4 Disturbances in Consciousness and 4.1 Approach to Disturbances of Consciousness 4.1.1 Faints and Fits Clear Hx most important Important to differentiate between: □ Vertigo: abnormal of movement □ Unsteadiness: ataxia, proprioception, weakness53, visual disturbance, joint diseases… □ Lightheadedness: presyncope, syncope, hypoglycaemia, anxiety, hyperventilation, panic attack, psychogenic non-epileptic attacks □ Epilepsy Loss of consciousness (LOC) only occurs in the last two categories □ Suggests a generalized dysfunction of the brain D/dx Syndrome Mechanism Features Causes - Neurocardiogenic (autonomic - Preceded by brief feeling of lightheadedness reflex-related): (presyncope) Situational, eg. - LOC typically for <1min micturition Generalized - Associated S/S: darkening of vision, tinnitus, Vasovagal Syncope hypoperfusion hyperventilation, distal tingling, nausea, Hypertensive carotid to the brain clamminess or sweating sinus syndrome - Recovery quick and without confusion Postural hypotension - Often precipitated by pain, emotion or standing - Cardiogenic (insufficient CO): position Arrhythmia LV outflow obstruction - May be preceded by aura (eg. peculiar taste/smell, déjà vu feeling, auditory hallucination, anxiety, nausea, abdominal pain) - Course varies according to type - Epilepsy54 - LOC, falling + clonic movements (generalized - Secondary causes: congenital, Electric tonic-clonic) Seizure dysfunction - LOC + staring w/o movement (absence) hydrocephalus, hypoxia, drugs, of the brain - Localized contractions ± LOC (focal) toxins, metabolic, infective, - LOC typically lasts >1 min inflammatory, degenerative - Associated with incontinence and tongue-biting - Recovery slow with prolonged confusion, headache and focal neurological signs - Episodes often prolonged, sometimes >30min - Specific emotional trigger Pseudo- Psychogenic - Partially retained awareness - Psychogenic (~10% of LOC) seizure - Rapid recovery or subsequent emotional distress - Tongue biting, incontinence unlikely but possible

Toxic/ Toxic - Transient, intermittent coma - Alcohol, solvents, barbituates

53 Sudden weakness due to TIAs may result in sudden collapse, but the patient should not suffer from any LOC. 54 Seizure is the symptom, epilepsy is the tendency to have recurrent seizures. - Page 76 of 179 -

Metabolic - LOC - Insulin coma Metabolic - Often preceded by sweating, weakness, confusion - Oral hypoglycaemic

Hx Obtain Hx from both pt and informant Hx from pt: Common forms of aura: □ Context: - Peculiar taste or smell → During blood-taking, micturition (syncope) - Feeling of déjà vu → During sleep (seizure) - Feeling of jamais vu → Standing (orthostatic hypotension) - Hearing of familiar music → During exercise (outflow obstruction) - Feeling of fear or anxiety welling up in chest □ Prodrome: - Visceral feelings, eg. nausea, → Aura (seizure) abdominal pain → Light-headedness, sweatiness, visual fading (syncope) □ Recovery: → Rapid (syncope) → Gradual with drowsiness (seizure) □ Associated: tongue-biting, incontinence (seizure) □ Drug history Hx from informants: □ Duration: <1min (syncope), >1min (seizure), >30min (psychogenic) □ Movement: → Brief, asynchronous jerking (syncope) → More prolonged synchronous tonic-clonic movement (seizure) □ Colour changes: pallor (syncope), cyanotic (seizure) □ Recovery

Ix EEG for epilepsy ECG ± Holter monitor for arrhythmia Tilt-table test for neurogenic syncope and orthostatic hypotension Echocardiography for cardiomyopathy Blood glucose for hypoglycaemia

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4.1.2 Coma and Persistent Loss of Consciousness Ref: Davidson P. 1159, Neurology and Neurosurgery Illustrated P. 85, WCS29, 30 A. Physiology of Consciousness Consciousness: state of awareness of self and surrounding Components: □ Arousal: state of being ‘awake’ □ Awareness: cognitive and affective mental function (i.e. the ‘content’) Dependent on: □ Reticular activating system (RAS) in brainstem, hypothalamus, thalamus □ Cerebral hemisphere Reticular activating system (RAS): a loosely grouped aggregation of neurones in upper brainstem and medial thalamus □ Fx: maintains cerebral cortex in a state of wakeful consciousness □ Mechanism: → Thalamic relay neurones connected brainstem RAS neurones and activate cortical pyramidal neurones → govern level of consciousness → Tonic mode: thalamic neurones fire and activate cortex in a nonrhythmic (desynchronized manner) - Occurs in wakefulness or REM sleep → Burst mode: thalamic neurones fire55 and activate cortex in a rhythmic, bilateral synchronous manner → sleep spindles on EEG - Occurs in non-REM sleep B. Coma Coma: severe impairment of arousal ± awareness □ Definition: GCS ≤8 → No eye-opening to pain (E≤1) → Inability to speak (V≤2) → Inability to obey command (M≤5) □ Cause: suggestive of impairment of maintenance of arousal by RAS → Diffuse bilateral cortical impairment → Brainstem impairment (direct damage/suppression of RAS or its projections)

55 This is likely mediated by T-type Ca channels. - Page 78 of 179 -

1. Causes of Coma Intracranial lesions: □ Traumatic: diffuse white matter injury, haematoma □ Vascular: SAH, ICH, cerebral infarct with ↑ICP, brainstem infarct/haemorrhage □ Neoplastic: tumour with oedema □ Infective: meningitis, abscess, encephalitis □ Others: epilepsy, hydrocephalus Extracranial lesions: □ Metabolic: electrolyte imbalances, liver/renal failure, endocrine disorders □ Drugs/toxins: sedatives, anticonvulsants, anaesthetics, alcohol, heavy metals, CO… □ Vascular occlusion: vertebral artery disease, bilateral carotid disease □ Cardiorespiratory insufficiency □ Psychiatric: hysteria, catatonia

2. Approach to Coma Patients Cardiorespiratory stabilization GCS assessment Abort seizure if any (may ↑ICP) Control ICP if raised Investigate and treat underlying cause □ Hx and P/E as appropriate □ Blood test if extracranial diseases suspected → Should include L/RFT, BG, ABG, drug screen, blood culture (if pyrexic □ Urgent CT ± LP if intracranial diseases suspected

3. Terminology and Related Disorders of Consciousness Coma: deep sleep-like state from which patient cannot be aroused at all Stupor: state of baseline unresponsiveness with pt only aroused by vigorous stimuli Lethargy: state between alertness and stupod Vegetative state (VS): awake but unresponsive state □ No cognitive neurological function □ Retained non-cognitive (vegetative) neurological function (eg. cardiac action, respiration, maintenance of BP) □ May show head and limb movement but seldom meaningful response to external/internal environment □ Cause: extensive cortical gray/subcortical white matter lesion with relative preservation of brainstem functions → Most commonly cardiac arrest and head injuries □ Prognosis: almost nil in regaining mental fx after several months of PVS

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Akinetic mutism: □ Partially or fully awake □ Able to form impressions and think but remains immobile and mute □ Cause: damage in medial thalamic nuclei, frontal lobe or hydrocephalus

Abulia: mental and physical slowness with ↓ability to initiate activity □ Mild form of akinetic mutism

Inattention: inability to sustain uninterrupted thought and actions □ Earliest outward sign: disorientation □ Can be an early sign of neurological disease (eg. encephalitis)

Locked-in syndrome: □ Fully alert and aware with ability to carry out meaningful behaviour □ Completely paralyzed except for eye movements (quadriplegia + lower CN palsies) □ Cause: bilateral ventral pontine lesion (eg. basilar artery occlusion)

Catatonia: hypomobile and mute syndrome a/w major psychosis □ Appear awake with eyes open □ Make no voluntary or responsive movements □ Blinks spontaneously, swallow and may not appear distressed □ NO clinical evidence of cerebral damage □ Long considered a psychiatric symptom but recently demonstrated in some neurological conditions (eg. NMDA receptor encephalitis)

Pseudocoma (malingering)

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4.1.3 Ref: Davidson P. 1161, Crash Course in Psychiatry P. 106, WCS29 Delirium: acute confusional state with impairment in both consciousness and cognition □ Represents a common final pathway of disrupted homeostasis □ Very common (aka ‘decreased GC’), 14-24% among hospitalized, ↑ with age □ Heralds presence of life-threatening conditions in 10-30% older pt presenting to A&E (35-40% 1y mortality) Definition in DSM-V:

Pathogenesis: poorly understood Clinical features: acute and fluctuating course of □ Impaired consciousness: ↓arousal, disorientation □ Inattention: ↓attention, concentration, ↑distractibility □ Disorganized thinking: disorganized or incoherent speech, rambling or irrelevant conversations □ Impaired cognition: disorientation, (recent > distant), language impairment, ↓comprehension □ Perceptual hallucination: illusions, hallucinations (30%) → Esp VH (psychotic ds more commonly presents with AH) □ Psychomotor disturbances: agitation or retardation □ Altered sleep-wake cycle: characteristic for delirium, ranges from daytime drowsiness + nighttime insomnia to complete sleep cycle reversal □ Mood disturbances: depression, euphoria, anxiety, anger, fear, apathy… Precipitating factors: □ Dementia: leading RF, 2/3 of delirium occurs in dementia patients □ ↓oral intake: dehydration, malnutrition □ Drugs: polypharmacy, psychotropics, alcohol abuse □ Medical conditions: severe illness, organ impairment, neurological disease, metabolic derangements, terminal illness Often confused with dementia: □ Both common in elderly □ Careful Hx taking should illustrate a chronic, insidious Hx of isolated cognitive impairment sparing consciousness w/o fluctuations □ Esp note Lewy body dementia w/ cognitive fluctuations and vivid VH

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Clinical approach: □ Document change in mental status, eg. MoCA, MMSE □ Search for underlying causes: Ix as appropriate → Basic workup: CBC, L/RFT, electrolytes → Primary neurological disorders: CT brain, LP, EEG → Systemic infections: MSU, CXR, blood culture, sputum culture → Organ failure: ABG, ECG, Indications for neuroimaging in delirium:

→ Metabolic: blood glucose/ketones, Ca/PO4, amylase, Mg, porphyrins (1) New focal neurological signs → Drug toxicity: Hx, urine tox screen, serum alcohol/AG (2) Hx or signs of head trauma (3) Fever (for CNS infection) → Nutritional: thiamine, B12, folate (4) No other identifiable cause □ EEG: diffuse slowing of background cortical activities (5) Nil or incomplete Hx → Limited role, FN 17%, FP 22% (6) Neurological exam cannot be → Useful when suspecting non-convulsive seizures and psy ds completed □ Neuroimaging: low yield, indications see RHS

Mx: □ Treat underlying causes and complications □ Supportive care □ Rx for behavioural S/S: ONLY when threatens own or others’ safety or interferes with essential Tx → Antipsychotics: haloperidol (1st line), risperidone, olanzapine, quetiapine56 → Benzodiazepines: lorazepam (2nd line)57 → Antidepressants: trazodone Prevention: □ Orientation & therapeutic activities for cognitive impairment □ Early mobilization □ Nonpharmacological approaches (minimize psychoactive drugs use) □ Interventions to prevent sleep deprivation □ Communication methods & adaptive equipment for vision & hearing impairment □ Early intervention for volume depletion 4.1.4 Brain Death Ref: Davidson P. 1160, Neurology in Practice P. 181, WCS29 Pre-requisites for diagnosis: □ Deep coma: no cerebral or brainstem function (spinal reflexes may be retained) □ No spontaneous respiration: on ventilator □ Irreversible brain damage for >24h58 with established cause □ Not resulting from potentially reversible causes: → Drug intoxication, eg. CNS depressants (narcotics, hypnotics, tranquilizers) and NMB → Hypothermia: body temperature >35oC → Severe metabolic disturbances, eg. electrolytes, acid-base, blood glucose…

56 Atypical antipsychotics are tested only in small uncontrolled studies and may be a/w ↑mortality in older pt with dementia 57 Lorazepam is mainly reserved for sedative/alcohol withdrawal, PD and neuroleptic malignant syndrome. 58 A longer period of observation should be allowed for children due to their higher recovery potential. - Page 82 of 179 -

Absence of brainstem reflexes: Reflex Description Sources of FN Local eye diseases, eg. cataract Pupillary Pupils fixed (but not necessarily widely dilated) Atropine in cardiac arrest Corneal No eye blink upon corneal stimulation Barbiturates and CNS depressants Oculocephalic No eye movement on head turning Barbiturates and CNS depressants Local disease of ear canals Oculovestibular No eye movement to warm/cold saline irrigation to ears AEDs, antidepressants, ototoxic Abx, alcohol, NMBs Oropharyngeal No gag/cough reflex during endotracheal suction Barbiturates and CNS depressants No ventilatory effort to apnoeic oxygenation Post-hyperventilation apnoea Respiratory with PaCO2 >6.6kPa (tested by disconnecting from ventilator) NMB, AEDs, antidepressants

Electrocerebral silence: isoelectric EEG indicating absent cerebrocortical function □ NOT mandatory in some authorities 4.2 Seizures and Epilepsy Ref: Davidson P. 1178, Neurology and neurosurgery illustrated P. 92, WCS29 Terminology: □ Seizure (epileptic attack): S/S due to hyper-synchronized activity in the brain → Reactive (provoked) seizures: occurring at the time of or in close temporal association59 with a documented brain insult (eg. stroke, TBI, encephalopathy, SDH) → Primary (idiopathic) seizures: no structural lesions or neurological disorders - Cryptogenic seizure: seizure with a presumable yet unidentified structural cause → Secondary (symptomatic) seizures: due to chronic, irreversible conditions that ↑risk of seizures, eg. tumours, stroke, autoimmune diseases □ Epilepsy: an enduring tendency (≥60% risk) to develop unprovoked seizures → Defined as (ILAE 2014) - ≥2 unprovoked seizures at least 24h apart60; - 1 unprovoked seizure + ≥60% risk of recurrent seizure in next 10y (i.e. similar to those after 2 unprovoked seizures) - Diagnosis of an epilepsy syndrome □ Epilepsy syndromes: epilepsy with specific age of onset, electroclinical manifestations and treatment responsiveness

59 The time window within a seizure is considered provoked may vary based on type of insult. 60 Multiple seizures may occur in clusters (acute repetitive seizures, ARS) and do not imply as much ↑future seizure risk as separate seizures. - Page 83 of 179 -

4.2.1 Seizures 1. Pathogenesis Basis of brain function depends on cooperation between disparate networks □ Each network consists of reciprocally stimulation and inhibition components □ Oscillations generated by cortical neurones within each network depend on: → Activity of inhibitory neurones (eg. GABA neurones) → Communication between different neurones (eg. synaptic transmission) → Intrinsic neuronal properties (eg. ability to maintain burst firing) Causes of seizure: □ Acute symptomatic seizure may be caused by virtually any acute brain insult → Eg. stroke (esp lobar haemorrhage), SAH, SDH, TBI, brain abscess, meningitis, encephalitis □ Epilepsy: underlying predisposition to development of unprovoked seizure due to → Eg. genetic, structural, metabolic, immune, infectious, unknown These conditions result in: □ ↑connectivity □ ↑excitatory transmission □ Failure of inhibitory mechanisms □ Changes in intrinsic neuronal properties Result: repeated synchronous oscillating neuronal discharge → seizure

2. Types of Seizures Focal seizures: attacks beginning from a one or more localized foci within one hemisphere □ Usually due to underlying focal CNS lesions □ Discharge arises from a cortical location

Generalized seizures: attacks beginning simultaneously in both cerebral hemispheres □ Usually with a strong genetic component □ Discharge arises from subcortical location and spreads to bilateral cortex simultaneously

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a. Focal (Partial) Seizures Cause: usually associated with local CNS insults that lead to disturbance in cortical architecture Generally divided into: □ Simple partial if consciousness is preserved □ Complex partial if consciousness is impaired → Usually indicates involvement of → Commonest type of seizure in adults □ Secondarily generalized if progress into a generalized seizure (usually tonic-clonic) Focal seizures can often be mapped onto a particular location in the brain: □ Frontal lobe: focal clonic movements → Jacksonian march: marching clonic movement beginning in hand or face then proceed to involve other muscle groups of body → Other bizarre motor manifestations if involve higher motor centres □ Parietal lobe: focal/spreading paraesthesia or tingling sensation □ Occipital lobe: visual hallucinations (rare) □ Temporal lobe: complex ‘aura’ ± progression into impairment in consciousness → Aura (i.e. simple partial seizure if alone) may involve - Visceral disturbances: gustatory and olfactory hallucinations, epigastric sensation - Psychiatric symptoms: déjà vu, jamais vu, , specific emotions, blank staring - Sensory symptoms: visual/auditory hallucinations, visual distortions → After LOC (i.e. complex partial seizure), there may be - Automatisms: semipurposeful involuntary motor activity (eg. lip smacking, picking at clothing, screaming, crying, laughing…) - Others: speak unintelligibly, ictal arrhythmias (eg. asystole), SGTCS → Example: mesial (mTLE) - Results in complex partial seizures originating from mesial temporal lobe - Most commonly due to hippocampal sclerosis → amenable to surgical resection □ Secondary generalized tonic-clonic seizures (SGTCS) presents with initial symptoms associated with focal onset followed by generalized tonic-clonic seizures

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b. Generalized Seizures Cause: usually associated with ion channel mutations (epilepsy syndromes) □ Most associated with a complex inheritance pattern □ Some show Mendelian inheritance associated with single gene mutations Tonic-clonic seizures: previously ‘grand mal’ □ Aura: present in SGTCS, content depends on location of foci □ Tonic phase (10s): rapid generalized cortical discharge → Loss of consciousness and falls onto ground (‘like a log’) → All muscles contract synchronously: - Eyes open, pupils dilated - Arms pronated, legs extended, teeth clenched - Breathing stops → central cyanosis - Loss of bowel/bladder control at the end of this phase □ Clonic phase (1-2min): gradual ↓frequency of cortical discharges → Tremor followed by violent generalized jerking contractions → Tongue bitten, tachycardia → Breathing restarts at end of phase □ Deep coma (a few minutes): cannot be aroused □ Post-ictal confusion: confused, disorientated, amnesic □ May feel unwell, sleepy, headache, myalgia for hours afterward Do NOT insert anything Absence seizures: previously ‘petit mal’ in the mouth of the □ Always starts in childhood patient! (Tongue-biting occurs at seizure □ Usually present as brief episodes (5-15s) of vacant staring onset and cannot be prevented □ May occur multiple times a day (20-30 times) by observers.) → often mistaken as daydreaming/poor concentration Myoclonic seizures: sudden, brief generalized muscle contractions □ Often occur in the morning or upon awakening from sleep □ Tend to be provoked by fatigue, alcohol or sleep deprivation □ Myoclonus on the edge of sleep is normal! Other types of seizures: □ Tonic seizures: generalized ↑tone + associated LOC (usually not isolated) □ Clonic seizures: generalized tonic-clonic seizures without preceding tonic phase □ Atonic seizures: brief loss of muscle tone + LOC (usually not isolated) c. Postictal Period Post-ictal period: period of transition from ictal state back to baseline level of awareness and function Presentation: □ Post-ictal confusion □ Todd’s paralysis (post-ictal paresis): focal neurological deficits following seizures → Esp affects areas previously affected by seizure Mx: place patient in recovery position

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3. Diagnosis of a Seizure Usually based on history and selected tests Suggested by transient occurrence of: □ Altered awareness □ Abnormal behaviour □ Involuntary movement D/dx of epileptic seizures:

4.2.2 Epilepsy IAEA 2014 definition ≥2 unprovoked seizures Epilepsy: an enduring tendency to develop unprovoked seizure ≥24h apart; Epidemiology: 1 unprovoked seizure + □ Prevalence: ~45M worldwide, ~6-8/100k ≥60% risk of recurrent (note that 5% of population may suffer from a single seizure at some time) seizure in next 10y □ Incidence: ~26-40/100k/y, ↑ in infants and >60y (i.e. similar to those after 2 □ Type: ~70% adults with new-onset epilepsy have focal seizures unprovoked seizures) (generalized seizures more common in children) Diagnosis of an epilepsy Causes61: varies with age syndrome □ <1y: hypoxia, hypoGly, hypoCa, kernicterus, birth trauma, ICH, congenital anomalies □ 1-5y: intracranial infections, febrile seizures □ 5-20y: idiopathic epilepsy, head injury, cortical dysplasia, hippocampal sclerosis □ 20-60y: cerebral tumours, alcohol, drugs and toxins, CNS infections, AVM □ >60y: cerebrovascular disease, neurodegenerative diseases, systemic illnesses, brain metastases

61 In general, 62% of epilepsy is idiopathic, 9% is due to stroke, 9% head trauma, 6% alcohol, 4% neurodegenerative disease, 3.5% static encephalopathy, 3% brain tumour, 2% infection, others, eg. anti-NMDAr encephalitis. - Page 87 of 179 -

1. Approach to Epilepsy Aim: □ Diagnosing epilepsy + eliminate alternative dx □ Classifying type of epilepsy □ Look for underlying cause Detailed Hx most important in making diagnosis Neurological examination for any focal neurological signs □ Normal in most patients with epilepsy Skin abnormalities for neurocutaneous syndromes □ Eg. neurofibromatosis with cutaneous tumours or café-au-lait spots □ Eg. tuberous sclerosis with facial angiofibromas CT/MRI brain in ALL first-time seizures for identification of any underlying structural cause □ CT: appropriate for emergency situations □ MRI: more sensitive than CT in detecting structural lesions casually Electroencephalogram (EEG): important Ix but NEVER relied on to r/o or confirm diagnosis □ Inter-ictal EEG may show epileptiform patterns → Help assist dx and classification of seizures (as focal or generalized) → Abnormal in only 50% of first seizures → cannot be used to exclude dx of epilepsy nor as standalone proof of epilepsy dx → ↑yield of abnormality if - Repeated; or - Performed after sleep deprivation → Ambulatory EEG if indicated □ Video EEG indicated if non-epileptic attacks are suspected → Gold-standard of diagnosis → May catch synchronous EEG discharges at the same time of attacks □ Consider invasive depth electrodes when surgery is indicated to localize the epileptic foci

Selected tests to identify any underlying systemic cause □ CBC for infection □ LFT for liver derangement □ Electrolytes: urea, Ca, Mg □ ECG for cardiogenic syncope leading to secondary hypoxic seizure □ Substance abuse in adolescents/adults with unexplained generalized seizures

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2. Classification of Epilepsy and Epilepsy Syndromes ILAE levels of epilepsy diagnosis: □ Seizure type: focal, generalized or unknown □ Epilepsy type: predominant type of seizure suffered by patients □ Epilepsy syndromes: clusters of epilepsy features including age of onset, electroclinical manifestations and treatment responsiveness that tend to occur together → Many are idiopathic generalized epilepsy syndromes with strong genetic component □ Epilepsy with aetiology, eg. gene mutation

Generalized epilepsy with febrile seizure plus (GEFS+): □ Definition: → Febrile seizures62; plus → ≥1 of other types of seizures: absence, myoclonic, atonic, afebrile GTCS □ Cause: mutation in SCN1B (voltage-gated Na channel β1 subunit, ch19q) → modify gating and inactivation properties of Na channel → ↑depolarization and hyerpexcitability in neurones □ Inheritance: AD with incomplete penetrance

Other common epilepsy syndromes:

62 Febrile seizure refers to seizures resulting from high body temperature (eg. due to infection). - Page 89 of 179 -

3. Management of Epilepsy a. Non-pharmacological Early repeated discussion of impact of diagnosis on patient Lifestyle changes: discourage from activities leading to ↑risk of injury/mortality should seizure occur □ Driving: prohibited until seizure-free for 3mo to 1y □ Operating high-risk power equipment □ Working at heights and hiking alone □ Swimming/bathing alone → use low bath tub water level □ Cooking over fire alone → should use non-fire heat source Note that diagnosis of epilepsy should be made as accurate as possible because of the huge impact on patient’s life, eg. job, insurance… b. Antiepileptic Drugs (AED) Indications for starting AED: Scenario Usual practice Exceptions Start AED if ↑risk of seizures NO treatment - Head injury or surgery (eg. post-head injury) - High-risk conditions, eg. AVM, brain tumour, SAH Start AED if ↑↑risk for recurrence - Clearly epileptiform activity on EEG Single seizure NO treatment - Progressive cerebral disorder - High risk jobs or lifestyle Withhold AED if - Seizures widely separated in time (>1y) ≥2 seizures AED indicated - Precipitating factors identified, eg. alcohol, sleep deprivation - High probability of poor compliance, eg. personality disorder

Types of antiepileptics: □ Broad-spectrum AEDs: reasonable initial choices in most adult patients regardless of type of seizures/epilepsy syndromes → Includes valproate, lamotrigine, topiramate, levetiracetam, zonisamide □ Narrow-spectrum AEDs: restricted to focal epilepsy ± secondarily generalized seizures → Focal onset only: carbamazepine, oxycarbazepine, phenytoin, tiagabin, gabapentin, pregabalin → Absence seizures only: ethosuximide → Less effective than broad spectrum agents in idiopathic generalized epilepsy syndromes (eg. juvenile myoclonic epilepsy, childhood absence epilepsy) → May even exacerbate some seizure types in these patients63

63 For example, phenytoin, carbamazepine, gabapentin and pregabalin may worsen absence and myoclonic . - Page 90 of 179 -

Caution in women: □ Gynaecological ds: valproate a/w polycystic ovaries, anovulatory cycles and hyperandrogenism □ Interactions with OCP: → Hepatic enzyme-inducing AEDs (PHT, CBZ, phenobarbital, topiramate) → ↑clearance of OCP → OCP → ↑clearance of lamotrigine → need dose adjustment □ Pregnancy: → ↑clearance of many AEDs, esp lamotrigine → consider TDM → Teratogenicity (6%): no AED is absolutely safe - Highest with valproate (NTD, ↓IQ), lowest with lamotrigine and levetiracetam - Should choose monotherapy at minimal effective dose - Teratogenicity occur in 1st trimester → too late to stop AED when discovered to be pregnant → consider folic acid supplementation + effective contraception → Generally considered safe in breast-feeding (usually low concentration)

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Response to AED: □ 1/2 becomes seizure-free after taking first AED □ ~2/3 becomes seizure-free after taking 2nd or 3rd AED □ ~20% cannot be controlled with medications alone → Further AEDs unlikely to confer benefit if not controlled by two AEDs → Should consider surgery Drug-resistant epilepsy (DRE): □ Definition: failure to achieve seizure remission for >12mo after adequate trials of ≥2 AEDs □ Approach: → Look for precipitating factors, eg. alcoholism, drug abuse, sleep deprivation, stress, and eliminate if possible → Check drug compliance and monitor AED levels → Review underlying cause esp for any progressive brain disorders → Review choice of AED in relation to seizure type → Consider possibility of non-epileptic attacks □ Mx: further add drugs or consider surgery Therapeutic drug monitoring: NOT routine esp for newer drugs □ Establish therapeutic range to guide future treatment □ Assist in dx of clinical AED toxicity □ Assess adherence □ Guide dose adjustments esp when changing regimens, breakthrough seizures or pregnancy

Withdrawal of AED: □ Should be maintained for ≥2y once initiated even if patient is free of any seizures □ Consider withdrawal if remain seizure-free for 2y → Should be done by gradually ↓dose over weeks or months → Driving or occupation precautions may be necessary → If done abruptly (eg. in severe complications), may use short-term BZD cover c. Epilepsy Surgery Pre-op evaluation: to localize epileptogenic zone and determine adjacent cortical fx □ Video EEG ± invasive intracranial EEG □ Neuroimaging □ WADA test: determine language lateralization and memory fx of each temporal lobe □ Cortical mapping

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Temporal lobe epilepsy (TLE): most common cause of pharmacoresistant epilepsy □ Open surgical resection: preferred over continued medical therapy → Modality: - Standard anterior temporal lobectomy: anterior 2/3 of temporal lobe removed - Amygdalohippocampectomy → Prognosis: 60-70% seizure-free at 2-5y (cf 0-10% with continued medical Tx) → S/E: - Short-term memory loss (if dominant temporal lobe) - Rarely infections, VF defects, CN palsies, hemiparesis, death Non-TLE epilepsy: □ Usually guided by prior invasive EEG to localize epileptic focus → C/I if located in eloquent regions because of unacceptable S/E, eg. dysphasia, hemiplegia □ Prognosis: ↓likely to be seizure-free d. Neurostimulation Vagus nerve stimulation (VNS): regular pulsed stimulation via vagus nerve → desynchronize cerebral activity + ↑synthesis of inhibitory neurotransmission Deep brain stimulation (DBS): usually at anterior thalamus to abort seizure spread 4. Status Epilepticus (SE) Status epilepticus (SE): prolonged (>5min) or repeated seizures without full recovery of consciousness between attacks □ MEDICAL EMERGENCY!:the later a seizure is stopped, the more difficult it is to be stopped □ Mortality: 3-20% (↑ if prolonged seizure or identified acute brain insult) Types: □ Convulsive SE, eg. generalized tonic-clonic SE (most commonly recognized SE) □ Non-convulsive SE, eg. absence SE, complex partial SE Causes: □ Acute cerebral insult due to → CNS infections (classically encephalitis) → Neurotoxins incl. drugs, eg. lignocaine, amphetamine □ Rapid withdrawal of AEDs Mx: immediate treatment! □ ABC: → Airway protection → Oxygen, intubation + ventilatory support → IV fluid to maintain volume status + BP □ Close monitoring of status: vitals, ECG, EEG □ AED to terminate seizure activity (HA guidelines) → Early status (0-10min) → give short-acting anticonvulsant - Bolus benzodiazepine, eg. IV lorazepam, IV diazepam, IM midazolam → Established status (10-60min) → give IV loading + maintenance long-acting anticonvulsant - Eg. IV phenytoin, IV valproate, IV levetiracetam, IV phenobarbital → Refractory status (despite BDZ + AED) → general anaesthesia in ICU → Super-refractory status (despite GA ≥24h) → consider ketamine, Mg, immunotherapy, ketogenic diet etc

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