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PR3136 > Treatment of Epilepsy > Flashcards

Treatment of Epilepsy Flashcards

1
Q

Differentiate between seizure vs epilepsy

A

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

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2
Q

Pathophysiology in seizures & epilepsy

A
  • 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

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3
Q

Etiology of seizures

A
  • Traumatic brain injury
  • Stroke
  • CNS infection
  • Febrile illness
  • Metabolic
  • Structural
  • Genetic
  • Immune
  • Infectious
  • Toxic substances/drugs
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4
Q

Clinical presentation of Focal Seizures

A

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

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5
Q

Clinical presentation of Generalised Seizures

A

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

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6
Q

Lab tests & investigations to diagnose Seizures

A
  • 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

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7
Q

Risks of seizure recurrence

A

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
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8
Q

When to start treatment for Seizures?

A

After 2 unprovoked, non-febrile seizures

To consider:
- Recurrent risk, potential seizure morbidity, personal circumstances, risk of treatment

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9
Q

Goal of Seizure Treatment

A
  • Absence of epileptic seizures
  • Absence of SE
  • Maintain optimal QOL
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10
Q

Key features in ILAE Classification

A

3 key features:

  • Where seizures begin in the brain
  • Level of awareness during seizure
  • Other features of the seizure
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11
Q

Psychosocial Challenges faced by persons with epilepsy

A
  • Social stigma
  • Employment
  • Prohibited from driving, depending on country/state
  • Caregiver burden
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12
Q

Comorbidities in patients with epilepsy

A

Physical & psychiatric comorbidities associated with:

  • Poorer health outcomes
  • Increased healthcare needs
  • Decreased QOL
  • Social exclusion
  • Depression & anxiety
  • Intellectual disability common in children with epilepsy
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13
Q

Seizure Triggers

A
  • Hyperventilation
  • Photostimulation
  • Phy & emotional stress
  • Sleep deprivation
  • Electrolytes imbalance
  • Sensory stimuli
  • Infection
  • Hormonal changes
  • Drugs
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14
Q

Patient education for patients with epilepsy

A
  • Avoiding preventable triggers
  • Keep a seizure diary
  • AEDs: SE, DDI
  • Activities to avoid
  • Community resources
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15
Q

Appropriate seizure first aid

A
  • 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
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16
Q

Non-Pharmacological Treatment for Epilepsy

A

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

17
Q

Factors influencing choice of ASM

A

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

18
Q

List ASMs for Generalised Tonic Clonic Epilepsy

A
  • Lamotrigine
  • Valproate
  • Carbamazepine
  • Topiramate
19
Q

List ASMs for Focal Onset Epilepsy

A
  • Carbamazepine
  • Valproate
  • Lamotrigine
  • Levetiracetam
  • Oxcarbazepine
20
Q

PK of ASMs (Protein binding & Elimination)

A

1st generation (CBZ, PHT, VPA, PB)

  • Hepatic elimination
  • Highly protein-bound

2nd generation

  • Renal elimination (Exception: Lamotrigine)
  • Less protein-binding
21
Q

PK of ASMs (Effects on Drug Metabolism)

A

Potent enzyme inducers
- Carbamazepine, phenytoin

Moderate inducer
- Topiramate ( > 200mg: Significant DDI)

Potent enzyme inhibitors
- Valproate

No effects on CYP:
- Levetiracetam, Gabapentin, Pregabalin

22
Q

Issues with enzyme-inducing ASMs

A
  • DDI
  • Reproductive hormones, sexual function, OC in women
  • Sexual function & fertility in men
  • Bone health
  • Vascular risk
23
Q

Common DDI associated with ASMs

A
  • Antidepressants & Antipsychotics
  • Immunosuppressive therapy
  • Antiretroviral therapy
  • Chemotherapeutic agents
24
Q

PK Quirks of Phenytoin

A

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
25
Q

PK Quirks of Valproate

A

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

26
Q

PK Quirks of Carbamazepine

A

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

27
Q

How to minimise the occurence & severity of ASMs dose-related side effects?

A
  • 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
28
Q

Primary Toxic SE of ASMs

A

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
29
Q

Rare but Severe Adverse SE of ASMs

A
  • 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
30
Q

Chronic SE of ASMs

A

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

31
Q

Risk management strategies to reduce risk of Hypersensitivity Reactions

A

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

32
Q

Why TDM for ASMs

A
  • 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
33
Q

Indications for TDM of ASMs

A

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

34
Q

Counselling for women of childbearing age

A
  • Receive counselling on impt of early discussion on family planning
  • Potential risk to foetus
  • Use of OC
35
Q

Can ASMS be discontinued? If so, when

A

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
36
Q

Clinical definition of status epilepticus

A

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

37
Q

Pharmacological Treatment of Status Epilepticus

A

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)

PR3136 (14 decks)

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