2. Seizures
Manifestation of abnormal hypersynchronous or
hyperexcitable discharges of cortical neurons
Occur when there’s an imbalance between
inhibitory and excitatory neurotransmission
Clinical signs or symptoms of seizures depend on:
- location of the discharges in the cerebral cortex
- the extent and pattern of the propagation of the
discharge in the brain
3. Epilepsy
Medical disorder marked by recurrent
tendency to spontaneous, intermittent,
abnormal electrical activity in part of the
brain; manifest as seizures
Traditionally, the diagnosis requires the
occurrence of at least 2 unprovoked seizures
4. Cryptogenic
-Unknown etiology
- not associated with
a previous CNS insult
Symptomatic seizure
- caused by a previously known or
suspected disorder of the CNS
- associated with a previous CNS insult
known to increase the risk of
developing epilepsy
Epileptic seizure
Remote symptomatic seizure
-occurs longer than 1 week following a
disorder
-These disorders may produce static or
progressive brain lesions.
Acute symptomatic
seizure
- occurs following a
recent acute disorder
Provoked
Unprovoked
6. Epidemiology
The lifetime likelihood of experiencing at least 1
epileptic seizure is about 9%
Lifetime likelihood of receiving a diagnosis of
epilepsy is almost 3%
7.
8. Management of a first
seizure
Is this a seizure?
What type of seizure is this?
Any provoking factors?
How to manage?
9. Management
Admission for investigation and observation
If required – treat
NICE
- All children, young people and adults with a recent
onset suspected seizure should be seen urgently by
a specialist.
- To ensure precise and early diagnosis and initiation of
therapy as appropriate to their needs.
11. 1. Chance for recurrent seizure is greatest within 2 years after the first
seizure: 21 – 45%
2. Immediate AED therapy, as compared with delay of treatment
pending a second seizure, is likely to reduce recurrence risk within
the first 2 years
but may not improve quality of life.
Clinicians’ recommendations should be based on individualized
assessments
- Weigh the risk of recurrence against the adverse events of AED
therapy
- To consider educated patient preferences
- Risk of AED adverse events may range from 7-31%
12. AED
General consensus is that anticonvulsant
treatment is needed after 2 seizures
The decision to provide anticonvulsant treatment
after 1 seizure should be individualized
Consider if:
- Risk of recurrence is high
- e.g. unprovoked, structural brain lesions, status
epilepticus, epileptiform EEG
15. AED
Seizure type 1st line Adjunctive
Convulsive status
epilepticus in
hospital
IV Lorazepam
IV Diazepam
Buccal midazolam
IV phenobarbital
Phenytoin
Refractory
convulsive status
epilepticus
IV midazolam
Propofol
Thiopental sodium
Prolonged/repeat
ed seizures +
convulsive status
epilepticus in
community
Buccal midazolam
Rectal Diazepam
IV Lorazepam
16. PHENYTOIN
Mechanism of Action:
Stabilises neuronal membranes and decreases
seizure activity by increasing efflux or
decreasing influx of sodium ions across cell
membranes in the motor cortex during
generation of nerve impulses
17. Indications
Generalised tonic-clonic seizures
Complex partial seizures
Prevention of early post-traumatic seizures
Contraindications
Pregnancy
Hypersensitivity to phenytoin
21. Extravasation
“Purple glove syndrome"
Discoloration with oedema and pain of distal limb
Symptoms may resolve spontaneously
Skin necrosis and limb ischemia may occur
- May require interventions eg fasciotomies, skin
grafts, and amputation (rare)
22. “Purple glove syndrome"
To reduce risk, inject phenytoin slowly and directly
into a large vein through a large gauge needle or
IV catheter; follow with NS flushes
23. Anti-epilepsy (Adults)/ Status epilepticus (Adults)
IV
Loading dose – 10-20 mg/kg
Maintenance dose – 100 mg 8-hourly (5-7
mg/kg/day in 3 divided doses)
Telemetry monitoring
Peak concentration is usually reached in 20-25
minutes
Recommended Dosing
24. Oral
Loading dose – 10-20 mg/kg (in 3 divided doses 2-4
hours apart to minimise gastrointestinal disturbances
and maximise oral absorption)
Maintenance dose – 300 mg/day (or 5-7 mg/kg/day
Onset: 8-12 hours
Peak concentration is usually reached in 4-12 hours
To reload a patient with subtherapeutic level:
Loading dose = (goal total phenytoin level - current
total phenytoin level) x weight in kilograms
Recommended Dosing
25. Monitoring
Cardiac monitoring
- during intermittent IV infusions and for 2 hours after
end of infusion
Outpatient Follow up:
LFT: baseline and q3-6 months initially, then q 6-12
months if patient remains stable
FBC: baseline and every 3-6 months initially, then
every 6-12 months if patient remains stable
26. Normal renal function:
Severe renal impairment:
Steady-state concentrations are reached 5-10 days after
initiation or changes in doses
Correction
• Predominantly bound to plasma proteins (albumin) in the
blood stream
Therapeutic drug monitoring
27.
28. Range Total phenytoin Symptoms
Conventional 10-20 (Free phenytoin: 1-2.5)
Mild to
moderate
20 - 40 Unsteady gait
Nystagmus
Ataxia
Slurred speech
Nausea/vomitting
Fever
Cardiac dysrhythmias
Toxic >40 AMS
Coma
Cardiac dysrhythmias
Seizures
Fatal >100 Death
Therapeutic drug monitoring
29. Relative to dose:
Trough level within 1 hour of dose
Repeat assay at or near steady-state
Routine use in haemodynamically stable patients
with no (or mild) hepatic impairment:
On arrival at steady-state concentration
Repeat concentration at steady-state after
each dosage adjustment
Timing of sampling
30. Routine use in haemodynamically unstable patients with
moderate-to-severe hepatic impairment:
Initial assay after loading dose
- 2 hours after an IV loading dose, or
- 6-8 hours after an oral loading dose
Trough in 3-4 days, then weekly thereafter
Frequency is also dictated by changes in concurrent disease
states or drug therapy, lack of adequate response to previously
adequate doses, and signs/symptoms of toxicity
Patients with recurrent status epilepticus require more intensive
monitoring
31. Diazepam
IV or IM: 0.2 to 0.3 mg/kg IV up to 10 mg/dose
maximum (may repeat once in 5 minutes)
Rectal: 0.5 mg/kg per Rectum up to maximum of 20
mg
Pharmacokinetics:
Onset: 1-3 minutes
Duration of action: 5-15 minutes
32. Lorazepam
Initial: 0.1 mg/kg IV (<2 mg/minute) up to 4 mg
maximum
May repeat once in 5-10 minutes
Avoid more than 2 doses in children due to risk
of respiratory depression
Phamacokinetics:
Onset: 2-3 minutes
Duration of action: 12-24 hours
33. Sodium valproate
Load: 20 mg/kg IV over 1 to 5 minutes
Maintain: 5 mg/kg/hour
Less Sedation, respiratory depression, and
cardiovascular effects than any of the other
agents
Risk of hepatotoxicity
Risk of hyperammonemia
34. Levetiracetam (Keppra)
Load: 20-30 mg/kg IV at 5 mg/kg/min
(may give additional second 20 mg/kg IV dose)
Maximum: 3 grams (or 80 mg/kg/day)
Editor's Notes
Traditionally, the diagnosis of epilepsy requires the occurrence of at least 2 unprovoked seizures. Some clinicians also diagnose epilepsy when 1 unprovoked seizure occurs in the setting of a predisposing cause, such as a focal cortical injury, or a generalized interictal discharge occurs that suggests a persistent genetic predisposition.
Thus, seizure symptoms are highly variable, but for most patients with 1 focus, the symptoms are usually very stereotypic.
Traditionally, the diagnosis of epilepsy requires the occurrence of at least 2 unprovoked seizures. Some clinicians also diagnose epilepsy when 1 unprovoked seizure occurs in the setting of a predisposing cause, such as a focal cortical injury, or a generalized interictal discharge occurs that suggests a persistent genetic predisposition.
, but for most patients with 1 focus, the symptoms are usually very stereotypic.
Prenatal, perinatal, or postnatal complications of pregnancy and delivery
Febrile seizure, which must be differentiated between a complex febrile seizure and a simple febrile seizure
Cerebrovascular disease, such as cerebral infarction, cerebral hemorrhage, and venous thrombosis
Head trauma, which is more significant when it occurs with loss of consciousness lasting longer than 30 minutes, posttraumatic amnesia lasting longer than 30 minutes, focal neurologic findings, or neuroimaging findings suggesting a structural brain injury
Neurodegenerative diseases
Autoimmune disease
Brain neoplasm
Genetic diseases
Drug intoxication, drug withdrawal, or alcohol withdrawal
Metabolic medical disorders, such as uremia, hypoglycemia, hyponatremia, and hypocalcemia
Focal (partial) seizures — Focal seizures originate within networks limited to one hemisphere. A focal seizure may or may not be associated with impaired consciousness or awareness during the attack. When consciousness is fully maintained, the seizure is described as a focal seizure without impairment of consciousness (previously referred to as simple partial seizure). Focal seizures with impaired consciousness correspond to what have previously been called complex partial seizures [1,4]. Impaired consciousness is defined as the inability to respond normally to exogenous stimuli by virtue of altered awareness and/or responsiveness [4]. "Complex" does not refer to the behavior per se, a mistake made by many physicians when describing a focal seizure.
Focal seizures are further subdivided primarily on the basis of the clinical signs and symptoms and the EEG localization. Examples include:
●Motor seizures may manifest as focal motor activity, sometimes with an anatomic spread or march of activity (Jacksonian), versive movement (turning of the eyes, head and/or trunk), vocalization, or arrest of speech.
●Sensory seizures can be manifest by paresthesias, feelings of distortion of an extremity, vertigo, gustatory sensation, olfactory symptoms, auditory symptoms, and visual phenomena such as flashing lights.
●Autonomic seizures may include an epigastric "rising" sensation (a common aura with medial temporal lobe epilepsy), sweating, piloerection, and pupillary changes.
●Focal seizures without impairment of consciousness may also manifest higher cortical, psychic symptoms including dysphasia, feelings of familiarity ("deja-vu"), distortions of time, affective changes (particularly fear), illusions, and formed hallucinations. Such seizures are often referred to as auras.
●During focal seizures with impairment of consciousness, the patient may have a variety of repetitive semipurposeful movements that are referred to as motor automatisms. These can include oral-buccal movements (chewing, swallowing, sucking), complex motor phenomena including bicycling and kicking movements, flailing of the arms, and even running, jumping, and spinning. Such seizures involve regions of both hemispheres, thus explaining the impaired consciousness and the more complex and often bilateral motor symptomatology.
Focal seizures may start in a "silent" area of the brain such as the frontal lobe and become clinically apparent only when they spread to neighboring cortex such as the precentral gyrus of the frontal lobe or the hippocampus of the temporal lobe. In these cases, the EEG monitoring can be critical to the detection of a focal seizure onset.
Many patients who have a single seizure do not require anticonvulsant therapy. The physician and patient or family should decide jointly whether to institute anticonvulsant therapy after a single seizure. This decision is based on a discussion of the risk of seizure recurrence, the effectiveness of anticonvulsant treatment, and the adverse medical and socioeconomic effects of anticonvulsant treatment.
Many patients who have a seizure recover spontaneously and fully with normal consciousness after a short time interval. Patients with incomplete recovery or a prolonged postictal state may require inpatient hospitalization.[
AE -> likely predominantly mild and reversible
Immediate anticonvulsant treatment reduces the likelihood of a second seizure by half.
Phenytoin is a major substrate of the hepatic isozymes cytochrome P450 (CYP) 2C8 and CYP2C9, and a minor substrate of CYP3A4.
Ensure proper catheter / needle position prior to and during infusion.
Ensure proper catheter / needle position prior to and during infusion.
dysrhythmias, hypotension, bradycardia and cardiac arrest)
Hypotension, bradycardia, proarhymthic
Interpretation of serum phenytoin concentration is based on serum albumin concentration.
time to steady-state is variable; generally 5-7 days, although may range from 3-50days
an initial assay may be drawn to assess attainment of therapeutic concentrations
Sodium Valproate:
Use
Oral, IV: Monotherapy and adjunctive therapy in the treatment of patients with complex partial seizures; monotherapy and adjunctive therapy of simple and complex absence seizures; adjunctive therapy in patients with multiple seizure types that include absence seizures
Additional indications: Depakote, Depakote ER, Stavzor: Mania associated with bipolar disorder; migraine prophylaxis
Limitation of use: Do not administer to a woman of childbearing potential unless essential for the management of her condition.
Dosing: Adult
Seizures: Note: Administer doses >250 mg/day in divided doses.
Oral:
Simple and complex absence seizure: Initial: 15 mg/kg/day; increase by 5-10 mg/kg/day at weekly intervals until therapeutic levels are achieved; maximum: 60 mg/kg/day.
Complex partial seizure: Initial: 10 to 15 mg/kg/day; increase by 5 to 10 mg/kg/day at weekly intervals until therapeutic levels are achieved; maximum: 60 mg/kg/day.
Note: Regular release and delayed release formulations are usually given in 2 to 4 divided doses per day; extended release formulation (Depakote ER) is usually given once daily. Depakote ER is not recommended for use in children <10 years of age. In patients previously maintained on regular release valproic acid therapy (Depakene) who convert to delayed release valproate tablets or capsules (Depakote, Stavzor), the same daily dose and frequency as the regular release should be used; once therapy is stabilized, the frequency of Depakote or Stavzor may be adjusted to 2 to 3 times daily.
Conversion to Depakote ER from a stable dose of Depakote: May require an increase in the total daily dose between 8% and 20% to maintain similar serum concentrations.
Conversion to monotherapy from adjunctive therapy: The concomitant antiepileptic drug (AED) can be decreased by ~25% every 2 weeks; dosage reduction of the concomitant AED may begin when valproate therapy is initiated or 1 to 2 weeks following valproate initiation.
IV: Total daily IV dose should be equivalent to the total daily dose of the oral valproate product; administer dose as a 60-minute infusion (≤20 mg/minute) with the same frequency as oral products; switch patient to oral products as soon as possible. Alternatively, rapid infusions of 1.5 to 6 mg/kg/minute have been used in clinical trials to quickly achieve therapeutic concentrations, and were generally well tolerated (Ramsay, 2003; Venkataraman, 1999; Wheless, 2004). One study reported undiluted valproic acid administered at ≤10 mg/kg/minute (dose of ≤30 mg/kg) was well tolerated (Limdi, 2007).
