Epilepsy and Non-Epilepsy Seizures

• A general pathophysiologic process underlying all epilepsies involves disturbed regulation of electrical activity in the brain.
• This results in synchronized and excessive neuronal discharge.
• The International League Against Epilepsy (ILAE) defines epilepsy as a disorder plus consequences.
• It raises considerations about patient's ability to drive.
• ILAE characterizes epilepsy as a brain disorder with an enduring predisposition to generate epileptic seizures.
• It notes that the neurobiologic, cognitive, psychological, and social consequences stem from these seizures.
• The US prevalence of epilepsy is 1.2%.
• Epilepsy involves a synchronized electrical disturbance.
• About 10% of the general population will experience at least one seizure from any cause in their lifetime.
• Seizures involve muscle movements and behaviors.

Non-Epilepsy Seizures: Drugs

• Illegal drug overdose (i.e., cocaine) can cause non-epilepsy seizures.
• Alcohol, benzodiazepine, or barbiturate withdrawal can cause non-epilepsy seizures.
• The following drugs can cause seizures:
  • Bupropion
  • Haloperidol
  • Clozapine
  • Theophylline
  • Meperidine (opioid)
  • Imipenem (carbapenem)

Non-Epilepsy Seizures: Non-Drugs

• Brain hemorrhage can cause non-epilepsy seizures.
• Hypocalcemia can lead to seizures.
• Hypoglycemia.
• Uremia.
• Febrile seizures.
• Psychogenic nonepileptic seizures.
• Somatic manifestation of distress.
• Infections.
• Hyperventilation.
• Photostimulation.
• Sleep deprivation.
• Hormonal changes, including puberty, menses, or pregnancy.

Etiology factors

• Epilepsy etiologies can be generally classified into six categories:
  • Genetic
  • Structural
  • Infectious
  • Metabolic
  • Immune
  • Unknown
• These categories are not mutually exclusive.

Etiology: Genetic

• Genetic etiologies are usually present in young children.
• Dravet syndrome is associated with mutations in the SCN1A gene in sodium channels, a voltage-gated type I alpha subunit.
• Childhood Absence Epilepsy (CAE) is associated with many different mutations in T-type Ca2+ channels and GABA receptor subunits.
• Juvenile Myoclonic Epilepsy (JME) is associated with many different mutations, including mutations in EFHC1 and ICK.

Etiology: Structural

• Cortical dysplasia, resulting from disruptions in neuronal migration, proliferation, and differentiation during brain development, is a common cause of childhood-onset drug-resistant epilepsy.
• Mesial temporal lobe epilepsy is a common type of adult-onset epilepsy responsible for many drug-resistant epilepsies.
• Sclerosis occurs in the hippocampus and is characterized by glial scarring, reduced hippocampal volume (MRI), and decreased cellular density (biopsy).
• Traumatic brain injury epilepsy results from blunt force injury or stroke that causes structural lesions in the brain.

Etiology: Infectious

• This acquired form of epilepsy occurs when a patient develops epilepsy as the sequelae of an infection, and not when a patient experiences seizures in the setting of acute infection such as meningitis or encephalitis.
• In developing countries, neurocysticercosis, a parasitic infection of the brain resulting from ingestion of eggs from a pork tapeworm, causes structural injury that promotes the development of epilepsy.

Etiology: Metabolic

• Lafora disease, abnormal glycogen metabolism and subsequent development of insoluble glycogen inclusion bodies,can result in epilepsy.

Etiology: Immune

• Anti-N-methyl-D-aspartate (anti-NMDA) receptor encephalitis can result in autoimmune-mediated central nervous system (CNS) inflammation and resulting epilepsy.

Pathophysiology

• Neuronal hyperexcitability and hypersynchronization play a role.
• Alterations in the number, type, and biophysical properties of voltage- or ligand-gated K+, Na+, Ca2+, and Cl= ion channels in neuronal membranes play a significant role.
• Carbamazepine and phenytoin reduce neuronal excitability by binding sodium channels in their inactive state and slowing channel recovery from inactivation.
• This prevents hyperexcitable neurons from rapidly and repetitively firing.
• Benzodiazepines bind to the gamma subunit of the GABA receptor, leading to an increase in chloride ion conductance and inhibition of action potentials.
• Synaptic vesicle protein 2A (SV2A), a protein responsible for the fusion of vesicles to the membrane, has been found to be upregulated in certain models of epilepsy.
• Levetiracetam targets SV2A.
• Dysfunction of SVA2 impairs synaptic GABA release.
• Gamma-aminobutyric acid (GABA) is an inhibitory neurotransmitter.
• Vigabatrin is an irreversible inhibitor of y-aminobutyric acid transaminase (GABA-T).
• Seizures can manifest physically in a variety of ways.
• Can range from intense involuntary repetitive muscular contractions (e.g., convulsions) to subtle alterations in sensation or consciousness
• Seizures are classified based on three key features:
  • Where in the brain the seizure originates.
  • Patient's level of awareness during a seizure.
  • Other features of the seizures.
• Seizures are classified into an initial three categories depending on how they begin in the brain.
• Focal seizures start in a network of cells on only one side of the brain.
• Generalized seizures start in a bilaterally distributed network.
• Unknown onset: these can be recategorized when it becomes clear how seizures begin in a particular patient's brain.

Clinical Presentation: Focal Seizures

• Focal aware seizure:
• The patient is cognizant during the seizure.
• It does not mean they can respond to questions.
• Focal impaired seizure:
  • Loss of awareness may occur at any point.
• Motor signs:
  • Myoclonus (e.g., twitching and jerking).
    • Tonic contraction (e.g., stiffening).
  • Automatisms (e.g., smacking lips or rubbing hands).
• Nonmotor signs:
  • Changes in sensation, emotions, thinking or experience.
• Focal seizures may propagate beyond the brain's one hemisphere to the contralateral hemisphere resulting in focal to bilateral tonic-clonic seizures.
• The person usually becomes unconscious and displays bilateral convulsive features.
• Do not confuse with generalized-onset seizures.

Clinical Presentation: Focal Seizure Symptoms

• Abnormal movements indicates seizure activity in motor pathways. -Reported feelings of numbness or tingling indicates sensory or somatosensory involvement and may indicate parietal lobe involvement. -Feelings of fear, depression, joy, anger, or memory phenomena such as feelings of familiarity (déjà vu) or unfamiliarity (jamais vu) indicates temporal lobe seizure activity. -Visual disturbances or hallucinations indicates seizure activity involving the occipital lobe. -Ringing or buzzing sounds in the ears indicates seizure activity in auditory areas. -Sweating, salivation or pallor indicates seizure activity in autonomic areas.

• Generalized-onset seizures start in a network that is bilaterally distributed to both hemispheres of the brain.

• They usually involve impaired awareness and are divided into motor and nonmotor seizures.

  • With tonic-clonic seizures, there is loss of consciousness, sudden sharp tonic contraction, subsequent period of rigidity and clonic movements.

• During the seizure, the patient may cry or moan, due to muscles in the larynx being activated or the patient may lose sphincter control with bladder and/or bowel incontinence or bite their tongue.

  • Postictally, after the patient regains consciousness, the patient may experience confusion, drowsiness, lack of coordination, soreness throughout the body, and amnesia.

• Atonic seizures are not preceded by myoclonic or tonic features and can be very brief.

• These may present as a head drop, the dropping of a limb, or a slumping to the ground and are a hallmark feature of Lennox-Gastaut syndrome.

  • Typical absence seizures: There are sudden onset interruptions of ongoing activities, a blank stare, and possibly a brief upward rotation of the eyes indicating the abrupt onset and offset of impaired consciousness. -After cessation of the seizure, the patient will often return to the previous activity as if nothing had happened.

• Absence seizures with myoclonia

• Absence seizures with eyelid myoclonia

• Seizures of unknown onset can be motor or nonmotor.

• After seizure types are determined, the epilepsy should be classified into one of the following four categories:

  • Focal epilepsy: patient only has focal-onset seizures
  • Generalized epilepsy: patient displays evidence of only generalized-onset seizures
  • Combined generalized and focal epilepsy
  • Unknown: the epilepsy type is unknown.

• After establishing the epilepsy type, epilepsy syndromes should be determined if possible.

• Epilepsy syndromes are characterized by a known etiology and by a cluster of signs and symptoms including distinctive comorbidities such as intellectual and psychiatric dysfunction.

• Syndromes include childhood absence epilepsy (CAE), juvenile absence epilepsy (JAE), and juvenile myoclonic epilepsy (JME), West syndrome, Lennox-Gastaut syndrome (LGS) and Dravet syndrome.

Diagnosis of Epilepsy

• Video EEG is the gold standard for diagnosing epilepsy
• Involves hospital admission to facilitate recording video and continuous EEG monitoring until the patient has a typical event.
• This is not standard for most patients and is generally reserved for cases unresponsive to medication or difficult to characterize.
• CT is commonly performed in a patient who presents after their first seizure to evaluate for a brain tumor, cerebral bleeding, or gross anatomical injury.
• MRI is preferred for validation of an epilepsy diagnosis as it is the preferred imaging technique to identify more subtle structural abnormalities.
• Some clinicians choose to start an antiseizure drug (ASD) treatment after one seizure with a definite abnormal MRI or epileptiform EEG.
• Others do not initiate treatment until a second seizure has occurred.
• Do not treat if there is low propensity for recurrent seizures.

Treatment

• Probability of recurrent seizures is higher if certain findings are present.
• Brain imaging abnormalities (such as from stroke, trauma, CNS infection, cerebral palsy, and other cognitive developmental disabilities) -EEG with epileptiform abnormalities (characterized by spikes or sharp waves)
• A nocturnal seizure.
• Accurate identification of seizure type and epilepsy diagnosis is critical for treatment.
• Ethosuximide is efficacious in childhood absence epilepsy (CAE).
• Phenytoin or carbamazepine is detrimental in CAE.
• Consider ASD efficacy for the specific seizure type, epilepsy, or epilepsy syndrome when making a selection.
• Select an ASD with the most tolerable adverse effect profile, considering patient-specific factors, including age and gender.
• Select an ASD that can also treat the patient's other comorbid conditions.
• Be aware of drug-drug interactions with other medications.

Additional Treatment Factors

• Consider the ability to adhere to a prescribed regimen (e.g., three or four times daily dosing) and insurance coverage, as this can affect ASD adherence and effectiveness.
• Consider the need for therapeutic levels to be reached quickly.
• Children may be more susceptible to neuropsychiatric adverse effects.
• Women with child-bearing potential should not be on ASDs with unacceptable teratogenicity.
• Elderly may be more susceptible to adverse cognitive effects.

Comorbidity Treatment Options

• Epilepsy + migraine: topiramate
• Epilepsy + bipolar disorder: lamotrigine
• Epilepsy + neuropathy: pregabalin
• Start dosing low and titrate.
• If the patient is seizure free with no adverse effects at a minimal therapeutic dose, then an optimal dose has been achieved, and no further increase in dose is necessary.
• If the patient continues to have seizures at a minimal or moderate-therapeutic dose, further titration to a maximum dose may be needed for optimal seizure control.
• If the patient continues to have seizures at a maximum dose, or if the patient experiences intolerable adverse effects at any dose, adding a second ASD and then tapering and discontinuing the ineffective or intolerable first ASD is appropriate.
• Monotherapy is preferred but additional drugs may need to be considered for therapy failure at max dose or intolerable side effects.

Adverse Effects of Pharmacologic Therapy

• Concentration-dependent effects include sedation, dizziness, blurred or double vision, difficulty with concentration, ataxia, and impaired cognition.
• Barbiturates and sodium channel inhibitors appear to cause more sedation and cognitive impairment in particular.
• Barbiturates paradoxically causes hyperactivity in children.
• Topiramate is known to cause substantial cognitive impairment.

Idiosyncratic Reactions

• Drug rashes can range from mild to life-threatening (Steven-Johnsons syndrome (SJS) or toxic epidermal necrolysis (TEN)) / DRESS (Drug Reactions with Eosinophilia and Systemic Symptoms).
• More commonly associated with carbamazepine, phenytoin, oxcarbazepine or lamotrigine.
• Test patients with Asian ancestry for HLA-B*1502 allele – strong recommendation for carbamazepine.
• Hepatotoxicity; -Felbamate.
  • A warning on suicidal behavior and ideation also accompanies all ASDs.
• Chronic therapy can cause osteomalacia and osteoporosis through interference of vitamin D metabolism.
  • Supplement vitamin D and calcium and perform bone mineral density testing.
• Use phenytoin, phenobarbital, carbamazepine, oxcarbazepine, felbamate and valproate with caution.
• Avoid valproic acid and carbamazepine during pregnancy.
• High-dose folic acid (4-5 mg daily) is recommended to reduce neural tube defects.
• Alternatives include lamotrigine, levetiracetam, carbamazepine, oxcarbazepine, zonisamide, phenytoin, phenobarbital, or topiramate.

First Generation ASDs

• Carbamazepine
• Mode of Action- NA+
• FDA indication: Monotherapy and adjunctive therapy for focal-onset, TC, and mixed seizure types except for absence seizures
• Advantages: Useful in comorbid bipolar disorder or trigeminal neuralgia -Disadvantages: Worsens other seizure types.

Carbamazepine DDIs

• Potent inducer of CYP3A4, CYP1A2, CYP2B6, CYP2C9/19 & glucuronyltransferase (UGT); decreases levels of brivaracetam. clonazepam, eslicarbazepine

• Phenobarbital, phenytoin, primidone decrease levels; valproate increases carbamazepine-10,11 epoxide Rare and Serious Adverse effect- Boxed warning Increased risk of SJS/TEN and HLA-B*1502 Alleles. Osteoporosis. Long term Adverse effect: Hyponatremia; metabolic bone disease-

• Clonazepam

• Mode of Action- Binds GABA Receptor. FDA Indication- Monotherapy.

• Advantages: useful in patients with panic disorder. MAY INCREASE seizure types Rare and serious adverse effects:: Concomitant use with opioids may result in profound.Physiologic dependence hair loss. Adverse effects of Diazapam. Ethosuximide inhibition of T-type and calcium seizures. Use caution with caution in Hepatic issues and Renal-Rarely Serious blood issues

• Phenobarbital is not FDA approved - used for focal onset and generalized seizures- CAUSES Fetal harm.

Second Generation Drugs- Valporic, Keppra, and Topiramate

-Valporiic acid; Likely potentiates Gaba Transmission,. Contra indicated with hypersensitivity.. Pregnancy can cause fetal risk. Common side effects include gl effects -Topiramate causes metabolic and renals stones

Third Generation

• Third Generation drug: Briveracetam is a well controlled drug that controls well from levetricetam and had hepatic impairment.,
• Orphan Drug Act*
• Tax credits on 50% costs,. 7 year Marketing, Orphan Drug limited

Lamictal

• Lamictal must be renited of patient, and has 5 half live.Consider day after missing 2 Oral contraceptives increase with lamotrigine dose. The main issues is the SJS and 10 % risk

Non Pharmacological Therapy,

• Ketogenic Diet: Increase fat diet Vagus Stimulation, refractory device Surgery Is selective patients.

Status eliptictus.

• Generalized Convulsive, aggressive treament
• There are two types of SE and GCSe _ It was founded to lorazapram is preferred Benzo of IC

Discontinuing chronic therapy.

• Patients remain on therapy over lifetime. History should be followed before a new patient enters.Normal neurological EEg can be normal

Diazapam and valtoco

• Used to treat seizures at home
• Rectal form
• A nasal form as well

Hope this helps