Neurology JC029: Seizure And Loss Of Consciousness: Delirium And Encephalopathy, Epilepsy, Coma And Brain Death, Care Of Unconscious Patients, Electrophysiology

Question 1

Consciousness

Answer 1

Definition:
- State of awareness of self and surroundings

Alterations in consciousness conceptualised into 2 types:
1. **Arousal affected
2. **Cognitive + Affective mental function affected (e.g. dementia, delusions, confusion, inattention)

Question 2

Reticular Activating System

Answer 2

(Ascending) RAS:
- Loosely grouped aggregation of neurons located in **Upper brainstem and **Medial thalamus
- maintain cerebral cortex in a state of ***wakeful consciousness

Circuitry between Thalamus and Cerebral cortex
—> Thalamic relay neurons activate **Cortical pyramidal neurons (via GABA) either in:
1. **Tonic mode (wakefulness / REM sleep)
2. ***Burst mode (non-REM sleep), possibly mediated by T-type Ca channels

Normal awake state:
- Thalamic relay neurons fire in **Tonic mode —> activate cortex (sensory information) in a **non-rhythmic, ***desynchronised way

Normal non-REM sleep:
- Thalamic relay neurons fire in **Burst mode —> activate cortex in **rhythmic, ***bilaterally synchronous way (observed as sleep spindles on EEG)

ARAS: Diffuse neurons in Reticular formation
1. Locus coeruleus
—> Norepinephrine system —> ***Fight/flight response

2. Raphe nucleus
   —> Serotonin system —> Functions of ***basal ganglia, Emotion
3. Pontine
   —> ACh system —> ***Sleep/wake cycle, Wakefulness
4. Substantia nigra / Ventral Tegmental Area (VTA)
   —> Dopamine system —> **Dopaminergic neurons of basal ganglia, Cognitives, **Memory, Incentive feelings

Question 3

Definition of terms

Answer 3

Alert: A perfectly normal state of arousal

Sleep: Only normal form of altered consciousness

Coma: Deep sleep-like state from which patient cannot be aroused, complete ***unresponsiveness to arousal

Stupor: State of baseline unresponsiveness, patient can only be aroused by ***vigorous stimuli (better than Coma)

Lethargy: Lies between Alert and Stupor

記: Alert / Sleep —> Lethargy —> Stupor —> Coma

Question 4

Disorders of consciousness

Answer 4

1. Persistent Vegetative State (PVS) (持續性植物狀態)
2. Akinetic mutism (運動不能性緘默症)
   - partially / fully awake
   - able to form impressions and **think but remain **immobile and mute
   - due to damage in ***Medial thalamic nuclei / Frontal lobes / Hydrocephalus
3. Abulia (意志喪失)
   - mental and physical slowness + **diminished ability to initiate activity
   - **mild form of akinetic mutism
4. Inattention
   - inability to ***sustain uninterrupted thought and actions
   - disorientation: earliest outward sign

Question 5

Persistent Vegetative State (PVS)

Answer 5

• An ***awake but unresponsive state
• Lost cognitive neurological function but retain vegetative / non-cognitive function such as cardiac action, respiration, BP maintenance (***yawning, coughing, swallowing, limb and head movement persist but few meaningful responses to external and internal environment)

Cause:
- **Extensive cortical grey / subcortical white matter lesion with **relative preservation of brainstem function

Clinical causes:
- Cardiac arrest / Head injuries

Prognosis for regaining mental function once vegetative state has supervened for several months (Persistent vegetative state PVS) is almost none

Question 6

Glasgow Coma Scale

Answer 6

3-15

Motor response (M)
6: Obey
5: Localise
4: Withdraw
3: **Abnormal flexion (Decorticate)
2: **Extensor response (Decerebrate)
1: Nil

Verbal response (V)
5: Oriented, coherent speech
4: Confused speech
3: Inappropriate words
2: Incomprehensible sound
1: Nil

Eye opening (E)
4: Spontaneous
3: Open to speech
2: Open to pain
1: Nil

Question 7

DDx of Coma (Mimicking conditions)

Answer 7

1. PVS
2. Akinetic mutism, Abulia
3. Locked-in syndrome (閉鎖綜合症)
   - **alert and aware
   - **quadriplegic with **lower CN palsy
   - due to bilateral **ventral pontine lesions
4. Catatonia (緊張性抑鬱障礙)
   - hypomobile and mute syndrome
   - a **psychiatric condition
   - can be a psychiatric phenomenon of a neurological disorder (e.g. Autoimmune encephalitis: NMDA receptor encephalitis)
   - associated with a major **psychosis
   - appear **awake with **eyes open but make no voluntary / responsive movements
   - blink spontaneously, swallow and may not appear distressed
   - ***NO clinical evidence of cerebral damage
5. Pseudocoma

Question 8

Consciousness: Principals of Coma

Answer 8

1. Lesions that damage ***RAS / its projections (i.e. Thalamo-cortical projections)
2. Destruction of large portions of both ***cerebral hemispheres
3. Suppression of reticulo-cerebral function by drugs, toxins / metabolic derangements such as **hypoglycaemia, anoxia, azotemia, **hepatic failure with high ammonia level

Question 9

Causes of Coma

Answer 9

Symmetrical causes

Non-structural
1. Toxins
- ***lead, thallium, mushrooms, cyanide, methanol, ethylene glycol, CO

2. Drugs
   - ***sedatives, barbiturates, tranquilliser, opiate, alcohol, amphetamine, anticholinergic
3. Metabolic
   - hypoxia, hypercapnia, **DKA, lactic acidosis, **hypoglycaemia, hyper/hyponatraemia
4. Infections
   - bacterial ***meningitis, viral encephalitis, sepsis, syphilis
5. Others
   - diffuse ***ischaemia to brain (CHF, MI, arrhythmia), hypotension, hypertensive encephalopathy, hypothyroidism, post-ictal

Structural:
1. Bilateral ICA occlusion
2. **Bilateral ACA occlusion —> bilateral frontal lobe infarction
3. **SAH
4. Bilateral thalamic haemorrhage
5. Diffuse trauma (contusion, concussion)
6. **Hydrocephalus
7. **Basilar artery occlusion —> bilateral cerebellar + extensive brainstem infarction
8. ***Midline brainstem tumour
9. Pontine haemorrhage

***記: Occlusion, Haemorrhage, Tumour, Hydrocephalus

Question 10

***Seizure

Answer 10

(Epileptic) Seizure: a **transient occurrence of S/S (1-3 mins), due to abnormal **excessive / synchronous activity in the brain
1. **Altered awareness
2. **Abnormal behaviour
3. ***Involuntary movements

Diagnosis:
- Careful history (most important element in Dx)
- Selected investigations

**Seizure: Provoked / Unprovoked
**Epilepsy: Unprovoked seizure

Question 11

DDx of Epileptic seizures (Mimicking conditions)

Answer 11

1. ***Hyperventilation
   - perioral cyanosis
   - hand paresthesia
   - carpopedal spasm
2. ***Migraine
   - slow progression neurologic symptoms
   - visual symptoms prominent
   - basilar migraine: unusual features e.g. weakness, impaired consciousness, bilateral blindness
3. Panic attack
   - abrupt onset with intense feeling of fear, sense of impending death / inability to breathe
   - autonomic features prominent e.g. tachycardia, sweating, nausea
   - **last longer (5-30 mins) than typical seizure (1-3 mins)
   - **no loss of consciousness
4. ***Psychogenic seizure
   - fluttering eye movement, forceful eye closure
   - out-of-phase, thrashing limb movement, pelvic thrusting
5. **Syncope
   - occur in **cardiac arrhythmia (can be benign e.g. **vasovagal syncope / sinister e.g. heart block, significant bradycardia in sick sinus syndrome)
   - prodrome of dizziness
   - **brief LOC (<20 sec), rapid return to normal
   - muscle jerks (convulsive syncope) can occur at end ∵ hypoxia
6. **Transient global amnesia
   - isolated amnesic syndrome
   - prolonged duration (several hours)
   - **no alteration of consciousness
   - no confusion, weakness, aphasia
   - persistent memory gap during period of attack, recurrence unusual
7. ***Transient ischaemic attack
   - sudden onset without progression of symptoms
   - variable symptoms related to brain and vascular anatomy
   - negative features (e.g. weakness, loss of sensation, aphasia) predominate

Question 12

Causes of Seizure (Having seizure =/ Having epilepsy)

Answer 12

Seizures common in:
1. Metabolic conditions
- **Uraemia
- **Hypoglycaemia
- Hyperglycaemia
- ***Hepatic failure

2. Toxic conditions
   - Drug overdose
   - ***Withdrawal
3. Infection
   - **Meningitis
   - **Encephalitis

Seizures with above underlying causes = Provoked seizures —> in theses cases seizures =/ Dx of Epilepsy

Question 13

***Epilepsy

Answer 13

Definition (any 1 of 3):
1. >=2 seizures **NOT provoked by other illnesses / circumstances (>=2 unprovoked seizures occurring >24 hr apart)
2. A single unprovoked seizure if **recurrence risk is high (>60% over next 10 years)
3. Diagnosis of epilepsy syndrome

Epidemiology:
- affect >70 million ppl worldwide
- prevalence: ~4-12 per 1000
- incidence: ~40-70 per 100,000 person-years, higher in infants / >50 yo

Question 14

Causes of Epilepsy

Answer 14

1. ***Unknown (majority)
   - probably genetic (mutations in genes producing ion channels, synaptic proteins, transcriptional regulators)
2. ***Stroke
3. ***Head trauma
4. Alcohol
5. Neurodegenerative disease (e.g. Alzheimer’s)
6. ***Static encephalopathy (e.g. Chronic severe hepatic encephalopathy, Uraemic encephalopathy)
7. ***Brain tumours
8. ***Infection
9. ***Autoimmune (e.g. NMDA receptor AutoAb encephalitis)

Question 15

***Classification of Seizures (Lecture + Youtube)

Answer 15

According to Clinical features:
1. ***Generalised seizures (entire brain involved)
- Myoclonic (sudden brief jerks / twitches of muscles like hit by electricity)
- Absence (aka Petit mal, brief loss of awareness, blank stare, may have lip smacking / eye blinking)
- Clonic (rhythmic jerky movement)
- Tonic-clonic (GTCS, aka Grand mal) (muscle stiffening + jerking)
- Tonic (increased muscle tone)
- Atonic (Astatic) (uncommon) (suddenly lose muscle tone and fall to ground i.e. sudden drop attack)

2. **Partial (Focal / Local) seizures (part of brain involved)
   - Simple partial seizure (SPS): **unimpaired consciousness (unusual feelings, strange sensation, uncontrollable jerky but remain conscious)
   - Complex partial seizure (CPS): ***impaired consciousness
   - Partial seizure secondarily generalised

ILAE (International League Against Epilepsy framework) classification
1. Focal Motor
- Automatism
- Atonic
- Clonic
- Myoclonic
- Tonic
- Epileptic spasms
- Hyperkinetic

2. Focal Non-motor
   - Autonomic
   - Behaviour arrest
   - Cognitive
   - Emotional
   - Sensory
3. Generalised Motor
   - Tonic-clonic
   - Clonic
   - Tonic
   - Myoclonic
   - Atonic
   - Epileptic spasms
4. Generalised Non-motor
   - Typical
   - Atypical
   - Myoclonic
   - Eyelid myoclonia (rare)
5. Unclassified (Unknown onset)

Question 16

Classification of Epilepsy

Answer 16

1. Generalised
   - predominant type of seizure begin simultaneously in **both cerebral hemispheres
   - strong **genetic component
   - ***always LOC (SpC Paed)
   - no warning (no aura)
   - symmetrical seziure
   - bilaterally synchronous seizure discharge on EEG
2. Partial (Localisation-related)
   - seizures originate in >=1 **localised foci
   - most believed to be result of **CNS insult (but mostly cannot be identified)
   - onset in one of cerebral hemisphere (begin in a relatively small group of dysfunctional neurons in one of hemisphere) (SpC Paed)
   - may be preceded by aura
   - ***may / may not have LOC

Question 17

Epilepsy syndromes

Answer 17

***記: Types of Seizure, Neurological abnormalities, EEG

Cardinal features:
- Predisposition to recurrent **unprovoked seizures, classified according to
1. **Types of seizures
2. Presence / Absence of **neurological / developmental abnormalities
3. **EEG findings

Example:
***Juvenile myoclonic epilepsy (JME) characterised by:
1. Myoclonic seizures, GTCS, Absence seizures (less frequently) in adolescents
2. Normal intellectual function
3. EEG: Rapid, Generalised spike-wave + Polyspike-wave discharges
- Treatment: Valproate lifelong (due to high risk of recurrence esp. deprived of sleep / after alcohol) (SpC Paed)

SpC Paed Senior tutorial:
Generalised epilepsy syndromes:
1. **Infantile spasm
2. **Juvenile myoclonic epilepsy
3. ***Lennox-Gastaut syndrome

Partial epilepsy syndromes:
1. ***Benign rolandic epilepsy

Question 18

***Mechanism of Seizure

Answer 18

Brain function:
- depend of cooperation between separate networks, probably mediated through ***oscillations within these networks

Cortical neurons generate oscillations which depend on:
1. Inhibitory neurons
2. Neuronal communication (e.g. synaptic transmission)
3. Intrinsic neuronal properties (e.g. ability of neurons to maintain burst firing)

Occurrence of epileptic activity might be an emergent property of such oscillatory networks

Epileptic seizure: Due to **Abnormal excessive / Synchronous activity in the brain
- Transition from normal to epileptiform behaviour probably caused by greater spread and neuronal recruitment secondary to combination of:
1. **Enhanced connectivity
2. **Enhanced excitatory transmission
3. **Failure of inhibitory mechanisms
4. ***Changes in intrinsic neuronal properties

Example of mutations:
- Ion channels
- Synaptic proteins
- Transcriptional regulators (mTOR)

Question 19

Generalised epilepsy

Answer 19

Mutation of genes encoding:
1. **Ion channels (e.g. Na, K channel)
2. **Neurotransmitter receptors
3. Synaptic support proteins (regulate synaptic function)
4. ***mTOR pathway regulators (cell growth and proliferation)
5. Chromatin remodelling and transcription regulators

Most have complex inheritance pattern, only a few with Mendelian inheritance associated with single gene mutations

Question 20

Generalised epilepsy with febrile seizures plus

Answer 20

Febrile seizures + >=1 of other seizure types:
1. Absence
2. Myoclonic
3. Atonic
4. Afebrile GTCS (generalised tonic-clonic seizure)

• AD heritance
• incomplete penetrance
• mutation in gene for voltage-gated Na channel β1 subunit (**SCN1B) —> modify gating + inactivation properties of Na channel —> promote **depolarisation and hyperexcitability in neurons —> ↑ tendency to fire repetitive bursts

Question 21

Partial epilepsy

Answer 21

**Most common seizure disorder in adults, often stem from **local lesions:
1. Head trauma
2. Stroke
3. Tumour

**Mesial temporal lobe epilepsy (mTLE):
- CPS arise from mesial temporal lobe
- most common lesion in mTLE: **Hippocampal sclerosis
- Ictal onset in mesial temporal lobe structures (Hippocampus, Amygdala, Parahippocampal cortex) —> resection of these areas may abolish seizures

Question 22

Partial epilepsy: Complex Partial Seizure (CPS)

Answer 22

CPS:
- common in ***Temporal lobe epilepsy (TLE)

Begin with
—> **Olfactory / Gustatory hallucinations
—> **Epigastric sensation
—> ***Psychiatric symptoms - deja vu, jamais vu, depersonalisation
—> Blank episodes (Stare blankly)

Once progress to loss of awareness, patient may
1. Speak unintelligibly
2. Lip smacking
3. Picking at clothing
4. Other Automatisms (e.g. screaming, crying, laughing, cardiac arrest)
- more / less coordinated **involuntary motor activity occurring during **clouding of consciousness either during / after a seizure, usually without recollection

Question 23

***Evaluation of Epilepsy

Answer 23

1. History taking
   - remote head ***injury
2. Neurological examination
   - ***normal in most epilepsy patients
   - some may have skin manifestations e.g. NF, Tuberous sclerosis
3. Patients with unprovoked first seizures should undergo
   - **EEG
   - Neuroimaging: **MRI (with epilepsy protocol) more sensitive than CT in detecting parenchymal structural lesions related to epilepsy
   - **Blood tests: CBC, Electrolytes (Ca, PO4, Mg), LRFT (including **NH3)
   - Adolescents / Adults with unexplained generalised seizures —> Screen for substance abuse —> ***Toxicology screen (e.g. cocaine, amphetamine)

Question 24

EEG

Answer 24

Epileptiform EEG patterns:
- Spikes wave
- Sharp wave
- assist in ***diagnosis + classification of seizures —> Focal / Generalised

Normal EEG:
- cannot exclude diagnosis of Epilepsy

Interictal EEG (In-between seizures):
- cannot confirm diagnosis of Epilepsy
- ∵ some ***healthy population can have abnormal EEG

EEG abnormal in ~50% of patients presenting with a first seizure (Epileptiform discharges in only ~50% of these patients)
- Incidence of abnormalities ↑ when EEG **repeated / performed after **sleep deprivation
- Video EEG monitoring necessary if
—> nonepileptic events are suspected (i.e. pseudo-seizure)
—> to identify epileptogenic focus (ictal EEG)
—> hospitalised for 7-10 days (record seizure when withdrawal of epileptic drugs)

Question 25

***Management of Epilepsy

Answer 25

Diagnosis of epilepsy can considerably affect:
- patients’ mood
- interpersonal relationships
- employability
- social functioning
- QOL
- ability to drive
—> Early + Repeated discussions suggested

Pharmacological:
- ***controversial in patient with a single seizure
- ~25% patients have recurrent seizures within 2 years in absence of factors that predict high probability of recurrence:
—> epileptiform activity on EEG
—> known cause e.g. a remote major head trauma
—> with >=1 risk factors, risk of recurrent seizures only <=40%

1. Anti-epileptic drugs (AED) (almost always justified when ***Dx of epilepsy made (i.e. >=2 recurrent unprovoked seizure))

***Broad-spectrum AED (initial choices in most adult regardless of seizure type / epilepsy syndrome)
- Valproate
- Lamotrigine
- Levetiracetam
- Topiramate
- Perampanel

**Narrow-spectrum AED (restricted to patients having **Focal epilepsy with Partial / Secondarily generalised seizure)
- Carbamazepine, Oxcarbazepine
- Phenytoin
- Lacosamide
- Gabapentin, Pregabalin

Non-pharmacological:
1. Discourage from activities for which seizures ↑ risk of injury / mortality
- **driving (prohibited from driving, duration of time without seizures varies 3 months - 1 year)
- **operating high risk power equipment
- working at heights
- swimming, bathing, hiking alone (low bath tub water level)
- cooking over fire alone (use non-fire heat source)

2. Neuromodulation
   - palliative options when surgery not possible / fail
   - **electrical pulses to peripheral nerves / specific brain areas in response to enhanced rhythmicity to **counteract potential seizure generation / propagation
   - ***vagus nerve stimulation: reduce seizure frequency in ~1/3, ↑ QOL, ↓ SUDEP risk

Question 26

Narrow spectrum AED

Answer 26

• Less effective than Broad spectrum in Idiopathic ***generalised epilepsy syndromes e.g. JME, childhood absence epilepsy
• May even exacerbate some seizure types in these patients (e.g. Phenytoin, Carbamazepine, Gabapentin, Pregabalin may worsen **Absence epilepsy and **Myoclonic seizure)

Question 27

AED by seizure types

Answer 27

Focal / Most Generalised seizures:
- BDZ
- Phenobarbital
- **Valproate
- **Lamotrigine
- **Levetiracetam
- **Topiramate
- Perampanel

Focal seizure only:
- Brivaracetam
- **Carbamazepine, Oxcarbazepine
- **Phenytoin
- Lacosamide
- ***Gabapentin, Pregabalin

Absence seizure only:
- ***Ethosuximide

Question 28

Valproate

Answer 28

Broad-spectrum

Effective in:
1. Primary GTCS
2. Absence
3. Myoclonic
4. Partial seizure (2nd line)

MOA:
- ***Voltage-dependent blockade of Na channels

PK:
- highly protein bound
- t1/2: 7-17 hours
- metabolised in liver
- not induce liver enzymes

SE:
- Tremor
- **Weight gain
- Sedation
- Pancreatitis
- BM suppression
- Thrombocytopenia
- **Interfere with urea cycle (mild ↑ NH3)
- **Impair platelet function
- **Teratogenicity and children exposed to valproate in utero —> lower IQ score compared to PHT, CBZ, LG —> Avoid in female of child-bearing age

Question 29

Phenytoin (PHT)

Answer 29

Narrow-spectrum
Established effectiveness (>50 years)

Effective in:
1. Partial seizure
2. GTCS

MOA:
- ***Voltage-dependent blockade of Na channels

PK:
- **Enzyme-inducing
- metabolised via P450 system —> catabolic enzymes saturable —> zero-order kinetics
- at point of saturation —> small ↑ dose —> large ↑ in serum concentration
- highly protein bound —> systemic disease / other drugs can change concentration of unbound fraction
—> **Narrow therapeutic index

SE:
- **Neurotoxicity (dose-related, nystagmus, dizziness, unsteady gait, lethargy)
- **Hypersensitivity skin reactions
- **Gingival hyperplasia
- **Hirsutism
- Coarsening of facial features (cosmetic disfigurement)
- Hypocalcaemia (impair Vit D absorption)
- ***Megaloblastic anaemia (interfere folate metabolism)

Fosphenytoin:
- prodrug
- less irritative
- parenteral use

Question 30

Carbamazepine (CBZ)

Answer 30

Narrow-spectrum

Effective in:
1. Partial seizure
2. GTCS

***Not effective in (may even exacerbate):
1. Absence
2. Myoclonic

MOA:
- Prevent repetitive firing in depolarised neurons through blockade of Na channels

PK:
- Hepatic metabolism
- induce own metabolism, need to ↑ dose after 1st month
- significant, complex, unpredictable **interaction with other AED / drugs e.g. Corticosteroids, Theophylline, Haloperidol, Warfarin, Estrogen OCP
- **Enzyme inducing —> render OCP ineffective

SE:
- **Neurotoxicity (dose-related, diplopia, dizziness, headache, nausea, somnolence)
- **Allergic morbilliform rash (can progress to **SJS)
- Reversible leukopenia
- Hyponatraemia
- **Toxic hepatitis
- Orofacial dyskinesia
- Cardiac arrhythmia
- Severe idiosyncratic blood dyscrasias (rare) —> causing leukopenia

Question 31

Lamotrigine (LG)

Answer 31

Broad-spectrum
Preferred 1st line AED in ***Elderly patients (∵ few drug interactions)

Effective in:
1. Partial seizure
2. GTCS

MOA:
1. Antifolate activity (inhibit dihydrofolate reductase)
2. Inhibit Voltage-dependent Na currents

PK:
- ~55% protein bound
- hepatic metabolism
- excreted in urine
- t1/2: 30 hours (monotherapy)
- ***NOT affect metabolism / plasma levels of CBZ, PHT, Phenobarbital, Valproate

SE:
- **Rash (can progress to **SJS)
- Drowsiness
- Dizziness
- Unsteady gait
- Headache
- Tremor
- Nausea

Question 32

Levetiracetam

Answer 32

Broad-spectrum

Effective in:
- ***Adjunct treatment for Partial seizures with / without Secondary generalisation

MOA:
- Binds to synaptic vesicle protein ***SV2A —> act presynaptically to modulate exocytotic function of SV2A

PK:
- minimal protein binding
- partially metabolised by enzymatic hydrolysis, NOT dependent on P450 system
- drug and metabolite excreted in urine (↓ dose in renal impairment)
- t1/2: 6-8 hours
- unaffected by other AED
- NOT alter levels of other AED
- NOT affect kinetics of other drugs e.g. OCP, warfarin, digoxin

SE:
- ***Hyperactivity (+ other behavioural symptoms e.g. irritability) (esp. in young children)
- Somnolence
- Asthenia
- Dizziness
- Infection

Question 33

AED: Adverse effects and cautions in women

Answer 33

Hepatic enzyme-inducing AED —> ***↑ OCP clearance:
1. PHT
2. CBZ
3. Phenobarbital
4. Topiramate

Lamotrigine:
- dose need adjustment with OCP intake —> OCP ↑ clearance of LG

***Pregnancy:
- ↑ clearance of many AED (esp. LG)

***Babies born to women with epilepsy:
- ↑ rate of malformation (attributable to AEDs) (most AED are teratogenic esp. Valproate)

Valproate:
- Teratogenic
- associated with Polycystic ovaries, Anovulatory cycles, Hyperandrogenism
- ***Avoid in women of childbearing age unless NO alternative

No AED absolutely safe
- highest risk: Valproate
- lowest risk: LG, Levetiracetam

**Monotherapy + **Minimal effective dose —> prescribed for pregnant women —> minimise risk of birth defects

Question 34

AEDs: Effective on cognition of children of women with epilepsy

Answer 34

• ↑ Risk of poor cognitive outcomes (lower IQ) in children from women taking valproate while child-bearing
• Children exposed to Valproate in utero have lower IQ than PHT, CBZ, LG at 4.5 yo
• Carbamazepine NOT ↑ such risk

Question 35

Epilepsy treatment: Response to AED

Answer 35

• ~50% newly diagnosed epilepsy become seizure-free while taking 1st AED
• ~2/3 patients become seizure-free after receiving 2nd / 3rd AED
• ~20-30% still have ongoing seizure —> ***Drug-resistant Epilepsy

Question 36

Drug-resistant Epilepsy

Answer 36

• Assumed after failure of adequate trial of ***2 tolerated, appropriately chosen and used AEDs
• Further AED unlikely to confer benefit if uncontrolled by 2 AEDs
• Candidates for epilepsy ***surgery (esp. Partial epilepsy)

TLE (Temporal lobe epilepsy):
- most common cause of drug-resistant epilepsy
- open surgical resection: safe + effective compared to continued medical therapy
- TLE from unilateral hippocampal sclerosis —> Standard anterior temporal lobectomy / More selective ***amygdalohippocampectomy

SE of open surgery:
- **short-term memory loss in dominant temporal lobe surgery
- low rates of infection
- visual field defects
- CN palsies
- **hemiparesis
- death

Non-TLE:
- ***Invasive EEG used to localised epileptic focus (usually more heterogeneous) —> less likely to experience seizure freedom

Question 37

Neuromodulation

Answer 37

Indication:
- Seizure **uncontrolled by AED
- **No epileptic focus identified
- Epileptic focus identified but surgery associated with excessive injury / SE to patient —> epilepsy surgery ***not feasible

• Palliative options when surgery not possible / fail
• Electrical pulses to peripheral nerves / specific brain areas in response to enhanced rhythmicity to counteract potential seizure generation / propagation
• Vagus nerve stimulation: reduce seizure frequency in ~1/3, ↑ QOL, ↓ SUDEP risk

Question 38

Status Epilepticus (SE)

Answer 38

Definition:
- **Prolonged (>3/5 mins) / Repeated seizures **without full recovery of consciousness between attacks

• ***Medical emergency
• Convulsive status epilepticus e.g. Generalised tonic-clonic status —> Most common SE
• Non-convulsive status epilepticus (i.e. without obvious convulsions) e.g. Absence SE (confusion, clouding of consciousness), Complex partial SE (partial responsiveness, semipurposeful automatism, total unresponsiveness, speech arrest, stereotypical automatisms) —> Diagnosis is difficult

***Rmb: Later a seizure is stopped —> more difficult to be stopped (∵ more neurons recruited into abnormal synchronous activities)

Causes:
1. **Acute cerebral insult
- **CNS infection (classically viral encephalitis e.g. HSE)
- **Neurotoxins (including drugs e.g. Lignocaine, Amphetamine)
- **Autoimmune encephalitis
(- **Neoplasia
- **Metabolic derangement (e.g. hypoglycaemia, hypoNa, hypoCa) (Davidson))

2. ***Rapid withdrawal of AED

Prognosis:
- 3-20% mortality
- prolonged seizure and an identified acute brain insult associated with higher mortality / morbidity

Question 39

Management of Status Epilepticus (SE)

Answer 39

• Time is critical
• ***ABC
• Airway protection (keep airway patent by aspiration of food bolus, sputum, saliva), O2, Intubate + Ventilatory support
• Adequate IV volume (by IV fluid), Maintain BP
• Observe vital signs
• ***ECG monitoring
• ***Terminate seizure activity
• ***Evaluate for + Treat underlying causes of SE
  —> Glucose, U+E, Ca, Mg, LFT, AED level, CBC, Clotting, Toxicology, CT brain (Davidson)
• ***EEG monitoring
• Prevent systemic complications (e.g. rhabodomyolysis, hypothermia, electrolyte disturbance)

Drug:
Step 1: ***IV BDZ
- Diazepam (short duration of action)
- Midazolam
- Lorazepam

Step 2: **IV Phenytoin
- **loading then ***maintenance —> to prevent recurrence of seizure
- other drugs: Valproate, Levetiracetam, Lacosamide, Perampanel

Refractory SE:
- Midazolam IV ***infusion (ICU only) —> can cause hypotension (need close BP monitoring)
- Phenobarbital: high risk of respiratory depression / arrest after BDZ
- Propofol: loading then maintainence infusion (ICU)
- Thiopental: loading then maintainence infusion (ICU)

Question 40

Delirium / Acute confusional state

Answer 40

Confusion:
- Mental + Behavioural state of ***reduced comprehension, coherence, capacity to reason

Delirium:
- **Acute confusional state characterised by **acute decline in attention, cognition (vs Dementia: chronic confusional state)
- common, life-threatening
- a symptom that confer presence of ***life-threatening conditions in 10-30%
- preventable clinical syndrome among >65 yo
- rate highest among hospitalised older patients (14-24% prevalence at hospital admission)
- incidence ↑ during hospitalisation, age
- 1 year mortality rate 35-40%

Diagnostic criteria for Delirium (DSM-4-R) include >=2 of following:
1. **Perceptual disturbance (misinterpretations / illusions / hallucinations)
2. **Incoherent speech at times
3. **Disturbance of sleep-wake cycle
4. **Increased / Decreased psychomotor activity

As confusion worsen —> more ***global mental impairments occur, including impairment of:
- Memory
- Perception
- Comprehension
- Problem solving
- Language
- Praxis
- Visuospatial function
- Emotional behaviour

Question 41

Diagnosis of Delirium

Answer 41

• Primarily clinical

Clinical features:
1. **Acute onset
2. **Fluctuating course
3. Inattention
4. Disorganised thinking (e.g. incoherent speech)
5. Altered level of consciousness
6. Cognitive deficits (e.g. memory deficits, disorientation)
7. **Perceptual disturbances (e.g. illusions / hallucinations)
8. **Psychomotor disturbance
- Hyperactive
- Hypoactive
- Mixed
9. ***Altered sleep-wake cycle
10. Emotional disturbance

• Often unrecognised due to:
  —> ***Fluctuating nature
  —> Overlap with dementia
  —> Lack of formal cognitive assessment
  —> Underappreciation of its clinical consequences
  —> Failure to consider the importance of diagnosis of delirium

Question 42

Pathophysiology of Delirium

Answer 42

• Poorly understood
• Potential role in:
  1. Cholinergic deficiency
  2. Dopaminergic excess
  3. Cytokines (breakdown of BBB + altered neurotransmission)
  4. Chronic hypercortisolism

EEG:
- ***diffuse slowing of cortical background activity (NOT correlate with underlying cause)

***Generalised disruption of higher cortical functions with dysfunction in:
- Prefrontal cortex
- Subcortical structures
- Thalamus
- Basal ganglia
- Frontal and Temporoparietal cortex
- Fusiform cortex
- Lingual gyri

Question 43

Precipitating factors for Delirium

Answer 43

1. Dementia
2. Male
3. Old age
4. Poor cognitive status
5. Poor functional status
6. Sensory impairment
7. Decreased oral intake
8. Drugs
9. Co-existing medical conditions
10. Primary neurologic diseases (e.g. stroke, meningitis, encephalitis)
11. Intercurrent illnesses (e.g. AMI, DKA)
12. Surgery
13. Environmental (e.g. stress, pain, multiple procedures)
14. Prolonged sleep deprivation

Question 44

Evaluation of Delirium

Answer 44

1. Determine acuity of changes in mental status
2. Brief but formal cognitive testing (e.g. ***MMSE) for every older hospitalised patient
3. Subtle delirium often missed, Delirium can last for months / years (Persistent Delirium)
4. Older patients should be aroused during ward rounds and evaluated daily for hypoactive form of delirium (often overlooked)
5. Search for underlying cause + precipitating factors of delirium
   —> Delirium often sole manifestations of serious underlying disease
6. Review medications + alcohol intake
7. EEG: limited role
   - most useful for detecting occult seizure + differentiate from psychiatric disorders
8. Neuroimaging: low clinical yield, only for
   - new focal neurological sign
   - signs of head trauma
   - fever (encephalitis / meningitis)
   - no other identifiable cause
   - incomplete history
   - neurological examination cannot be completed

Question 45

Investigations in Delirium

Answer 45

1. Basic
   - CBC
   - LRFT
   - Electrolytes
2. Neuroimaging
3. ***Lumbar puncture
4. ***Septic workup
   - including blood culture
5. ***ECG (for AMI)
6. ***Blood glucose, Ketone (for DKA)
7. ***ABG (for respiratory failure)

Question 46

Prevention of Delirium

Answer 46

Yale Delirium Prevention Trial
Towards 6 risk factors:
1. **Orientation + Therapeutic activities for cognitive impairment
2. **Early mobilisation
3. Non-pharmacological approaches (minimised psychoactive drugs use)
4. **Interventions to prevent sleep deprivation
5. **Communication methods + adaptative equipment for vision / hearing impairment
6. Early intervention for volume depletion

Question 47

Treatment of Delirium

Answer 47

1. Search + Treat underlying causes
2. **Supportive care
   - ABC, hydration, nutrition
   - positioning + mobilisation to prevent pressure sores / DVT
   - avoid physical restraints
   - non-pharmacological means for symptoms of delirium
   - calm comfortable environment
   - **orienting influences (e.g. calendars, clock, familiar objects from home)
   - **regular orienting communication with staff
   - limiting room and staff changes
   - coordinate schedules for drugs, vital signs assessment + procedures
   - **uninterrupted sleep (low level of noise / lighting)
   - encourage normal sleep-wake cycle
3. Prevent complications
4. Treat behavioural symptoms
5. Pharmacological
   - reserved for patients whose symptoms threaten self / others’ safety / result in interruption of essential therapy e.g. mechanical ventilation
   —> ***Haloperidol (typical antipsychotic, agent of choice)
   —> Risperidone (atypical)
   —> Olanzapine (atypical)
   —> Quetiapine (atypical)
   —> Lorazepam (BDZ, 2nd line)
   —> Trazodone (antidepressant)

Question 48

***Brain death

Answer 48

Criteria for establishment of brain death:
1. Coma (spinal reflexes may be retained)

2. ***No spontaneous respiration
   - absolute apnea require absence of spontaneous respiration at CO2 tension >= 60mmHg)
3. ***Absence of brainstem reflexes
   - pupillary, oculocephalic, corneal, gag reflexes ALL must be absent
4. ***Absence of any potentially reversible causes of marked CNS depression (e.g. drug intoxication, hypothermia, severe metabolic disturbance)
5. ***Electrocerebral silence
   - an isoelectric EEG signifying absence cerebrocortical function (some do not regard an EEG mandatory)