Treatment of Epilepsy Flashcards
Differentiate between seizure vs epilepsy
Seizure: Transient occurence of signs/symptoms due to abnormal excessive or synchronous neuronal activity in the brain
Epilepsy:
- At least 2 unprovoked seizures > 24h apart
- 1 unprovoked seizure + prob of further seizure similar to general recurrence risk
- Diagnosis of epilepsy syndrome
—> Conceptually: Enduring predisposition to general epileptic seizures
Pathophysiology in seizures & epilepsy
- Hyperexcitability & Hypersynchronization*
- Synchronised paroxysmal discharges occurring in a large population of neurons within the cortex
Hyperexcitability: Enhanced predisposition of a neuron to depolarize
- Excessive excitatory neurotransmitters & insufficient inhibitory neurotransmitters
Hypersynchronization: Intrinsic organization of the local circuits
Etiology of seizures
- Traumatic brain injury
- Stroke
- CNS infection
- Febrile illness
- Metabolic
- Structural
- Genetic
- Immune
- Infectious
- Toxic substances/drugs
Clinical presentation of Focal Seizures
W/o dyscognitive features:
Motor - Clonic movement (twitching, jerking), speech arrest
Sensory - Numbness tingling, visual disturbances
Autonomic - Sweating, salivation, pallor, BP, HR
Psychic - Flashbacks, hallucinations, affective symptoms incl fear, depression, anger & irritability
With dyscognitive features:
Aura (few secs)
Impaired consciousness
Automatisms - Lip smacking, chewing or picking at clothing unpurposefully
Clinical presentation of Generalised Seizures
1) Tonic-clonic
- Stiffening of limbs (tonic) followed by jerking of limbs & face (clonic)
- tonic phase: breathing decrease/cease
- clonic phase: ~1min, after which brain is hyperpolarised & insensitive to stimuli
- After seizure: HA, lethargy, confused, sleepy
- Full recovery takes several min-hrs
2) Absence
- Basic lapse in awareness, begins & ends abruptly
- Lasts a few secs
- > common in children
- Characteristic 3Hz spike waves
3) Atonic
- Classic drop attack
- Short ep followed by immediate recovery
Lab tests & investigations to diagnose Seizures
- Importance of hx taking:
- Onset, duration & characteristics
- Accurate hx
- Neurologic examination
- Concomitant medical conditions
*Scalp EEG
- Essential for diagnosis & classification
However…
- Not all Epileptic pts have abnormal EEG
- EEG can be abnormal in normal pts
MRI with gadolinium
- For adults with 1st seizure/ pts with focal neurologic deficits/ suggestion of focal onset seizure
Biochemical/toxicology
- Rule out electrolyte abnormalities
Risks of seizure recurrence
Lower risk (~30% within next 5yrs, higher in 1st 2yrs)
- First seizure
- Epileptiform abnormalities on EEG
- Prior brain insult
- Structural abnormality in brain imaging
- Nocturnal seizure
Higher risk (~70%) - Risk of recurrent seizures after 2 unprovoked seizures at 4yrs
When to start treatment for Seizures?
After 2 unprovoked, non-febrile seizures
To consider:
- Recurrent risk, potential seizure morbidity, personal circumstances, risk of treatment
Goal of Seizure Treatment
- Absence of epileptic seizures
- Absence of SE
- Maintain optimal QOL
Key features in ILAE Classification
3 key features:
- Where seizures begin in the brain
- Level of awareness during seizure
- Other features of the seizure
Psychosocial Challenges faced by persons with epilepsy
- Social stigma
- Employment
- Prohibited from driving, depending on country/state
- Caregiver burden
Comorbidities in patients with epilepsy
Physical & psychiatric comorbidities associated with:
- Poorer health outcomes
- Increased healthcare needs
- Decreased QOL
- Social exclusion
- Depression & anxiety
- Intellectual disability common in children with epilepsy
Seizure Triggers
- Hyperventilation
- Photostimulation
- Phy & emotional stress
- Sleep deprivation
- Electrolytes imbalance
- Sensory stimuli
- Infection
- Hormonal changes
- Drugs
Patient education for patients with epilepsy
- Avoiding preventable triggers
- Keep a seizure diary
- AEDs: SE, DDI
- Activities to avoid
- Community resources
Appropriate seizure first aid
- Ease the person to the floor & turn the person gently to one side
- Place something flat & soft under the person’s head
- Loosen any ties or objects around the neck that may hinder breathing
- Time seizure, call 911 if lasts > 5mins
- Do not put anything in the person’s mouth
- Do not try to give mouth-to-mouth breaths
- Do not offer food or drink
Non-Pharmacological Treatment for Epilepsy
1) Ketogenic Diet
- Prevention of seizures (children)
- Difficult to adhere to longterm
2) Vagus Nerve Stimulation (VNS)
- For intractable focal seizures
- Stimulator delivers cyclical stimulation
3) Responsive Neurostimulator System (RNS)
- Invasive, stimulator implanted in skull under scalp & leads implanted in brain
- Continuously monitor brain acitivity
Indication
- Frequent & disabling symptoms
- Undergone diagnostic testing that localised <= 2 epiloptogenic foci
- Refractory to >= 2 antiepileptic medications
4) Surgery
Factors influencing choice of ASM
1) Seizure type, epilepsy syndrome
- is rapid titration required?
2) Co-medication & comorbidity
- DDI
- Hepatic/Renal elimination
- Women w child-bearing potential: Levetiracetam/Lamotrigine
- Migraine: Topiramate/Valproate
- Depression/anxiety: Levetiracetam w caution
3) Pt’s lifestyle & preferences
4) National/Institutional guidelines
List ASMs for Generalised Tonic Clonic Epilepsy
- Lamotrigine
- Valproate
- Carbamazepine
- Topiramate
List ASMs for Focal Onset Epilepsy
- Carbamazepine
- Valproate
- Lamotrigine
- Levetiracetam
- Oxcarbazepine
PK of ASMs (Protein binding & Elimination)
1st generation (CBZ, PHT, VPA, PB)
- Hepatic elimination
- Highly protein-bound
2nd generation
- Renal elimination (Exception: Lamotrigine)
- Less protein-binding
PK of ASMs (Effects on Drug Metabolism)
Potent enzyme inducers
- Carbamazepine, phenytoin
Moderate inducer
- Topiramate ( > 200mg: Significant DDI)
Potent enzyme inhibitors
- Valproate
No effects on CYP:
- Levetiracetam, Gabapentin, Pregabalin
Issues with enzyme-inducing ASMs
- DDI
- Reproductive hormones, sexual function, OC in women
- Sexual function & fertility in men
- Bone health
- Vascular risk
Common DDI associated with ASMs
- Antidepressants & Antipsychotics
- Immunosuppressive therapy
- Antiretroviral therapy
- Chemotherapeutic agents
PK Quirks of Phenytoin
Dosage form: IV, capsules, syrup
F = 1
- Complete absorption, but slow
- Reduced by NGT (Space out 1-2hrs between feeds & dosing)
Highly albumin-bound
- Need to correct for low albumin
- low albumin -> Increases free albumin
Zero-order kinetics
Capacity-limited clearance
- Clearance decrease with increasing [ ]
- Conc increment not proportionate to dose increment
PK Quirks of Valproate
Dosage form: IV, tab (chrono form too), syrup
Highly albumin-bound
- saturable protein binding within therapeutic range
- Higher free fraction of valproate with low alb
Displacement by endogenous compounds
Total [valproate] increases in nonlinear function with dosage increase
- Unbound [valproate] increases in linear function
PK Quirks of Carbamazepine
Dosage form: Tablets (Immediate release & CR)
Highly protein bound
CYP3A4 Metabolism > 99%
Autoinduction
- Do not start with desired maintenance dose, gradually increase over initial first few weeks
Clearance increases & t1/2 shortens
- [Carbamazepine} will decline & stabilise in accord with the new clearance & t1/2
How to minimise the occurence & severity of ASMs dose-related side effects?
- Start low, go slow
- Avoid large dosing challenges
- Restricting therapy to one drug only
Adjusting adm schedule:
- Largest dose at bedtime
- Split into smaller doses
- Reduce total daily dose (if possible)
- SR formulation
Primary Toxic SE of ASMs
CNS: Somnolence, fatigue, dizziness, visual disturbances
GI: N/V (Carbamazepine, valproate)
Psychiatric: Behavioural disturbances (Levetiracetam)
Cognition: Usually speech fluency (Topiramate)
- Adverse SEs usually > prominent at higher ASM concentrations
Rare but Severe Adverse SE of ASMs
- Blood dyscrasia (aplastic anaemia, agranulocytosis)
- Hepatotoxicity (Phenytoin & valproate, carbamazepine)
- Pancreatitis (Sodium valproate)
- Lupus-like reaction
- Exfoliative dermatitis
- TEN/SJS
- Most likely to occur in 1st few months of therapy
Chronic SE of ASMs
Note: Tends to be drug-specific & not directly related to plasma concentrations of ASMs
[Connective Tissue]
1) Gingival Hyperplasia (~50% Phenytoin pts)
- Gum enlargement
2) Hirsutism (Phenytoin)
- Children & young adults
3) Alopecia (Sodium valproate)
[Neurological]
1) Encephalopathy (Prolonged phenytoin @ high doses, phenobarbitone)
2) Peripheral neuropathy (Prolonged phenytoin, may also occur with carbamazepine & phenobarbitone)
- May respond with folate supplementation
[GI]
1) Increased weight gain (sodium valproate)
2) Anorexia & weight loss (topiramate)
[Endocrine]
1) Osteomalacia (Phenytoin, carbamazepine, phenobarbitone & valproate also)
- Increased clearance of Vit D leading to secondary hyperparathyroidism, increased bone turnover & reduced bone density
[Hemotological]
1) Blood dyscrasias
2) Megaloblastic anaemia
[Neonatal cognitive defects]
- Phenytoin, Phenobarbitone, Topiramate
- Valproate (cognition)
[Suicidal ideation]
- No change, just monitor
Risk management strategies to reduce risk of Hypersensitivity Reactions
1) Pharmacogenetic testing (HLA-B1502 testing for Carbamazepine)
- Han Chi & other Asian ethnic groups
- HLA-B1502 + : Avoid CBZ/PT
2) Follow dosing guidance (Lamotrigine)
- Risk of serious cutaneous rxns with high starting doses, rapid dose escalations, concomitant valproate (CYP inhibitor)
3) Identify potential cross-sensitivity reactions (ASMs with aromatic rings)
- ASMs with aromatic rings: Phenytoin, Carbamazepine, Phenobarbital, Lamotrigine, Oxcarbazepine
- -> Can form arene-oxide intermediate that can b.c immunogenic through interactions with proteins/cellular macromolecules
- -> If allergic: Prefer to switch
- -> If mild rash & benefit > risk: May want to stick to it & monitor
Why TDM for ASMs
- Plasma [ASM] correlate much better with clinical effects
- ASM treatment prophylactic
- -> Seizures occur @ irregular intervals
- -> Difficult to ascertain whether prescribed dose can produce long-term control
- Not easy to recognise signs of toxicity
- ASMs subjected to PK variability
- -> Diff in dosage requirements across pts
- No lab parameters to monitor clinical efficacy/toxicity for ASM
Indications for TDM of ASMs
1) To establish an individual’s therapeutic range
- Helps in subsequent changes
2) To assess lack of efficacy
3) To assess loss of efficacy (breakthrough seizures)
4) To assess potential toxicity
Counselling for women of childbearing age
- Receive counselling on impt of early discussion on family planning
- Potential risk to foetus
- Use of OC
Can ASMS be discontinued? If so, when
May be discontinued after a min of 2yrs w/o a seizure
- Decision to stop med involves balance between risks of continuation & implications of relapse
- Discussions with pts & their carers/family members
Clinical definition of status epilepticus
Conditions resulting either from:
i) Failure of mechanisms resp for seizure termination
ii) Initiation of mechanisms
leading to…
- Abnormally prolonged seizures that can have long-term consequences
Pharmacological Treatment of Status Epilepticus
0-5min Stabilization phase: Stabilise patient & time seizure
5-20min Initial therapy: Benzodiazepine 1st line
i) IM Midazolam/ IV Lorazepam/ IV Diazepam
or not
ii) IV phenobarbital/ Rectal Lorazepam/ INS Midazolam
20-40min 2nd therapy: (To be given as single dose)
i) IV fosphenytoin/ IV Valproic acid/ IV Levetiracetam
or not
ii) IV phenobarbital
40-60min 3rd therapy:
Repeat 2nd line therapy or
Anaesthetic doses of midazolam/ thiopental/ pentobarbital/ propofol (with continuous EEG monitoring)
