Seizures and Epilepsy¶

Chapter 436 | Part 13: Neurologic Disorders · Part 13 – Neurologic Disorders · Chapter 436

Key Clinical Points¶

A seizure is a transient occurrence of signs or symptoms due to abnormal excessive or synchronous neuronal activity in the brain.
Epilepsy is a clinical phenomenon characterized by a risk of recurrent seizures due to a chronic, underlying process.
The 2017 ILAE classification system categorizes seizures by onset (Focal, Generalized, Unknown) and awareness (Intact or Impaired).
Focal seizures can evolve into generalized seizures (secondary generalization), often starting with an aura.
Typical absence seizures show a 3-Hz spike-and-slow-wave pattern on EEG and are characterized by sudden, brief lapses of consciousness without loss of postural control.
Mesial temporal lobe epilepsy (MTLE) is characterized by hippocampal sclerosis and is often refractory to anticonvulsants but responsive to surgery.
Drugs like sodium channel blockers (e.g., carbamazepine) should be avoided in SCN1A-related epilepsy (Dravet syndrome).
The ketogenic diet is the gold standard treatment for refractory epilepsy due to GLUT1 deficiency.
Febrile seizures occur in 3–5% of children and are not necessarily associated with epilepsy.
Epileptogenesis is the process where a normal neuronal network transforms into one that is abnormally hyperexcitable.

DEFINITION & OVERVIEW¶

• Seizure: ◦ Definition: A transient occurrence of signs or symptoms due to abnormal excessive or synchronous neuronal activity in the brain. • Epilepsy: ◦ Definition: A clinical phenomenon characterized by a risk of recurrent seizures due to a chronic, underlying process. ◦ Clinical Context: ◦ Epilepsy is a clinical phenomenon rather than a single disease entity. ◦ A single seizure, or recurrent seizures due to correctable or avoidable circumstances, does not necessarily mean the patient has epilepsy. ◦ A single seizure associated with clinical or electroencephalographic features portending high risk of recurrence may establish the diagnosis of epilepsy. • Epidemiology: ◦ Incidence: ~0.3–0.5% in different populations worldwide. ◦ Prevalence: 5–30 persons per 1,000. ◦ General Population: ~5–10% will have at least one seizure. ◦ Febrile Seizures: 3–5% prevalence (higher in some regions like Asia). • ILAE 2017 Classification: ◦ Based on clinical features and electroencephalographic findings; excludes etiology or cellular substrate. ◦ Focal Seizures: Originate within networks limited to one brain region; often associated with structural abnormalities. ◦ Generalized Seizures: Arise within and rapidly engage networks distributed across both cerebral hemispheres; may result from cellular, biochemical, or structural abnormalities. ◦ Awareness: Categorized as Intact or Impaired. ◦ Table 436-1 (Classification of Seizures): ◦ Focal Onset: Can be further described by awareness (intact/impaired), motor or nonmotor onset, or evolution to bilateral tonic-clonic. ◦ Generalized Onset: ◦ Motor: Tonic-clonic; Other motor (e.g., atonic, myoclonic). ◦ Nonmotor: Absence. ◦ Unknown Onset: Motor, nonmotor, or unclassified.

ETIOLOGY & PATHOPHYSIOLOGY¶

• Mechanism: Result of a shift in the normal balance of excitation and inhibition within the CNS. • Epileptogenesis: ◦ Definition: The process where injury results in a long-lasting pathologic change in the CNS that transforms a presumably normal neuronal network into one that is abnormally hyperexcitable. ◦ Drivers: Stroke, infection, neurodegeneration, and abnormalities of CNS development. • Precipitants: ◦ Intrinsic: Psychological or physical stress, sleep deprivation, hormonal changes. ◦ Exogenous: Toxic substances, certain medications, intermittent photic stimulation. • Genetic Factors & Epilepsy Syndromes (Table 436-2): ◦ CHRNA4 (20q13.2): Nicotinic acetylcholine receptor; leads to Sleep-related hypermotor epilepsy (SHE). ◦ KCNQ2 (20q13.3): Voltage-gated potassium channel subunits; mutation causes self-limited familial neonatal epilepsy. ◦ SCN1A (2q24.3): α-Subunit of a voltage-gated sodium channel; common cause of Dravet syndrome and GEFS+; Avoid sodium channel–blocking medications. ◦ LGI1 (10q24): Influence on glutamatergic circuits; causes Autosomal dominant epilepsy with auditory features (ADEAF). ◦ DEPDC5 (22q12.2): Inhibits mTOR-mediated processes; leads to Autosomal dominant familial focal epilepsy with variable foci (FFEVF). ◦ GRIN2A (16p13.2): Encodes NMDA receptor subunit; linked to BECTS and Landau-Kleffner syndrome. ◦ CDKL-5 (Xp22.13): Serine-threonine kinase; mutation causes CDKL-5 deficiency disorder (CDD); Ganaxolone is a recently approved treatment. ◦ SLC2A1 (1p34.2): Glucose transporter protein 1 (GLUT1); deficiency leads to metabolic encephalopathy; Ketogenic diet is the gold standard for refractory cases. ◦ CSTB (21q22.3): Cystatin B; mutation causes Progressive myoclonic epilepsy (PME) (Unverricht-Lundborg disease). ◦ EPM2A (6q14): Laforin; mutation causes Progressive myoclonic epilepsy (Lafora’s disease). ◦ Doublecortin (Xq21-24): Regulates microtubule polymerization; mutation leads to classic lissencephaly with severe mental retardation.

CLINICAL FEATURES¶

• Focal Seizures: ◦ Manifestations: Motor (tonic, clonic, myoclonic) or nonmotor (sensory, autonomic, emotional). ◦ Example: Right primary motor cortex seizure → involuntary movements of the contralateral left hand. ◦ Awareness: Can be intact or impaired. ◦ Auras: Stereotypic experiences (e.g., sensory, emotional) preceding the ictal phase. ◦ Focal Seizures with Impaired Awareness: ◦ Often begin with a stereotypic aura. ◦ Marked by a motionless stare at the onset of impaired awareness. ◦ May include automatisms (chewing, lip smacking, swallowing, 'picking') or complex behaviors (running, emotional display). ◦ Postictal State: Disorientation; recovery takes seconds to hours. May show anterograde amnesia or transient deficits (aphasia, hemineglect, visual loss) due to postictal inhibition. • Generalized Seizures: ◦ Typical Absence: ◦ Sudden, brief lapses of consciousness without loss of postural control. ◦ Duration: Seconds; sudden recovery; no postictal confusion. ◦ EEG: 3-Hz spike-and-slow-wave pattern. ◦ Tonic-Clonic (from Figure 436-4): ◦ Tonic phase: Muscle stiffness, impaired consciousness. ◦ Clonic phase: Superimposition of muscle relaxation on tonic contraction. ◦ Atonic: ◦ Sudden loss of postural muscle tone; 'drop attacks'. ◦ Myoclonic: ◦ Sudden, brief muscle contraction (single part or whole body).

DIFFERENTIAL DIAGNOSIS¶

• Non-Epileptic Mimics: ◦ Syncope: ◦ Triggered by emotional stress, Valsalva, or orthostatic hypotension. ◦ Duration: Seconds (30–60 s) vs. minutes in seizure. ◦ Appearance: Pallor during syncope vs. cyanosis/frothing in seizure. ◦ Psychological: Psychogenic seizure, panic attack, hyperventilation. ◦ Metabolic/Medical: Hypoglycemia, delirium tremens, alcohol blackout, TIA, migraine (basilar). ◦ Sleep Disorders: Narcolepsy, sleepwalking, night terrors. ◦ Movement Disorders: Tics, paroxysmal choreoathetosis. • Table 436-6 (Differential Diagnosis of Seizures): ◦ Syncope (Vasovagal, Cardiac arrhythmia, Orthostatic hypotension). ◦ Psychological (Psychogenic seizure, Panic attack). ◦ Metabolic (Hypoglycemia, Delirium tremens). ◦ Neurological (TIA, Migraine, Sleep disorders). • Table 436-7 (Distinguishing Tonic-Clonic Seizure from Syncope): ◦ Precipitating factors: None in seizure; Emotional/Valsalva/Orthostatic in syncope. ◦ Aura: Present in seizure (e.g., odd odor); absent in syncope. ◦ Duration of unconsciousness: Minutes in seizure; seconds in syncope. ◦ Facial appearance: Cyanosis/frothing in seizure; Pallor in syncope. ◦ Post-event muscle ache: Often present in seizure; only sometimes in syncope. • Table 436-5 (Drugs and Substances causing Seizures): ◦ Alkylating agents (busulfin, chlorambucil), Antimalarials (chloroquine, mefloquine). ◦ Antimicrobials/antivirals (Acyclovir, Ganciclovir). ◦ β-Lactam and related compounds, Quinolones. ◦ Anesthetics and analgesics (Meperidine, Fentanyl, Tramadol). ◦ Psychotropics (Antidepressants like bupropion, Antipsychotics like clozapine, Lithium). ◦ Drugs of abuse (Amphetamine, Cocaine, Phencyclidine). ◦ Other: Alcohol, Baclofen, Barbiturates, Benzodiazepines (short-acting), Zolpidem.

DIAGNOSTIC APPROACH¶

Initial Assessment: History and Physical Examination.
Branch 1: Patient with history of epilepsy/current ASD treatment.
Assess adequacy of current therapy (side effects, serum levels).
Perform labs (CBC, Electrolytes, Glucose, LFTs, UA, Toxicology).
Evaluate Neuroimaging:
If Normal → Check for subtherapeutic drug levels → Appropriate increase/resumption of dose.
If Abnormal or change in neuroimaging → Treat identifiable abnormality; if no cause found, consider alternative anti-epileptic drugs.
Branch 2: Patient with NO history of epilepsy.
Perform metabolic screen (CBC, Electrolytes, Glucose, LFTs, UA, Toxicology).
If Positive metabolic screen or signs of infection → Treat underlying metabolic abnormality; if infection suspected, perform culture/CSF.
Final Action: Consider anti seizure drug therapy.
If Negative metabolic screen → Perform MRI and ECG.
If Clear features of seizures (mass, stroke, etc.) → Treat underlying disorder.
If No clear features (Idiopathic) → Consider anti seizure drug therapy.

MANAGEMENT & TREATMENT¶

Pharmacologic Management of Status Epilepticus (Flowchart 2):
Impending and early SE (5–30 min):
Administer IV benzodiazepine (LZP or MDZ).
If not resolved → Move to IV antiseizure drug (PHT, VPA, or LEV).
Established and early refractory SE (30 min to 48 h):
For Generalized convulsive or "subtle" SE: Administer IV MDZ ($0.2 ext{ mg/kg} → 0.2-0.6 ext{ mg/kg/h}) and/or IV PRO (2 ext{ mg/kg} → 2-10 ext{ mg/kg/h}$).
For Focal-complex, myoclonic or absence SE: Proceed to further IV/PRO antiseizure drug (VPA, LEV, LCM, TPM, PGB, or other).
Late refractory SE (>48 h):
Administer PTB (THP) (5 ext{ mg/kg} (1 ext{ mg/kg}) → 1-5 ext{ mg/kg/h}).
Refractory Cases (Multi-modal):
Other medications: Lidocaine, verapamil, magnesium, phenytoin, ketogenic diet, immunomodulation.
Other anesthetics: Isoflurane, desflurane, ketamine.
Other approaches: Surgery, VNS, RNS, rTMS, ECT, hypothermia.
Antiseizure Drug Selection (Table 436-8):
Generalized Tonic-Clonic: First-line: Lamotrigine, Valproic acid. Alternatives: Zonisamide, Phenytoin, Levetiracetam, Carbamazepine, Oxcarbazepine, Topiramate, Phenobarbital, Primidone, Felbamate, Perampanel.
Focal: First-line: Lamotrigine, Carbamazepine, Oxcarbazepine, Eslicarbazepine, Phenytoin, Levetiracetam. Alternatives: Zonisamide, Brivaracetam, Topiramate, Valproic acid, Tiagabinea, Gabapentina, Lacosamidea, Phenobarbital, Primidone, Felbamate, Perampanel.
Typical Absence: First-line: Valproic acid, Ethosuximide, Lamotrigine. Alternatives: Clonazepam, Zonisamide, Levetiracetam.
Atypical/Myoclonic/Atonic: First-line: Valproic acid, Lamotrigine, Topiramate. Alternatives: Clonazepam, Felbamate, Clobazam, Rufinamide, Fenfluramine.
Dosage and Side Effects (Table 436-9):
Brivaracetam: Focal; 100-200 ext{ mg/d} bid; 10-20 ext{ mg/kg} per d; bid. Side effects: Fatigue, dizziness, ataxia.
Clobazam: Lennox-Gastaut; 10-40 ext{ mg/d} bid. Side effects: Sedation, ataxia.
Eslicarbazepine: Focal; 400-1600 ext{ mg/d}. Side effects: Dizziness, diplopia.
Felbamate: Focal/Lennox-Gastaut; 2400-3600 ext{ mg/d} tid-qid. Risk: Aplastic anemia, hepatic failure.
Fintepla: Dravet/Lennox-Gastaut; 0.1-0.35 ext{ mg/kg} bid. Side effects: Ataxia, somnolence.
Carbamazepine: Tonic-clonic/Focal; 600-1800 ext{ mg/d}. Risk: Leukopenia, hepatotoxicity.
Levetiracetam: Focal; 20-30 ext{ mg/kg} (LEV) or 100-400 ext{ mg/d} (Epidiolex).

PROGNOSIS & COMPLICATIONS¶

• Refractory Epilepsy: ◦ Often associated with structural abnormalities (e.g., MTLE, hippocampal sclerosis). ◦ May require surgical intervention or specialized diets (Ketogenic). • Status Epilepticus: ◦ Risk of neurological damage if not treated promptly. ◦ Requires escalation to anesthetics and multi-modal therapy in refractory cases.

SPECIAL CONSIDERATIONS¶

• Pediatric Considerations: ◦ Febrile seizures (3–5% of children) are common but not always indicative of epilepsy. ◦ Absence seizures often present in childhood (ages 4–10). ◦ Dravet syndrome and Lennox-Gastaut syndrome typically have early onset. • Age-Related Etiologies (Table 436-4): ◦ Neonates (<1 month): Perinatal hypoxia/ischemia, hemorrhage, infection, metabolic disturbances, drug withdrawal, genetic disorders. ◦ Early onset: Often intractable; may be due to genetics or infections. ◦ Adolescents (12–18 years): Trauma, genetics, infection, drugs, tumors. ◦ Older adults (>35 years): Cerebrovascular disease, tumor, alcohol withdrawal, metabolic disorders (uremia, hepatic failure), Alzheimer's/degeneration, autoantibodies.

KEY PEARLS & CLINICAL TRAPS¶

• Diagnosis: A single seizure does not equal epilepsy; risk of recurrence is the defining factor. ◦ Imaging: MRI is essential for identifying structural causes (e.g., hippocampal sclerosis in MTLE). ◦ EEG: 3-Hz spike-and-wave is pathognomonic for typical absence seizures. • Management: ◦ Status Epilepticus: Treatment is time-sensitive; benzodiazepines are first-line, followed by midazolam/propofol, then anesthetics/surgery. ◦ Drug Selection: Choice depends on seizure type (e.g., Ethosuximide for absence, Carbamazepine for focal). ◦ Safety Alert: Avoid sodium channel blockers in patients with SCN1A mutations (Dravet syndrome). ◦ Metabolic: Ketogenic diet is the gold standard for GLUT1 deficiency.

Reference Tables¶

TABLE 436-1 Classification of Seizures a 1. Focal Onset¶

Harrison's 22e, p.3409

1. Focal Onset
  (Can be further described as having intact or impaired awareness, motor or
  nonmotor onset, or evolve from focal to bilateral tonic clonic)
  2. Generalized Onset
  a. Motor
  Tonic-clonic
  Other motor (e.g., atonic, myoclonic)
  b. Nonmotor (absence)
  3. Unknown Onset
  Motor, nonmotor, or unclassified

TABLE 436-2 Examples of Genes Associated with Epilepsy Syndromes a¶

Harrison's 22e, p.3412

GENE (LOCUS)	FUNCTION OF GENE	CLINICAL SYNDROME	COMMENTS
CHRNA4 (20q13.2)	Nicotinic acetylcholine receptor subunit; mutations cause alterations in Ca2+ flux through the receptor; this may reduce the amount of GABA release in presynaptic terminals	Sleep-related hypermotor epilepsy (SHE); childhood onset; brief, nighttime seizures with prominent motor movements; often misdiagnosed as primary sleep disorder	Rare; first identified in a large Australian family; other families found to have mutations in CHRNA2 or CHRNB2, and some families appear to have mutations at other loci
	Voltage-gated potassium channel subunits; mutation in pore regions may cause a 20–40% reduction of potassium currents, which will lead to impaired repolarization	Self-limited familial neonatal epilepsy; autosomal dominant inheritance; onset in first week of life in infants who are otherwise normal; remission usually within weeks to months; long-term epilepsy in 10–15%
SCN1A (2q24.3)	α-Subunit of a voltage-gated sodium channel; numerous mutations affecting sodium currents that cause either gain or loss of function; network effects appear related to expression in excitatory or inhibitory cells	Very common cause of Dravet syndrome (severe myoclonic epilepsy of infancy) and some cases of Lennox-Gastaut syndrome. Also found in other syndromes, including genetic epilepsy with febrile seizures plus (GEFS+); autosomal dominant inheritance; presents with febrile seizures at median 1 year, which may persist >6 years, then variable seizure types not associated with fever	Incidence of Dravet syndrome is 1 in 20,000 births, and de novo SCN1A mutation is found in ~80% of cases. Incidence in GEFS+ uncertain; identified in other families with mutations in other sodium channel subunits (SCN2B and SCN2A) and GABA receptor subunit (GABRG2 and GABRA1); A significant phenotypic heterogeneity within same family, including members with febrile seizures only. Avoid sodium channel–blocking antiseizure medications
	Leucine-rich glioma-inactivated 1 gene; previous evidence for role in glial tumor progression; recent studies suggest an influence in the postnatal development of glutamatergic circuits in the hippocampus	Autosomal dominant epilepsy with auditory features (ADEAF); a form of lateral temporal lobe epilepsy with auditory symptoms or aphasia as a major focal seizure manifestation; age of onset usually between 10 and 25 years
DEPDC5 (22q12.2)	Disheveled, Egl-10, and pleckstrin domain containing protein 5; exerts an inhibitory effect on mammalian target of rapamycin (mTOR)–mediated processes, such as cell growth and proliferation	Autosomal dominant familial focal epilepsy with variable foci (FFEVF); family members have seizures originating from different cortical regions; neuroimaging usually normal but may harbor subtle malformations; recent studies also suggest association with benign epilepsy with centrotemporal spikes	Study of families with the limited number of affected members revealed mutations in ~12% of families; thus, may be a relatively common cause of lesion-negative focal epilepsies with suspected genetic basis. Also associated with mutations in the GATOR1 genes NPRL2 and NPRL3
	Encodes NMDA receptor (NMDAR) subunit GluN2A	Spectrum of phenotypes ranging from benign childhood epilepsy with centrotemporal spikes (BECTS) to epilepsy-aphasia syndromes such as Landau-Kleffner syndrome (LKS) and other epileptic encephalopathies
CDKL-5 (Xp22.13)	Encodes cyclin-dependent kinase-like 5 (CDKL-5), a serine-threonine kinase involved in neural maturation and synaptogenesis	CDKL-5 deficiency disorder (CDD) results from pathogenic mutation in the CDKL5 gene that causes absence or nonfunctional CDKL-5 protein. CDD is a severe developmental epileptic encephalopathy characterized by very-early- onset seizures. X-linked, affects females more than males	Ganaxolone is a recently approved antiseizure drug that has been shown to significantly reduce CDD-associated seizures
	Glucose transporter protein type 1 (GLUT1); transports glucose across the blood-brain barrier	Loss of function of one allele leads to GLUT1 deficiency, a severe metabolic encephalopathy including intractable epilepsy, complex motor dysfunction, and intellectual disability. Milder GLUT1 deficiency causes a combination of movement disorder (paroxysmal exertional dyskinesia) and epilepsy with prominent absence seizures, though intellect is often normal
CSTB (21q22.3)	Cystatin B, a noncaspase cysteine protease inhibitor; normal protein may block neuronal apoptosis by inhibiting caspases directly or indirectly (via cathepsins), or controlling proteolysis	Progressive myoclonus epilepsy (PME) (Unverricht-Lundborg disease); autosomal recessive inheritance; age of onset between 6 and 15 years, myoclonic seizures, ataxia, and progressive cognitive decline; brain shows neuronal degeneration	Overall rare, but relatively common in Finland and western Mediterranean (>1 in 20,000); precise role of cystatin B in human disease unknown, although mice with null mutations of cystatin B have similar syndrome
	Laforin, a protein tyrosine phosphatase (PTP); involved in glycogen metabolism and may have antiapoptotic activity	Progressive myoclonus epilepsy (Lafora’s disease); autosomal recessive inheritance; age of onset 6–19 years, death within 10 years; brain degeneration associated with polyglucosan intracellular inclusion bodies in numerous organs
Doublecortin (Xq21-24)	Doublecortin, expressed primarily in frontal lobes; directly regulates microtubule polymerization and bundling	Classic lissencephaly associated with severe mental retardation and seizures in males; subcortical band heterotopia with more subtle findings in females (presumably due to random X inactivation); X-linked dominant	Relatively rare but of uncertain incidence; recent increased ascertainment due to improved imaging techniques; relationship between migration defect and seizure phenotype unknown

TABLE 436-3 Characteristics of the Mesial Temporal Lobe Epilepsy Syndrome History History of febrile seizures Family…¶

Harrison's 22e, p.3413

History
History of febrile seizures	Rare generalized seizures

TABLE 436-4 Causes of Seizures

Neonates (<1 month)	Perinatal hypoxia and ischemia Intracranial hemorrhage and trauma CNS infection Metabolic disturbances (hypoglycemia, hypocalcemia, hypomagnesemia, pyridoxine deficiency) Drug withdrawal Developmental disorders Genetic disorders
Early onset	Seizures often intractable
Clinical Observations
Behavioral arrest/stare	Memory loss
Unilateral posturing
Laboratory Studies
Unilateral or bilateral anterior temporal spikes on EEG
Hypometabolism on interictal PET
Hyperperfusion on ictal SPECT
Material-specific memory deficits on intracarotid amobarbital (Wada) test
MRI Findings
Small hippocampus with increased signal on T2-weighted sequences and loss of trilaminar hippocampal internal architecture
Small temporal lobe
Enlarged temporal horn
Pathologic Findings
Highly selective loss of specific cell populations within hippocampus in most cases, granule cell layer dispersion, gliosis
Adolescents (12–18 years)	Trauma Genetic disorders Infection Illicit drug use Brain tumor
Older adults (>35 years)	Cerebrovascular disease
	Brain tumor
	Alcohol withdrawal
	Metabolic disorders (uremia, hepatic failure, electrolyte abnormalities, hypoglycemia, hyperglycemia)
	Alzheimer’s disease and other degenerative CNS diseases
	Autoantibodies

TABLE 436-5 Drugs and Other Substances That Can Cause Seizures Alkylating agents (e.g., busulfan, chlorambucil)…¶

Harrison's 22e, p.3414

Alkylating agents (e.g., busulfan, chlorambucil)
Antimalarials (chloroquine, mefloquine)
Antimicrobials/antivirals
β-Lactam and related compounds
Quinolones
Acyclovir
Isoniazid
Ganciclovir
Anesthetics and analgesics
Meperidine
Fentanyl
Tramadol
Local anesthetics
Dietary supplements
Ephedra (ma huang)
Gingko
Immunomodulatory drugs
Cyclosporine
OKT3 (monoclonal antibodies to T cells)
Tacrolimus
Interferons
Psychotropics
Antidepressants (e.g., bupropion)
Antipsychotics (e.g., clozapine)
Lithium
Radiographic contrast agents
Drug withdrawal
Alcohol
Baclofen
Barbiturates (short-acting)
Benzodiazepines (short-acting)
Zolpidem
Drugs of abuse
Amphetamine
Cocaine
Phencyclidine
Methylphenidate
Flumazenila

TABLE 436-6 Differential Diagnosis of Seizures Syncope Vasovagal syncope Cardiac arrhythmia Valvular heart disease…¶

Harrison's 22e, p.3419

Syncope Vasovagal syncope Cardiac arrhythmia Valvular heart disease Cardiac failure Orthostatic hypotension Psychological disorders Psychogenic seizure Hyperventilation Panic attack Metabolic disturbances Alcoholic blackouts Delirium tremens Hypoglycemia Hypoxia Psychoactive drugs (e.g., hallucinogens) Migraine Confusional migraine Basilar migraine	Transient ischemic attack (TIA) Basilar artery TIA Sleep disorders Narcolepsy/cataplexy Benign sleep myoclonus Movement disorders Tics Nonepileptic myoclonus Paroxysmal choreoathetosis Special considerations in children Breath-holding spells Migraine with recurrent abdominal pain and cyclic vomiting Benign paroxysmal vertigo Apnea Night terrors Sleepwalking

TABLE 436-7 Features That Distinguish Generalized Tonic-Clonic Seizure from Syncope FEATURES Immediate precipitating…¶

Harrison's 22e, p.3419

FEATURES	SEIZURE	SYNCOPE
Immediate precipitating factors	Usually none	Emotional stress, Valsalva, orthostatic hypotension, cardiac etiologies
	None or aura (e.g., odd odor)
Posture at onset	Variable	Usually erect
	Often immediate
Duration of unconsciousness	Minutes	Seconds
	30–60 s
Facial appearance during event	Cyanosis, frothing at mouth	Pallor
	Many minutes to hours
Aching of muscles after event	Often	Sometimes
	Sometimes
Incontinence	Sometimes	Sometimes
	Sometimes

TABLE 436-8 Selection of Antiseizure Drugs¶

Harrison's 22e, p.3420

GENERALIZED- ONSET TONIC-CLONIC	FOCAL	TYPICAL ABSENCE	ATYPICAL ABSENCE, MYOCLONIC, ATONIC
First-Line
Lamotrigine Valproic acid	Lamotrigine Carbamazepine Oxcarbazepine Eslicarbazepine Phenytoin Levetiracetam	Valproic acid Ethosuximide Lamotrigine	Valproic acid Lamotrigine Topiramate
Alternatives
Zonisamidea Phenytoin Levetiracetam Carbamazepine Oxcarbazepine Topiramate Phenobarbital Primidone Felbamate Perampanel	Zonisamidea Brivaracetam Topiramate Valproic acid Tiagabinea Gabapentina Lacosamidea Phenobarbital Primidone Felbamate Perampanel Cenobamatea	Clonazepam Zonisamide Levetiracetam	Clonazepam Felbamate Clobazam Rufinamide Fenfluramine

TABLE 436-9 Dosage and Adverse Effects of Commonly Used Antiepileptic Drugs¶

Harrison's 22e, p.3421

GENERIC NAME	TRADE NAME	PRINCIPAL USES	TYPICAL DOSE; DOSE INTERVAL	HALF-LIFE	THERAPEUTIC RANGE	ADVERSE EFFECTS		DRUG INTERACTIONSa
						NEUROLOGIC	SYSTEMIC
Brivaracetam	Briviact	Focal onset	100–200 mg/d; bid	7–10 h	Not established	Fatigue Dizziness Weakness Ataxia Mood changes	Gastrointestinal irritation	May increase carbamazepine- epoxide causing decreased tolerability May increase phenytoin
	Epidiolex	Dravet and Lennox-Gastaut syndromes	10–20 mg/kg per d; bid	18–32 h	Not established	Sedation	Elevated transaminases Anorexia Weight loss Diarrhea
		Tuberous sclerosis complex- associated seizures
Carbamazepine	Tegretolc	Tonic-clonic Focal onset	600–1800 mg/d (15–35 mg/ kg, child); bid (capsules or tablets), tid-qid (oral suspension)	10–17 h (variable due to autoinduction: complete 3–5 wk after initiation)	4–12 μg/mL	Ataxia Dizziness Diplopia Vertigo	Aplastic anemia Leukopenia Gastrointestinal irritation Hepatotoxicity Hyponatremia Rash	Level decreased by enzyme- inducing drugsb Level increased by erythromycin, propoxyphene, isoniazid, cimetidine, fluoxetine
	Xcopri	Focal onset	100–400 mg/d; daily (tablets)	50–60 h	Not established	Cognitive dysfunction Dizziness Disequilibrium Gait disturbance Headache	Anorexia Constipation Diarrhea Dyspepsia Nausea
Clobazam	Onfi	Lennox-Gastaut syndrome	10–40 mg/d (5–20 mg/d for patients <30 kg body weight); bid	36–42 h (71–82 h for less active metabolite)	Not established	Fatigue Sedation Ataxia Aggression Insomnia	Constipation Anorexia Skin rash	Level increased by CYP2C19 inhibitors
	Klonopin	Absence Atypical absence Myoclonic	1–12 mg/d; qd-tid	24–48 h	10–70 ng/mL	Ataxia Sedation Lethargy	Anorexia
Eslicarbazepine	Aptiom	Focal onset	400–1600 mg/d; qd	20–24 h	10–35 μg/mL (as oxcarbazepine mono-hydroxy derivative)	Sedation Ataxia Dizziness Diplopia Vertigo	See carbamazepine	Level decreased by enzyme- inducing drugsb
	Zarontin	Absence	750–1250 mg/d (20–40 mg/kg); qd-bid	60 h, adult 30 h, child	40–100 μg/mL	Ataxia Lethargy Headache	Gastrointestinal irritation Skin rash Bone marrow suppression
Felbamate	Felbatol	Focal onset Lennox-Gastaut syndrome Tonic-clonic	2400–3600 mg/d, tid-qid	16–22 h	30–60 μg/mL	Insomnia Dizziness Sedation Headache	Aplastic anemia Hepatic failure Weight loss Gastrointestinal irritation	Increases phenytoin, valproic acid, active carbamazepine metabolite
	Fintepla	Dravet and Lennox-Gastaut syndromes	0.1–0.35 mg/kg/ dose bid (oral solution); dosage depends on coadministration with stiripentol and/or clobazam	20 h	Not established	Ataxia Behavioral disturbance Headache Somnolence	Anorexia Constipation Hypertension Serotonin syndrome Weight loss