, the newer antiseizure drugs are far safer than

valproic acid.

Because the potential harm of uncontrolled convulsive seizures on

the mother and fetus is considered greater than the teratogenic effects

of antiseizure drugs, it is currently recommended that pregnant women

be maintained on effective drug therapy. When possible, it seems

prudent to have the patient on monotherapy at the lowest effective

dose, especially during the first trimester. For some women, however,

the type and frequency of their seizures may allow for them to safely

wean off antiseizure drugs prior to conception. Patients should also

take folate (1–4 mg/d), because the antifolate effects of anticonvulsants

are thought to play a role in the development of neural tube defects,

although the benefits of this treatment remain unproved in this setting.

Enzyme-inducing drugs such as phenytoin, carbamazepine, oxcarbazepine, topiramate, phenobarbital, and primidone cause a transient

and reversible deficiency of vitamin K–dependent clotting factors in

~50% of newborn infants. Although neonatal hemorrhage is uncommon, the mother should be treated with oral vitamin K (20 mg/d,

phylloquinone) in the last 2 weeks of pregnancy, and the infant should

receive intramuscular vitamin K (1 mg) at birth.

■ CONTRACEPTION

Special care should be taken when prescribing antiseizure medications

for women who are taking oral contraceptive agents. Drugs such as

3324 PART 13 Neurologic Disorders

Cerebrovascular diseases include some of the most common and devastating disorders: ischemic stroke and hemorrhagic stroke. Stroke is

the second leading cause of death worldwide, with 6.2 million dying

from stroke in 2015, an increase of 830,000 since the year 2000. In

2016, the lifetime global risk of stroke from age 25 years onward was

25%, an increase of 8.9% from 1990. Nearly 7 million Americans age

20 or older report having had a stroke, and the prevalence is estimated

to rise by 3.4 million adults in the next decade, representing 4% of the

entire adult population. Conversely, case-specific disability-adjusted

life-years due to stroke are falling, likely due to better prevention and

treatment, but overall disease burden will continue to climb as the population ages, and stroke is likely to remain the second most common

disabling condition in individuals aged 50 or older worldwide.

A stroke, or cerebrovascular accident, is defined as an abrupt onset

of a neurologic deficit that is attributable to a focal vascular cause.

Thus, the definition of stroke is clinical, and laboratory studies including brain imaging are used to support the diagnosis. The clinical manifestations of stroke are highly variable because of the complex anatomy

of the brain and its vasculature. Cerebral ischemia is caused by a reduction in blood flow that lasts longer than several seconds. Neurologic

symptoms are manifest within seconds because neurons lack glycogen,

so energy failure is rapid. If the cessation of flow lasts for more than

a few minutes, infarction or death of brain tissue results. When blood

flow is quickly restored, brain tissue can recover fully and the patient’s

symptoms are only transient: this is called a transient ischemic attack

(TIA). The definition of TIA requires that all neurologic signs and

symptoms resolve within 24 h without evidence of brain infarction on

brain imaging. Stroke has occurred if the neurologic signs and symptoms last for >24 h or brain infarction is demonstrated. A generalized

reduction in cerebral blood flow due to systemic hypotension (e.g., cardiac arrhythmia, myocardial infarction, or hemorrhagic shock) usually

produces syncope (Chap. 21). If low cerebral blood flow persists for a

longer duration, then infarction in the border zones between the major

cerebral artery distributions may develop. In more severe instances,

global hypoxia-ischemia causes widespread brain injury; the constellation of cognitive sequelae that ensues is called hypoxic-ischemic

encephalopathy (Chap. 307). Focal ischemia or infarction, conversely, is

usually caused by thrombosis of the cerebral vessels themselves or by

emboli from a proximal arterial source or the heart (Chap. 427). Intracranial hemorrhage is caused by bleeding directly into or around the

brain; it produces neurologic symptoms by producing a mass effect on

neural structures, from the toxic effects of blood itself, or by increasing

intracranial pressure (Chap. 428).

APPROACH TO THE PATIENT

Cerebrovascular Disease

Rapid evaluation is essential for use of acute treatments such as

thrombolysis or thrombectomy. However, patients with acute stroke

often do not seek medical assistance on their own because they may

lose the appreciation that something is wrong (anosognosia) or lack

the knowledge that acute treatment is beneficial; it is often a family member or a bystander who calls for help. Therefore, patients

and their family members should be counseled to call emergency

medical services immediately if they experience or witness the

sudden onset of any of the following: loss of sensory and/or motor

function on one side of the body (nearly 85% of ischemic stroke

patients have hemiparesis); change in vision, gait, or ability to speak

426 Introduction to

Cerebrovascular Diseases

Wade S. Smith, S. Claiborne Johnston,

J. Claude Hemphill, III

carbamazepine, phenytoin, phenobarbital, and topiramate can significantly decrease the efficacy of oral contraceptives via enzyme induction and other mechanisms. Patients should be advised to consider

alternative forms of contraception, including intrauterine devices and

other long-acting reversible contraceptives, or their oral contraceptive

medications should be modified to offset the effects of the antiseizure

medications.

■ BREAST-FEEDING

Antiseizure medications are excreted into breast milk to a variable

degree. The ratio of drug concentration in breast milk relative to serum

ranges from ~5% (valproic acid) to 300% (levetiracetam). Given the

overall benefits of breast-feeding and the lack of evidence for long-term

harm to the infant by being exposed to antiseizure drugs, mothers with

epilepsy can be encouraged to breast-feed. This should be reconsidered, however, if there is any evidence of drug effects on the infant such

as lethargy or poor feeding.

■ FURTHER READING

Chen DK et al: Psychogenic non-epileptic seizures. Curr Neurol

Neurosci Rep 17:71, 2017.

Cornes SB, Shih T: Evaluation of the patient with spells. Continuum

(Minneap Minn) 17:984, 2011.

Crepeau AZ, Sirven JI: Management of adult onset seizures. Mayo

Clin Proc 92:306, 2017.

Ellis CA et al: Epilepsy genetics: Clinical impacts and biological

insights. Lancet Neurol 19:93, 2020.

Epi PM Consortium: A roadmap for precision medicine in the epilepsies.

Lancet Neurol 14:1219, 2015.

Fisher RS et al: Operational classification of seizure types by the

International League Against Epilepsy: Position paper of the ILAE

Commission for Classification and Terminology. Epilepsia 58:522,

2017.

Gavvala JR, Schuele SU: New-onset seizure in adults and adolescents: A review. JAMA 316:2657, 2016.

Golyala A, Kwan P: Drug development for refractory epilepsy: The

past 25 years and beyond. Seizure 44:147, 2017.

Jetté N et al: Surgical treatment for epilepsy: The potential gap

between evidence and practice. Lancet Neurol 15:982, 2016.

Kanner AM: Management of psychiatric and neurological comorbidities in epilepsy. Nat Rev Neurol 12:106, 2016.

Keezer MR et al: Comorbidities of epilepsy: Current concepts and

future perspectives. Lancet Neurol 15:106, 2016.

Krumholz A et al: Evidence-based guideline: Management of an

unprovoked first seizure in adults: Report of the Guideline Development Subcommittee of the American Academy of Neurology and the

American Epilepsy Society. Neurology 84:1705, 2015.

Kwan P, Brodie MJ: Early identification of refractory epilepsy. N Engl

J Med 342:314, 2000.

Lamberink HJ et al: Individualised prediction model of seizure recurrence and long-term outcomes after withdrawal of antiepileptic drugs

in seizure-free patients: A systematic review and individual participant data meta-analysis. Lancet Neurol 16:523, 2017.

Markert MS, Fisher RS: Neuromodulation: Science and practice in

epilepsy: Vagus nerve simulation, thalamic deep brain stimulation,

and responsive neurostimulation. Expert Rev Neurother 19:17, 2019.

McGovern RA et al: New techniques and progress in epilepsy surgery.

Curr Neurol Neurosci Rep 16:65, 2016.

Patel SI, Pennell PB: Management of epilepsy during pregnancy: An

update. Ther Adv Neurol Disord 9:118, 2016.

Pitkänen A et al: Advances in the development of biomarkers for

epilepsy. Lancet Neurol 15:843, 2016.

Rao VR et al: Cues for seizure timing. Epilepsia 62(Suppl 1):S15,

2021.