Epilepsy (Seizure Disorder)

Definition

A chronic disorder characterized by recurrent (≥2) epileptic seizures, not due to any obvious underlying reversible trigger/stressor.

Epileptic Seizure: Paroxysmal event due to an abnormal, unregulated cerebral (neuronal) electrical discharge that transiently disrupts normal brain function.

Classification of Epileptic Seizures:

There are more than 40 types of seizures; most are classified within 2 main categories.

EPILEPSY SYNDROMES

Epilepsy syndromes are disorders in which epilepsy is a main feature and have a relatively consistent seizure type, age of onset, etiology, and prognosis.

• Common syndromes
• Less common syndromes

Etiology

• Epilepsy and Seizures

Epidemiology

– Incidence

• Approximately 0.3-0.5% in different populations worldwide
• Approximately 15,500 new cases per year in Canada
• Approximately 200,000 new cases of epilepsy are diagnosed in the US each year
• Approximately 45,000 new cases in children <15 years old
• Incidence is growing most rapidly in the elderly

– Prevalence

• Approximately 50 million affected worldwide
• Approximately 5-10 persons per 1000
• Approximately 0.6% of the Canadian population

– Gender: Male = Female

– Family history: Increases risk 3-fold

Pathophysiology

Seizure has three phases:

• Initiation
• Propagation
• Termination

1) Initiation phase: Characterized by two simultaneous events:

• High-frequency bursts of action potentials
• Hypersynchronization of a neuronal population
• Bursting activity is caused by:
  • Long-lasting depolarization of the neuronal membrane due to influx of extracellular calcium (Ca²⁺) and sodium (Na⁺)
• This is followed by a hyperpolarizing afterpotential mediated by:
  • Gamma-aminobutyric acid (GABA) receptors
  • Potassium (K⁺) efflux
  • Chloride (Cl^–) influx
• Synchronized bursts from a sufficient number of neurons result in a spike discharge on EEG

2) Propagation phase: Characterized by spread of partial seizures within the brain.

3) Termination phase: Not fully understood but may involve restoration of neuronal inhibitory processes and/or “neuronal exhaustion”.

The mechanisms underlying absence seizures involve repetitive oscillations in a circuit between thalamic specific and reticular nuclei and the cerebral cortex. The abnormal neuronal firing in this circuit depends on calcium-T channels which are activated by GABA-mediated membrane hyperpolarization.

Clinical Presentation

Focal seizures:

Focal seizures with retained awareness:

• Patient is conscious
• Contractions (tonic) or rhythmic jerking (clonic) movements
  • May involve 1 entire side of body OR
  • May be more localized (e.g., hands, feet, face)
• Jacksonian march:
  • Sequential spread of seizure activity along a limb or hemibody
    (e.g. beginning in hand, progressing up the arm, to face); can be motor or sensory
• Todd’s paresis:
  • Focal symptoms, usually weakness (but may include speech dysfunction, etc.) for up to several hours post-ictally; reflects the function of the focus of origin of the seizure

Focal seizures with a loss awareness:

Most common epileptic seizures in adults

• Most commonly originate from temporolimbic structures
• Typically last <3 minutes
• Loss of contact with surroundings
• Dystonic posturing
• Brief, bilateral complex movements
• Automatisms (stereotyped, repetitive behaviors, purposeless speech and oral movements such as lip smacking)
• Aura may occur (often very individualized) and may include:
  • Dizziness, nausea, “epigastric rising” sensation, deja-vu, olfactory hallucination

Postictal phase, characterized by

• Somnolence/confusion
• ± Headache for up to several hours
• Amnesia for the event

Focal to bilateral tonic-clonic :

• Focal onset (speech, motor, sensory) with evolution into generalized seizures
• Todd’s paresis (described above)

Generalized seizures:

Absence seizures (formerly petit mal)-usually in childhood

• Typical absence seizures
  • Abrupt onset and ending
  • Unresponsiveness/behavior arrest
  • Typically last <10 seconds
  • Eye rolling upwards/blinking
  • May be precipitated by hyperventilation
• Atypical absence seizures
  • Gradual onset and ending
  • Slight movements of the lips
  • Often with tonic, atonic, myoclonic features
  • Not provoked by hyperventilation
  • Associated with Lennox-Gastaut syndrome
    A childhood epileptic encephalopathy, characterized by: Seizures, mental retardation and abnormal EEG with generalized slow spike-and-wave discharge
• Absence with special features
  • Myoclonic absence:
  • Usually lasts 8 to 60 sec
  • Abrupt onset of staring and unresponsiveness
  • Accompanied by myoclonic jerks of the shoulders, arms, and legs with a concomitant tonic contraction
  • Rhythmic protrusion of the lips, twitching of the corners of the mouth, or jaw jerking
  • Not provoked by hyperventilation
  • Eyelid myoclonia: (also known as Jeavons Syndrome)
  • May or may not be associated brief loss of awareness
  • Often precipitated by eye closure
  • Eyelids jerking at frequencies at least 3 per second
  • Upward eye deviation
  • Patients are photosensitive

Tonic-clonic Seizures (formerly grand mal)

• Loss of consciousness at onset
• Usually, last >30 sec and <5 minutes
• Eye deviation
• Clenched teeth or jaw with cheek, lip or tongue biting
• Frothy sputum
• Labored breathing/cyanosis
• Urinary/fecal incontinence
• Tonic phase (generalized muscle contraction and rigidity)
• Clonic phase (sustained contraction followed by rhythmic contractions of all 4 extremities)
• Postictal phase (confusion, somnolence, fatigue, ± headache)
• Todd’s paresis (as described above), suggests focal seizure onset with secondary generalization

Tonic seizures

• Impaired consciousness
• Sudden brief muscle stiffening
• Jaw clenching
• Brief periods of apnea (last usually <60 sec)

Clonic seizures

• Impaired consciousness(may last up to 2 minutes)
• Confusion
• Rhythmical jerking muscle contractions that usually involve:
  • Arms/neck/face/upper body

Atonic seizures (also known as drop seizures)

• Impaired consciousness, usually last <15 seconds
• Sudden, brief loss of muscle tone
• Falls, sometimes with injury are common

Myoclonic seizures

• Myoclonic:
• Sudden, brief <100 ms and sometimes repetitive muscle contractions
• Involuntary single or multiple contraction(s) of muscles(s) or muscle groups
• Can result in a “drop attack”
• Myoclonic atonic:
• Generalized seizure type with a myoclonic jerk
• Leading to an atonic drop
• Myoclonic tonic:
• Sudden, brief and sometimes repetitive muscle contractions
• Followed by a tonic seizure

Status Epilepticus (SE):

Neurological emergency

• Seizures may be generalized convulsive (tonic-clonic or myoclonic seizures), non-convulsive (absence) or partial (focal)
• Generalized tonic-clonic status: Presents as either
  • Continuous generalized seizures lasting >10 minutes
  • Patients do not fully regain consciousness between ≥2 generalized tonic-clonic seizures

Status epilepticus is a condition resulting either from the failure of the mechanisms responsible for seizure termination or from the initiation of mechanisms that lead to abnormally prolonged seizures (after time point t1). It is a condition that can have long-term consequences (after time point t2), including neuronal death, neuronal injury, and alteration of neuronal networks, depending on the type and duration of seizures.

Time point t1 indicates when treatment should be initiated, and time point t2 indicates when long-term consequences may appear

Differential Diagnosis

SEIZURES

• Syncope
• Psychogenic seizure/malingering (pseudoseizures)
• Panic attack
• Dissociative reaction
• Transient global amnesia
• Acute confusional states/encephalopathies
• Migraine
• Transient ischemic attack (TIA)
• Narcolepsy/cataplexy
• Benign sleep myoclonus
• Tic disorder
• Nonepileptic myoclonus

Investigation and Workup

History and Physical: Detailed description of seizures/ spells including triggering factors

1. New onset vs evidence of previous seizure disorder or history of prior seizures, including history of febrile seizures, unexplained nocturnal events, seizures misinterpreted as daydreaming or panic attacks
2. History of previous unexplained syncopal episodes
3. Family history of seizures
4. History of developmental delay-genetic-link or acquired brain injury
5. History of head trauma, stroke, intracranial infections (e.g. meningitis/encephalitis)
6. Assessment of prescribed medication including interactions which can reduce the efficacy of antiepileptic drugs
7. Excess or chronic use of alcohol and/or recreational/illicit drugs
8. Medication adherence for those already on anticonvulsants
9. Triggering or threshold-lowering factors including sleep deprivation, infections, and emotional upset
10. New persistent neurological deficits that might suggest structural brain injury
11. Psychogenic causes with or without secondary gain
12. Careful examination of the skin for: Harmatomas/facial angiofibromas (tuberous sclerosis) and neurofibromas (neurofibromatosis)

Laboratory Studies

Check for serum glucose, electrolytes, including Ca, Mg, and PO4 to assess for:

• Hypo/hyperglycemia
• Hypo/hypernatremia
• Hypomagnesemia
• Hypocalcemia
• Hypophosphatemia

Antiepileptic drug (AED) levels:

• Assessment of adherence and toxicity

Toxicology screens:

• Include alcohol, cocaine, narcotics, barbiturates, marijuana

Complete blood count (CBC):

Electroencephalography (EEG):

• A negative EEG does not exclude seizure disorder
• Most EEGs are interictal and findings which occur only during seizures may be missed
• Repeated EEGs and sleep deprivation increase the yield
• Even ictal EEGs may be negative with certain focal seizures

Various epileptiform abnormalities can also be seen in patients who have not had seizures. Focal spiking or generalized spike-wave discharges/bursts, however, have a high correlation with epilepsy.

Common EEG findings in epilepsy

Intensive EEG-Video monitoring:

• Used for differentiating non-epileptic from epileptic spells
• Can be done as an out-patient or in-patient
• Used for pre-surgical workup in candidates for epilepsy surgery to identify a focus and the nature of seizures

Ambulatory EEG monitoring:

• May be useful for some patients who are having seizures or spells in particular settings or infrequently

Brain electrical mapping:

• Sometimes done to locate a focal area of brain aberrant activity that has already been suggested on a regular EEG but rarely adds useful information

Imaging Studies

CT / MRI of brain:

• Brain imaging should be considered as part of the neurodiagnostic evaluation of adults presenting with an apparent unprovoked first seizure
• Magnetic Resonance Imaging (MRI) is the preferred neuroimaging method presenting with first afebrile seizure
• Rule-out acute intracranial pathology, such as tumors, hemorrhage, abscess, major developmental disorders, etc. MRI superior in evaluation of the temporal lobes, and particularly helpful for diagnosing subtle cortical dysplasias, migrational abnormalities, mesial temporal sclerosis, small tumors or hamartomatous lesions, cavernous hemangiomas

Treatment

Clinical Trials

• Ethosuximide, Valproic Acid, and Lamotrigine in Childhood Absence Epilepsy
• Comparison of levetiracetam and controlled-release carbamazepine in newly diagnosed epilepsy
• Comparison between lamotrigine and carbamazepine in elderly patients with newly diagnosed epilepsy
• A randomized study of gabapentin, lamotrigine, and carbamazepine
• The SANAD study of effectiveness of carbamazepine, gabapentin, lamotrigine, oxcarbazepine, or topiramate for treatment of partial epilepsy
• The SANAD study of effectiveness of valproate, lamotrigine, or topiramate for generalized and unclassifiable epilepsy
• The Teratogenicity of Anticonvulsant Drugs
• Final results from 18 years of the International Lamotrigine Pregnancy Registry
• Effectiveness of first antiepileptic drug
• A Randomized, Controlled Trial of Surgery for Temporal-Lobe Epilepsy drug
• Rufinamide for generalized seizures associated with Lennox-Gastaut syndrome
• Efficacy and safety of oral lacosamide as adjunctive therapy in adults with partial-onset seizures
• Efficacy and safety of adjunctive ezogabine (retigabine) in refractory partial epilepsy

Pipeline Agents

• Efficacy and safety of eslicarbazepine acetate as adjunctive treatment in adults with refractory partial-onset seizures
• Adjunctive brivaracetam for refractory partial-onset seizures: a randomized, controlled trial

Physician Resources

Tips for Patient Care:

• Encourage patient to identify and avoid triggers
• Lifestyle modifications especially for those with frequent, uncontrolled seizures:
  • Avoid sleep deprivation
  • Avoid alcohol and recreational drugs
  • Excessive use of video games may trigger seizures
  • Medication adherence
  • Reduce stress

Patient safety:

• Inform Transport Ministry-Re: Patient to avoid driving until symptoms have been brought under control
• Patient advised to avoid:
  • Operating/using heavy machinery, power tools
  • Driving
  • Solo use of bathtubs/hot-tubs (showers preferable)
  • Swimming alone
  • Heights (e.g. ladders; roofs, balconies in high rise buildings)
  • Cooking on exposed flames (microwave ovens preferred)
  • Front burners on stove (rear burners preferred)
  • Certain sports: rock-climbing, hang-gliding, scuba diving, downhill skiing, horseback riding
• Recommend a medic-alert bracelet/necklace

Advice for family members (during seizure attack):

• Place patient on the side and clear away any objects that may cause physical harm
• Do not place patient in restraints
• Protect patient’s head
• Avoid placing fingers or other objects (spoons) into the patient’s mouth
• With patient on his/her side excess saliva should flow out of the mouth
• Wipe away excess saliva
• Call Emergency medical services (911) for assistance
• Assess potential injuries sustained during a generalized tonic-clonic seizure
• Wounds or fractures can occur and urgent medical treatment may be required

Medications:

• Evaluate cost, affordability and insurance coverage for patients
• Whenever possible simplify medication regimens
• If possible, use monotherapy, and monitor serum levels of antiepileptic drugs (AEDs) as indicated
• Monitor all patients on AED therapy for notable behavior changes, e.g. suicidal thoughts, depression
• Consider concurrent risk factors and disease states when prescribing
• Discuss potential adverse events/side effects of medications.
• Counsel women of childbearing age regarding potential teratogenicity of AEDs

Social and stress factors:

• Patient & family members should be well informed about the type of epilepsy, triggers, treatment, safety measures and what should be done for an attack
• Certain types of childhood epilepsy improve with age while others may not
• Include family or social support in lifestyle modification

2. Scales and Tables:

• Status Epilepticus
• Epilepsy and Seizures
• Common Epilepsy Syndromes
• Less Common Epilepsy Syndromes

References

Core Resources:

• Brust JCM (2007) Current Diagnosis and Treatment (Neurology) (2^nd ed.) New York: McGraw Hill
• Compendium of Pharmaceuticals and Specialties (CPS). Canadian Pharmacist Association. Toronto: Webcom Inc. 2012
• Day RA, Paul P, Williams B, et al (eds). Brunner & Suddarth’s Textbook of Canadian Medical-Surgical Nursing. 2^nd ed. Philadelphia: Lippincott Williams and Wilkins; 2010
• Fisher RS, Cross JH, French JA, et al. Operational classification of seizure types by the International League Against Epilepsy: Position Paper of the ILAE Commission for Classification and Terminology. Epilepsia. 2017;58(4):522‐530. doi:10.1111/epi.13670
• Foster C, Mistry NF, Peddi PF, Sharma S, eds. The Washington Manual of Medical Therapeutics. 33^rd ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2010
• Gray J, ed. Therapeutic Choices. Canadian Pharmacists Association. 6^th ed. Toronto: Webcom Inc. 2011
• Kanner AM, Ashman E, Gloss D, et al. Practice guideline update summary: Efficacy and tolerability of the new antiepileptic drugs I: Treatment of new-onset epilepsy: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology and the American Epilepsy Society. Neurology. 2018;91(2):74‐81. doi:10.1212/WNL.0000000000005755
• Katzung BG, Masters SB, Trevor AJ, eds. Basic and Clinical Pharmacology. 11^th ed. New York: McGraw-Hill; 2009
• Liu G, Slater N, Perkins A. Epilepsy: Treatment Options. Am Fam Physician. 2017;96(2):87‐96
• Longo D, Fauci A, Kasper D, et al (eds). Harrison’s Principles of Internal Medicine. 18^thed. New York: McGraw-Hill; 2011
• Louis ED, Mayer SA, Rowland LP (2016) Merritt’s Neurology (13th ed.) Philadelphia: Wolter Kluwer
• McPhee SJ, Papadakis MA, eds. Current Medical Diagnosis & Treatment. 49^th ed. New York: McGraw-Hill; 2010
• Pagana KD, Pagana TJ eds. Mosby’s Diagnostic and Laboratory Test Reference. 9^th ed. St. Louis: Elsevier-Mosby; 2009
• Rowland LP et al. (2010) Merritt’s Neurology (9^th ed.) Philadelphia: Lippincott Williams and Wilkins
• Scheffer IE, French J, Hirsch E, et al. Classification of the epilepsies: New concepts for discussion and debate-Special report of the ILAE Classification Task Force of the Commission for Classification and Terminology. Epilepsia Open. 2016;1(1-2):37‐44. Published 2016 Jul 21. doi:10.1002/epi4.5
• Skidmore-Roth L. ed. Mosby’s drug guide for nurses. 9^th ed. St. Louis: Elsevier-Mosby; 2011
• Skidmore-Roth L, ed. Mosby’s nursing drug reference. 24^th ed. St. Louis: Elsevier-Mosby; 2011
• Trinka E, Cock H, Hesdorffer D, et al. A definition and classification of status epilepticus–Report of the ILAE Task Force on Classification of Status Epilepticus. Epilepsia. 2015;56(10):1515‐1523. doi:10.1111/epi.13121

Online Pharmacological Resources:

• e-therapeutics
• Lexicomp
• RxList
• Epocrates Online

Journals/Clinical Trials:

• Ben-Menachem E, Biton V, Jatuzis D, et al. Efficacy and safety of oral lacosamide as adjunctive therapy in adults with partial-onset seizures. Epilepsia, 2007;48:1308-17
• Brodie M.J., Perucca E., Rylin P., et al, for the Levetiracetam Monotherapy Study Group. Comparison of Levetiracetam and controlled-release Carbamazepine in newly diagnosed epilepsy. Neurology, 2007;68:402-408
• Brodie M.J., Overstall P.W., Giorgi L. and The UK Lamotrigine Elderly Study Group. Comparison between lamotrigine and carbamazepine in elderly patients with newly diagnosed epilepsy. Epilepsy Res., 1999;37:81-7
• Cunnington MC, Weil JG, Messenheimer JA et al. Final results from 18 years of the International Lamotrigine Pregnancy Registry. Neurology, 2011;76:1817-23
• Chung S, Ben-Menachem E, Sperling MR et al. Examining the Clinical Utility of Lacosamide: Pooled analyses of three Phase II/III clinical trials. CNS Drugs, 2010;24:1041-1054
• Elger C, Halász P, Maia J, et al; BIA-2093-301 Investigators Study Group. Efficacy and safety of eslicarbazepine acetate as adjunctive treatment in adults with refractory partial-onset seizures. Epilepsia, 2009;50:454-63
• French JA, Costantini C, Brodsky A, von Rosenstiel P; N01193 Study Group. Adjunctive brivaracetam for refractory partial-onset seizures: a randomized, controlled trial. Neurology, 2010;75:519-25
• Glauser T.A., Cnaan A., Shinnar S. et al, for the Childhood Absence Epilepsy Study Group. Ethosuximide, Valproic Acid, and Lamotrigine in Childhood Absence Epilepsy. N Engl J Med, 2010; 362:790-799
• Glauser T, Kluger G, Sachdeo R et al. Rufinamide for generalized seizures associated with Lennox-Gastaut syndrome. Neurology, 2008;70:1950-8
• Holmes LB, M.D., Harvey EA, Coull BA et al. The Teratogenicity of Anticonvulsant Drugs. N Engl J Med, 2001;344:1132-8
• Kwan P, Brodie MJ, et al. Effectiveness of first antiepileptic drug. Epilepsia, 2001;42:1255-60
• Marson AG, Al-Kharusi AM, Alwaidh M et al. on behalf of the SANAD Study group. The SANAD study of effectiveness of carbamazepine, gabapentin, lamotrigine, oxcarbazepine, or topiramate for treatment of partial epilepsy. The Lancet, 2007;369:1000-1015
• Marson AG, Al-Kharusi AM, Alwaidh M et al. on behalf of the SANAD Study group. The SANAD study of effectiveness of valproate, lamotrigine, or topiramate for generalized and unclassifiable epilepsy. The Lancet, 2007;369:1016-1026
• M.J. Brodie, MD, H. Lerche, MD, A. Gil-Nagel, MD, and On behalf of the RESTORE 2 Study Group. Efficacy and safety of adjunctive ezogabine (retigabine) in refractory partial epilepsy. Neurology, 2010;75:1817-1824
• Rowan A.J., Ramsay T.E., Collins J.F., et al and the VA Cooperative Study 428 Group. A randomized study of gabapentin, lamotrigine, and carbamazepine. N Engl J Med, 2010;362:790-799
• Wiebe S, Blume W, Girvin JP, et al, for the Effectiveness and Efficiency of Surgery for Temporal Lobe Epilepsy Study Group. A Randomized, Controlled Trial of Surgery for Temporal-Lobe Epilepsy drug. N Engl J Med, 2001;345:311-318