Neurology Flashcards
Stages of neural development
Dorsal induction Ventral induction Neuronal proliferation Neuronal migration Cortical organisation Myelination
Myelination on MRI
Pattern:
- Unmyelinated brain has more water than fat content –> relatively dark on T1 and brighter on T2 compared to cortex
- With myelination, this pattern reverses
- Spreads from central to peripheral, posterior to anterior
T1 precedes T2:
- T1 completed by 1 year
- T2 completed by 2 years
Subdural haematoma
Tearing of bridging VEINS (venous bleeding) –> bleeding into potential space
- Crescentic
- Cross sutures
- Follows dural folds
- Outlines subarachnoid space
- Most consistent finding with abusive head injury
Epidural haematoma
Arterial bleed secondary to skull fracture
- Lens-shaped bleeding from stripping of dura from the skull
- Bound by sutures
Subarachnoid haemorrhage
- Extends into sulci and fissures
2. Best seen on T2* or FLAIR MRI
Holoprosencephaly
Failure of embryonic forebrain to separate –> fusion of e.g. frontal lobes
*Abnormality of ventral induction i.e. separation
Lissencephaly
with agyria/pachygyria complex
Smooth brain with increased cortical thickness, cell-sparse layer
Agyria = absence of gyri; pachygyria = thickened cortex
DCX = more severe anteriorly; LIS1 = more severe posteriorly
*Abnormality of neuronal migration
Polymicrogyria
Lots of small gyri = appears nodular
- Can be focal or bilateral
- Overfolded cortex with false impression of cortical thickening
- Associated abnormal deep or elongated sulci
- Any disruptive process to cortex will be lined by polymicrogyria
Schizencephaly
Full-thickness cleft through hemisphere
- Often lined by polymicrogyria
- Open or closed lip
Causes:
- Intrauterine neuro insult (~20wk): CMV infection, HIE
- Genetic: COL4A1
Heterotopia
Abnormal position of grey matter
*Abnormality of neuronal migration
Focal cortical dysplasia
Subtle focal dysplastic cortex, can manifest as “blurring” of cortex (subtle finding)
*Accelerated myelination
EEG: normal background activity
- Alpha rhythm:
- 8-12Hz - usually gradually increases with age; infancy 6-8Hz, 3yrs >8Hz
- Prominent posteriorly on eye closure - Theta waves:
- 4-8Hz
- Normal in children up to 13yrs and in drowsiness/sleep - Delta waves:
- <4Hz
- Normal in deep sleep (stage 2 and 3)
- Focal finding: can be assoc with structural pathology
- Generalised finding: diffuse encephalopathy - Beta waves:
- >13Hz
- Often prominent in presence of drugs (barbituates, BZD)
- Commonly seen in frontal region
EEG: epileptiform discharges
- Sharply contoured discharges
- Sharp waves <200ms
- Spikes <70ms
- No difference in biological significance between 2 forms - Multiple phases
- Clearly disrupts background activity
- After-coming slow wave
- Sensible electrical field distribution
Genes associated with Charcot-Marie-Tooth Disease Type 1
Autosomal dominant inheritance: CMT1A - PMP22 (17p11) CMT1B - Po (1q22) CMT1C - LITAF (16p13) CMT1D - EGR2 (10q21)
Genes associated with Charcot-Marie-Tooth Disease Type 2 and Type 3
CMT2 - MFN2 (autosomal dominant)
CMT3 - PMP22 (point mutations) - 8q23, 17p11, 10q21
Risk factors for CP
Male
Prematurity - 43% of pts with CP are prem
Low birth weight - 43%
Multiple birth (twins/triplets) - 11%
Birth asphyxia/adverse intrapartum events - 10%
Infection in late pregnancy - sig. RF for term neonates
Previous/multiple MCs - ?genetic, clotting disorders
APGAR score at 1min
Breech position
Maternal smoking, illicit substance use
Genetic component
Strongest predictor of mortality in CP
Profound intellectual disability
- 22% die by 5yrs
- 50% die by 18yrs
GMFCS Level 1
- Can walk independently on all surfaces
- Can run and jump, but speed, co-ordination and balance are reduced
- 35% of CPs
GMFCS Level 2
Walks independently, but:
- Difficulty walking on uneven surfaces, inclines, crowded places
- 24% of CPs
GMFCS Level 3
- Requires assistive mobility devices, orthoses for walking
- Wheelchair required for long distances
- Sits independently, has independent floor mobility
- 12% of CPs
GMFCS Level 4
- Uses power mobility outdoors and in community
- Supported sitting function
- Requires assistance with standing transfers
- Mobility is limited
- 13% of CPs
GMFCS Level 5
- No independent mobility
- Poor antigravity head and trunk postures
- Require tilt in space and seating systems
- 15% of CPs
Selective dorsal rhizotomy
Laminectomy L1-S1 –> dorsal nerve root transection
- 20-30% sensory nerve rootlets from L2-S1
To reduce lower limb spasticity
Irreversible
Indications for selective dorsal rhizotomy
Spastic diplegia: GMFCS II to III
Moderate to severe spasticity
Limited contractures
Motivated patients and parents: intense functional training over 1-2yrs follows
Goal: gait kinematics improvement, spasticity management
- No supporting evidence that it improves function (i.e. general activities) and participation
*Does NOT prevent further need for orthopaedic surgery
Intrathecal baclofen
Indication: severe, generalised spasticity that has failed conservative treatment (including botox)
MOA: GABA agonist - delivered directly around spinal cord, decreases neurotransmission of afferent nerve fibres.
Advantage of IT baclofen c.f. PO
Delivered directly around spinal cord, overcomes side effects secondary to large oral doses
- 1/100th of oral dose
- Small amount crosses BBB
Side effects and withdrawal effects of IT baclofen
Overdosing:
- Sedation
- Light-headedness
- Respiratory depression
- Seizures
- LOC/Coma
Withdrawl: life-threatening
- Hyperthermia
- Rhabdomyolysis
- Seizures, coma
- Multiple organ system failure
Indications for Botulinum Toxin A
Indications:
- Spasticity and dystonia - specific muscle groups
- Interferes with function or cares
- Severe drooling - can inject into salivary glands
Aim: delay surgery
Side effects of BTA
Fibrosis
LRTI/URTI in those with pre-existing dysphagia and GMFCS V
Indication for deep brain stimulation in CP
Dyskinetic CP with dystonia and choreoathetosis
- Generalised condition
- Timing of implantation: earlier the better
MOA: disruption of electrical signals of extrapyramidal pathway
Effects: improvement noted subjectively but not on formal assessment
CP Prevention
- Magnesium sulfate: antenatal IV MgSO4 for mothers in premature labour with birth imminent before 32 weeks has shown significant reduction in risk of CP at 2yrs of age
- Cooling term infants with HIE to 33.3 degrees for 3 days starting within 6hrs of birth reduces risk of dyskinetic or spastic quadriplegic forms of CP
Causes of hemiplegic CP
- Injury to white matter in utero 34%
- Focal lesions that may have resulted from stroke 27%
- Infections (e.g. CMV)
- Cortical malformation: lissencephaly, polymicrogyria, schizencephaly, cortical dysplasia
- Focal cerebral infarction secondary to intrauterine or perinatal thromboembolism related to thrombophilic disorders e.g. anticardiolipin Abs
Clinical criteria for neurofibromatosis type 1:
2 or more of…
- 6 or more cafe-au-lait spots
- -> >5mm in prepubertal
- -> >15mm in pubertal
- 2 or more neurofibromas or 1 plexiform neurofibroma
- 2 or more Lisch nodules
- Inguinal/axillary freckling
- Optic glioma
- Distinctive osseous lesions (e.g. sphenoid bone dysplasia)
- 1st degree relative with NF
Features of NF1 more common in <5yo
- CAL (present at birth - increase in size, # and pigmentation)
- Plexiform neurofibromas (present from birth)
- Optic gliomas
- Freckling
- UBOs (increase in # until 10yo, then start disappearing)
Genetics of NF1
Autosomal dominant, but 30-50% are sporadic
Ch17q11.2
Mutation of NF1 gene - loss of function mutation of tumour suppressor gene
- Protein = neurofibromin - regulates cell signal transduction pathways, inhibitor of Ras (oncogene)
Clinical criteria for neurofibromatosis type 2:
1 of…
- Bilateral vestibular schwannomas
- First degree relative with NF2 AND
- Unilateral schwanomma OR
- 2 or more of: meningioma, schwannoma, glioma, neurofibroma or posterior subcapsular lens opacity - Multiple meningiomas (2 or more) AND
- Unilateral schwannoma OR
- 2 or more of: meningioma, schwannoma, glioma, neurofibroma or posterior subcapsular lens opacity
Genetics of NF2
Autosomal dominant, 50% are sporadic NF2 gene on ch 22q1.11 Tumour suppressor gene: merlin Merlin links between membrane proteins and cell cytoskeleton Phenotype depends on type of mutation: - Frameshift/nonsense: severe disease - Missense: milder disease
Management and prognosis of NF2
Mx:
- Annual MRI scans
- Early surgical treatment of schwannomas, aim = preserve hearing
- Regular ophthal review and monitor vision
- Avastin (bevacizumab) - shrinks vestibular schwannomas
Prognosis:
- Average age of death = 36yrs
- Average time from first Sx to death = 15yrs
- Major cause of morbidity = spinal tumours, vestibular schwannomas (pain, tinnitus, hearing loss)
Diagnostic criteria for tuberous sclerosis:
- 2 major criteria or 1 major and 2 minor criteria
Major criteria:
- Skin/eye: >3 hypomelanotic macules, shagreen patch, forehead plaques OR facial angiofibromata, peri(ungal) fibromas, multiple nodular retinal hamartomas
- CNS: subependymal nodules, cortical tubers, subependymal giant cell astrocytoma
- Others: renal angiomyolipoma, cardiac rhabdomyoma, lymphangioleiomyomatosis (LAM)
Minor criteria:
- Skin/eye: confetti skin lesions, dental enamel pits, intra-oral fibromas, retinal achromic patch
- CNS: cerebral white matter migration lines
- Other: non-renal hamartomas, multiple renal cysts, bone cysts, rectal polyps
Respiratory manifestations of tuberous sclerosis
LAM - lymphangioleioangiomyomatosis
- Proliferation interstitium and dilated lymphatics –> obstruction and subsequent cystic lung changes
- Presents with PTX and dyspnoea
- F»M, poor prognosis
CNS manifestations of tuberous sclerosis
85% of TS have CNS Cx!!!
- Seizures (most significant cause of morbidity - 75%)
- Infantile spasms (20%) - hard to treat
- Myoclonic, focal, GTCS
- Can be refractory to treatment - Intellectual disability (50%)
- 30% are profound - Behavioural issues
- ADHD, autism, sleeping problems, aggression, psychiatric disorders - CNS changes/tumours (>75%)
- Subependymal nodules, giant cell astrocytoma (teens), cortical tubers, white matter radial migration
- Obstructive hydrocephalus
mTOR inhibitors for tuberous sclerosis
- Sirolimus: reduction in size of angiomyolipomas, improved PFTs for LAM pts
- Everolimus: reduced seizure #, reduced subependymal giant cell astrocytomas
- Topical rapamycin: reduce size of facial angiofibromas
Genetics of tuberous sclerosis
Autosomal dominant, 2/3 - sporadic
- TSC1 gene (9q34): hamartin
- TSC2 gene (16p13.3): tuberin
- %proband with TS and confirmed mutation: TSC2 in 69%
- Simplex cases with TS: 60-70%
- If parents of confirmed TS pt is normal, recurrence risk is 2% (due to gonadal mosaicism)
Anencephaly
Incidence is 1 in 10000 live births (underestimated due to terminations/stillbirth)
Failure of closure of anterior neural tube
Absence of bilateral hemispheres and hypothalamus
- Absence of pituitary gland –> abnormal development of end-organs and associated Cx e.g. adrenal insufficiency
- Antenatal Ix: USS, maternal serum alpha-fetoprotein
Dandy-Walker Malformation
Continuum of posterior fossa anomalies:
- Cystic dilatation of 4th ventricle
- Hypoplasia of cerebellar vermis
- Enlarged posterior fossa with elevation of lateral venous sinuses and tentorium
- Hydrocephalus
DDx for acute hemiplegia
- Transient postictal hemiparesis (Todd’s paralysis): post-ictal phenomenon, usually lasts for 24-48hrs, EEG activity consistent with sz or post-ictal status. Secondary to neuronal exhaustion. MRI shows no acute infarct
- Complex migraine: usually assoc. with a significant headache with focal deficits lasting hours, positive FHx!, MRI shows no acute infarct
- Alternating hemiplegia of childhood: progressive neurological disorder presenting <2yrs, with distinct episodes of hemiplegia lasting minutes to hours where weakness alternates between sides. Seizures are common, but not during periods of weakness. Unknown aetiology.
AEDs:
Greatest risk of Stevens-Johnson Syndrome
Lamotrigine: 1/100
Others: CBZ, PHT, OXC - 1-6/10000
Avoid by starting low and going slow
Which AED is associated with SJS in Han Chinese population?
Carbemazepine
CBZ-SJS strongly associated with HLA-B*1502: Han Chinese, Hong Kong Chinese, Thai
Foetal valproate syndrome
Craniofacial abnormalities, radius/limbs abnormalities, CHD, genitourinary abnormalities (e.g. hypospadias), developmental delay, increased risk of autism
VPA associated with higher risk of teratogenicity and it is dose-dependent (>800mg) - if unavoidable, recommend <330mg daily in combination with LTG
Which AED is associated with the development of neural tube defects?
VPA 1-5%
CBZ 0.5-1%
AEDs:
The greatest risk factor for teratogenicity/malformations…
Polytherapy, high drug levels in 1st trimester
Teratogenic effects of topiramate
CHDs, orofacial clefts, hypospadias
Major cognitive side effects of AEDs
All AEDs can cause fatigue, impaired cognition - compounded by polytherapy
Suicidality risk reported as increased with all AEDs
PHB: long-term cognitive effects even after cessation of drug
LVT: psychosis, suicidality, homicidality
VBG: psychosis, depression
Inducers of CYP450 system
PHT, PHB, CBZ
AEDs that are renally excreted
GBP, VGB, TPM, LVT, ZNS
AEDs that undergo hepatic clearance
PHT, PHB (75%), CBZ, OXC, VPA, LTG, BZ (diazepam)
Phenytoin: MOA, Adv, Disadv, SE
- MOA: Na channel blocker > Ca channel blocker
- Adv: widely available, broad spectrum
- Disad: zero order kinetics, drug interactions
- SE: rash, SJS, serum sickness, hirsutism, gum hypertrophy, osteoporosis, headache, nausea, dizziness, somnolence/fatigue, ataxia, macro anaemia (decr. folate absorption)
Carbamazepine: MOA, Ind, Adv, Disadv, SE
- Dose: 5mg/kg/day –> 15-20mg/kg/day
- MOA: Na channel blocker
- Ind: focal sz and GTCs (+/- secondary generalisation)
- Adv: well tolerated, can be used for monotherapy or adjunctive, can be used for both focal and generalised epilepsies
- Disadv: interactions (decr OCP, warfarin) and autoinduction - lowers other AED levels, produces toxic metabolite - epoxide, worsens absence and myoclonus
- SE: rash, SJS (rare), transient leucopenia (10-20%), aplastic anaemia 1/200000, headache, nausea, dizziness, somn/fatigue, ataxia, hyponatremia, hepatotoxicity
Valproate: MOA, Ind, Adv, Disadv, SE
- Dose: 10mg/kg/day –> 20-30mg/kg/day
- MOA: Na channel blocker > Ca channel blocker, GABAergic action
- Ind: focal, GTC, absence sz, myoclonic, tonic
- Adv: broad spectrum (esp effective for generalised), well tolerated, can be given via multiple routes
- Disadv: teratogenicity! Interactions with other AEDs - raises other AED levels as it is a CYP enzyme inhibitor
- SE: weight gain, alopecia, essential tremour, thrombocytopenia/platelet dysfxn, hepatic failure (1/37000 –> esp <2yo, mental retardation and polytherapy), pancreatitis, thyroid dysfxn, other SE assoc. w/ Na channel blockers (headache, nausea etc)
Ethosuximide: MOA, Ind, Adv, Disadv, SE
- MOA: T-type Ca channel blocker
- Ind: CAE and JAE only - thalamo-cortical circuit in 3Hz spike and wave
- Adv: rapid, complete absorption, titrate to response
- Disadv: ineffective for GTC
- SE: rash –> SJS, GI Sx - nausea (33% at onset, requires slow titration), blood dyscrasias
Lamotrigine: MOA, Ind, Adv, Disadv, SE
- Dose: w/o VPA - 0.5mg/kg/day –> 5-15mg/kg/day
- Dose: w/ VPA - 0.2mg/kg/day –> 1-5mg/kg/day
- MOA: Na channel blocker > N-type & P-type Ca blocker
- Ind: GTC, focal, absence, myoclonic, tonic
- Adv: broad spectrum, well tolerated, recommended AED in pregnancy, synergistic with VPA, at right dose - no cognitive Sx
- Disadv: interactions - induced by CBZ & PHT, very slow titration, OCP will decrease levels, exacerbates sz in myoclonic epilepsy of infancy
- SE: rash in 3-5%, SJS in 1:100, severe hypersensitivity
Topiramate: MOA, Ind, Adv, Disadv, SE
- Dose: 1mg/kg/day –> 5-10mg/kg/day
- MOA (multiple!): Na channel blocker, GABA agonist, reduced glutamate > Ca channel blocker, increased GABA transmission
- Ind: LGS, GTC, focal sz, tonic
- Adv: broad spectrum
- Disadv: teratogenicity concerns
- SE: cognitive - somnolence (gradual titration), word finding difficulties, kidney stones 1.5%, anorexia and weight loss, glaucoma, acidosis, anhydrosis, hyperthermia
- -> Nephrolithiasis secondary to carbonic anhydrase activity
Vigabatrin: MOA, Ind, Adv, Disadv, SE
- Dose: 50-150mg/kg/day
- MOA: irreversible inhibition of GABA transaminase (metabolises GABA)
- Ind: first line therapy in TS pts for infantile spasms, infantile spasms - if pred fails after 2-4wks, focal sz and tonic sz
- Adv: renal excretion, no CYP450 effects
- SE: visual loss/visual field defect, irreversible, cumulative effect >6mth; incr myoclonus, weight gain, lethargy, psychosis
BZDs: MOA, Ind, Adv, Disadv, SE
- MOA: increase opening of Cl- channel in GABA receptor –> enhance inhibitory transmission
- Ind: 1st line drug in status, GTC, myoclonic, focal, tonic
- Adv: rapid onset action (lipophilic), can be used as adjunctive drug
- Disadv: short duration in most, rebound sz on withdrawal, tolerance
- SE: respiratory depression, sedation (esp w/ PHB), behavioural change, clonazepam - hypersecretion
Specific BZDs: clonazepam
Short-acting BZD
- Used as “temporising measure” e.g. if uptitrating AED, such as lamotrigine, in setting of high/increasing seizure frequency
- Tachyphylaxis after 6 weeks of use
Specific BZDs: clobazam
Long-acting BZD
- Half life of 18hrs
- Less sedation, active metabolite
- Potent and effective
Gabapentin: MOA, Adv, Disadv, SE
- MOA: increase GABA levels
- Ind: adjunctive therapy for focal seizures
- Adv: no interactions, not teratogenic, well tolerated, renally excreted
- Disadv: TID dosing, expensive, relatively non-potent
- SE: drowsiness, dizziness, weight gain
Levetiracetam: MOA, Ind, Adv, SE
- Dose: 10mg/kg/day –> 25-50mg/kg/day
- MOA: N-type Ca channel blocker, GABA agonist, synaptic vesicle modulation - binds SV2a - vesicular transport proteins
- Indication: refractory focal epilepsy, JME, PME, GTCs
- Adv: well tolerated, mainly renally excreted, no interactions (can use with OCP), rapid titration, broad spectrum
- SE: behavioural Sx, psychosis, suicidality, homicidiality, headache, sleep disturbance
Phenobarbitone: MOA, Ind, Disadv, SE
- Dose: load with 20mg/kg, maintenance 5mg/kg/day
- MOA: GABA agonist > Na channel blocker, N-type Ca blocker, reduced glutamate transmission
- Ind: second line for status epilepticus, neonatal seizures, GTCs, focal sz
- Disadv: interacts with VPA and BZDs
- SE: long-term cognitive effects even after cessation of drug, rash
Oxcarbazepine: MOA, Ind, Adv, Disadv, SE
- Dose: 5mg/kg/day –> 15-25mg/kg/day
- MOA: Na channel blocker, ?Ca channel blocker, converted to MHD
- Not identical to CBZ - has less side effects
- Ind: focal sz, GTCs (+/- secondary generalisation)
- Adv: no hepatic/autoinduction, effective monotherapy and adjunctive Tx for focal seizures
- Disadv: PHT decr OXC metabolite by 1/3, decr with enzyme inducers, expensive, worsens absence and myoclonus
- SE: hyponatraemia, 25% CBZ rash also develop rash with OXC, reversible agranulocytosis
Zonisamide: MOA, Ind Adv, Disadv, SE
- Dose: 2-4mg/kg/day –> 4-8mg/kg/day
- MOA: sulfonamide derivative, multiple mechanisms - blocks Na channel, inhibits T type Ca channel, carbonic anhydrase inhibition
- Ind: focal epilepsy, JME, IGE, LGS, IS, Ohtahara syndrome
- Adv: broad spectrum, renally excreted, good safety profile, no interactions with OCP
- DIsadv: decr by enzyme inducers, expensive
- SE: anorexia, sedation/somnolence, renal stones up to 2%, rarely high fever in kids, rash (hypersensitivity to sulphonamides)
Rufinamide: MOA, Ind, Disadv, SE
- MOA: prolongs inactivation of Na channels
- Ind: LGS
- Disadv: extensive interactions
- SE: hypersesitivity, headaches, nausea, somnolence, dizziness, ataxia
Cannabidiol in Dravet syndrome
- Open label trial in heterogeneous refractory epilepsy showed promise - 1/3 reduction in motor seizures, adequate safety profile
- Long term safety and efficacy not established, but looks promising
- SE: diarrhoea, vomiting, fatigue, pyrexia, somnolence, LFT derangement
Ketogenic diet
- Ind: refractory mixed seizures e.g. LGS
- Best response between 2-6yo
- Ind: refractory mixed sz e.g. LGS, glucose transporter type 1 defect, pyruvate dehydrogenase complex deficiency
- Disadv: difficult to initiate and maintain, significant adverse effects
AEDs for focal epilepsies
CBZ, OXC, GBP, PHT, PHB, VGA
CBZ - frontal and temporal lobe epilepsies
LVT or PHB - symptomatic focal epilepsies in infants
AEDs for generalised (and focal epilepsies)
VPA - if >3yrs
LTG, CLZ, LEV, TPA
- If <3yo: LEV, LTG, CLZ
Note: CBZ aggravates most generalised epileptic syndromes
AED for absence epilepsy
Ethosuximide
For CBZ failure in symptomatic/structural focal epilepsy
- Trial increasing dose of CBZ
- Check levels, SEs - Swap to OXC - similar drug with better SE profile if some benefit from CBZ
- Add: LVT or TPA depending on pt factors/urgency
For CBZ failure in idiopathic focal epilepsy (e.g. benign occipital, significant rolandic e.g. language delay apparent)
- Do not increase dose - can worsen seizures, stop CBZ
- Change to VPA
- If sz ongoing, EEG very active, language delay - consider combination of VPA and CLZ
For VPA failure in idiopathic generalised epilepsy
- Increase dose
- Add lamotrigine, then ethosuximide (if absence) or CLZ/TPA (if GTCs that are difficult to control)
- Aim for smaller doses of all AEDs if multiple agents used
For VPA failure in symptomatic generalised epilepsy
- Consider addition of LTG, TPA, CLZ, PHT
CNS side effects for Na channel blockers
- Blocks voltage-gated Na channels to reduce cortical excitability
- SE seen when given too much or dose titrated too quickly, multiple combinations etc
- Drowsiness, ataxia, tremour, diplopia, headaches, N/V
PHT, CBZ, LTG, VPA, TPA
CNS side effects for GABAergic AEDs
- Potentiates the activity of GABA on post-synaptic neurons
- Adverse behavioural effects are more commonly seen
- SE: hyperactivity, aggression, irritability, mood distrubance, sedation
PHB, LVT, BZD, VGA, VPA
AEDs that cause weight gain
VPA - major issue due to compliance
CBZ, LTG, GBP, VGB
AEDs that cause weight loss
TPA, Zonisamide
AEDs implicated in rickets, osteomalacia and osteoporosis
Mechanism:
- Direct effect of medication e.g. PHT
- Increased vit D catabolism by liver induction
- Decreased absorption of Ca
- Increased catabolism of sex steroids
PHT, VPA, TPM
Increases # risk and reduces BMD
Higher risk: developmental delay, wheelchair-bound, PEG fed and on multiple AEDs
AEDs to avoid in renal failure
GBP, LEV, VGB, TPM, ZNS
AEDs to avoid in hepatic failure
CBZ, OXC, PHT, PHB, VPA, LTG, BZ, ESM
AEDs to avoid with behavioural problems
LEV, BZ, PB, TPM
Psychosis: LEV, VGB
VPA and LTG are good mood stabilisers
AED titration rates: rapid titration
Can rapidly titrate +/- give loading dose (PO/IV):
- BZD, PHT, PHB, LEV, VPA, lacosamide
- Therefore, useful in situations where sz control is required quickly e.g. major seizures or very frequent (e.g. daily)
AED titration rates: slow titration
CBZ (wks), OXC (wks), LTG (mths), TPA (mths)
- Rash is a major problem if starting too quickly
- LTG and TPA are difficult to tolerate
Predictors of seizure recurrence (6)
- Intellectual disability (esp severe mental retardation - IQ <50)
- Abnormal neurological examinatinon - underlying brain abnormality/symptomatic aetiology
- Abnormal EEG before or during withdrawal
- Strong family history of epilepsy
- Certain recognised epilepsy syndromes
- Juvenile myoclonic epilepsy, photosensitive epilepsies, idiopathic generalised epilepsies, temporal/frontal lobe epilepsies - Recurrence after previous attempts to withdraw AEDs
Predictors of good outcome for seizure remission (4)
- NOVA SCOTIA Camfield et al
- Age of onset <12yrs
- Normal intelligence
- Lack of preceding neonatal seizures
- <21 seizures before diagnosis
If all present, by 10yrs after Dx, chance of remission was ~80%. If one factor absence, chance of remission was ~40%
Best predictors of outcome for seizure remission (4)
- Sillanpaa and colleagues
- 64% had 5yr terminal remission
- Cause of seizures
- Initial response to medication
- 75-100% reduction in seizure frequency by 3mth of Tx
- Best predictor - Initial seizure frequency
- Seizure type (remote symptomatic vs idiopathic)
Approach to an AED resistant epilepsy
- Review diagnosis - seizure and syndrome
- Identify and remove triggers, modify lifestyle
- Check pt compliance
- Check AED - is it the best medication for the sz type/syndrome?
- Trial maximum tolerated dose (depending on medication)
- Consider medication combinations
- Is it a surgically remediable epilepsy syndrome?
- Consider alternative therapies e.g. ketogenic diet
Focal lesional epilepsies
- Mesial temporal lobe epilepsy with hippocampal sclerosis
- Neocortical epilepsy secondary to tumours, focal cortical dysplasias (e.g. in frontal lobe), malformations, vascular malformations
- Hypothalamic harmatomas (gelastic seizures)
- Multilesional/unifocal epilepsies: tuberous sclerosis
Indications for vagal nerve stimulator
- Intractible epilepsy
- E.g. tonic drop attacks in LGS, recurrent status/clustering, frequent epileptic crises - Not surgical candidate for resection
- Consideration of callosotomy
- May benefit from seizure termination
- Fail appropriate AEDs
Efficacy of vagal nerve stimulator
- 50% have >50% of seizure REDUCTION
- <10% chance of seizure FREEDOM
- Will require to stay on AEDs
- Improvement in SEVERITY of seizures as evidenced by: not injuring themselves, reduction in AED doses, improvement in mood, not requiring hospitalisation
Indications and CI for ketogenic diet
Indications:
- Some refractory childhood epilepsies: generalised epilepsy, refractory myoclonic or absence epilepsy
- Pyruvate dehydrogenase deficiency
- GLUT transporter defect
- -> Need E to reach brain –> ketone bodies
CI:
- Metabolic diseases with fatty oxidation defects or produce lactic acidosis e.g. organic acidurias, carnitine deficiency, mitochondrial disorders
Reasons to avoid VPA in <2yo (2)
- Hepatic failure (esp multiple AEDs, ID)
- If undiagnosed metabolic condition can unmask mitochondrial disorders
- VPA is a mitochondrial toxin
West Syndrome - associated gene mutations
ARX, CDKL5, SPTAN1, STXBP1
Good prognostic indicators for West Syndrome (4)
- Normal development prior to/at the onset of spasms with preservation of visual function
- No symptomatic aetiology - normal neuroimaging
- 4-8mths of age
- Symmetrical epileptic spasms and symmetrical EEG hypsarrhythmia
Landau-Kleffner Syndrome - clinical manifestations
- Acquired epileptic aphasia: first Sx is verbal auditory agnosia (inability to comprehend speech) –> complete word deafness and non-linguistic sound agnosia
- Occurs in a child who previously achieved language milestones appropriately - Cognitive and behavioural abN: ADHD very common, severe disinhibition, psychosis
- Seizures: nocturnal sz that are heterogeneous e.g. GTCs, focal, atypical absence, atonic, automatisms etc
Landau-Kleffner Syndrome - EEG
Continuous bitemporal spike wave activity
Continuous status epilepticus of sleep
Landau-Kleffner Syndrome - prognosis
Seizures and EEG abN cease in adolescence/adulthood, but aphasia often persists
Significant speech abN in adulthood - 50%, better prognosis if onset is older (>6yo) and early initiation of speech Tx
Gelastic seizures
- Associated with hypothalamic hamartoma - intrinsic epileptogenicity within lesion that causes seizures
- Sz: “mirthless laughter” at inappropriate times, 10-30sec, can be associated with dacrystic (crying) episodes, sudden onset and termination, daily occurrence. Can occur with other sz types - usually generalised sz
- Autonomic Sx can occur with laughter
- Precocious puberty
- Develop progressive cognitive and behavioural impairment
Pathognomonic seizure for Dravet Syndrome
Hemiclonic seizures
Most effective AED in Dravet Syndrome
Stiripentol
- Increases GABAergic activity
- Inhibits LDH
- Interferes with reuptake and metabolism of GABA
Features suggestive of Dravet Syndrome
Febrile convulsions that are:
- Prolonged >15min
- Unilateral, mainly clonic
- Frequent
- Precipitated by low-grade fever (<38 deg)
- Early onset (before 1yr of age)
- Concurrent with non-febrile seizures
Dx is nearly certain if intractable myoclonic jerks and mental deterioration occur within 1 or 2 years from onest
AEDs to avoid in Dravet Syndrome
Sodium channel blockers: CBZ and PHT (esp if in status) - can exacerbate seizures
Remember: Dravet due to mutation in SCN1A - mutant sodium channels show remarkably attenuated/barely detectable inward Na currents –> no depolarisation
Management:
Generalised epilepsy
GTC: - >3yo: VPA - <3yo: LTG, LEV, CLZ Absence: - Ethosuximide Myoclonic: - VPA, CLZ
Management:
Focal epilepsy
CBZ or LTG
Avoid CBZ in HLA-B*1502 pos pts
Management:
Child absence epilepsy
First line: ethosuximide
Second line: VPA, LTG
Third line: LEV, CLZ, acetazolamide
Refractory: ketogenic diet, steroids
Management:
Juvenile myoclonic epilepsy
First line: VPA
Second line: LTG, LEV, TPM
Management:
Benign Rolandic Epilepsy
First line: CBZ (low dose), LTG
Second line: VPA, LEV
Management:
West Syndrome
First line: high dose prednisolone/ACTH, then taper
Second line: VGB, ketogenic diet
If TS, first line: VGB
If lesion: surgery
Management:
Dravet Syndrome
First line: VPA, CLZ
Second line: TPM, LEV, stiripentol (most effective)
Refractory: VNS, ketogenic diet
Management:
Lennox-Gastaut Syndrome
First line: VPA, CLZ
Second line: rufinamide, LTG, TPM, felbamate, ketogenic diet
Refractory: surgery/callosotomy, VNS
Management:
Doose Syndrome
First line: steroids, ketogenic diet
Management:
Landau-Kleffner Syndrome
First line: high dose VPA +/- CLZ +/- LEV
Second line: steroids
Refractory: IVIG, surgery
Management:
Symptomatic Focal Epilepsies (temporal, frontal)
First line: CBZ, PHT (temporal lobe epilepsy)
Second line: VNS, surgery
Interictal EEG patterns seen in neonates
- Electrocerebral inactivity of a flat or almost flat EEG of severe brain damage
- Burst suppression pattern of neonatal epileptic encephalopathies (Ohtahara, early myoclonic enceph), certain drugs or ischaemic encephalopathy (transient)
- Persistently focal sharp or slow waves in localised lesions
- Quasi-periodic focal or multifocal pattern in neonatal herpes simplex encephalitis
- Periodic complexes in glycine encephalopathy
Ohtahara Syndrome
- Early infantile epileptic encephalopathy - onset around first 10 days of life (up to 3mth)
- M>F
- Intractible sz of tonic spasms, erratic focal clonic sz, hemiclonic sz, myoclonic sz, spasms
- Aetiology: cortical malformation, genetic (same as West) and metabolic (rare)
- Usually transforms into West Syndrome as a rule in pts who survive infancy
- Grave prognosis: mortality rate of 50% with severe neurodevelopmental delay in survivors
- EEG: burst suppression pattern with continuous EEG abnormalities seen in awake and sleep states c.f. early myoclonic enceph where only seen in sleep EEG
- Mx: refractory, zonisamide, VBG, ?ACTH vs steroids, trial pyridoxine
Features suggestive of GEFS+ (5)
- Early onset (<6mo) of febrile convulsions
- Persistence of febrile convulsions beyond 6yrs (can be both febrile and afebrile sz)
- Association with afebrile sz e.g. GTCs, absence, myoclonic, myoclonic atonic sz, focal sz (frontal or temporal)
- FHx
- Multiple episodes of febrile convulsions
Febrile convulsions
Simple febrile convulsion (70%): occur in neurologically healthy children 6mo-5yr, brief (<15min), generalised (80%), occurs once in a 24hr period of febrile illness
Complex febrile convulsion (30%): neurologically normal OR focal onset, prolonged (>15min), repetitive (16%) with 2 or more within 24hrs
Febrile convulsion: recurrence risk
- Febrile seizures will recur in approx 30% of those experiencing first sz
- Major RF: <12mo, low grade febrile illness, short duration of illness before sz (fever duration <24hr)
- Minor RF: complex febrile sz, FHx of FS or epilepsy, day care, male, lower Na at presentation, persistent neuro abN
- 0 RF = recurrence risk 12%; 1 RF = 25-50%; 2 RF = 50-59%; 3 or more RF = 73-100%
Significance of family history and febrile convulsions
FHx of febrile convulsions are associated with 25% increments in absolute risk of recurrent febrile seizure
Febrile convulsion: RF for first febrile seizure
Risk is approximately 30% if any 2 of the following present:
- First or second degree relative with febrile convulsions
- Delayed neonatal discharge >28 days of life
- Parental reports of slow development
- Attending daycare
Risk factors for development of epilepsy after febrile convulsions
Baseline risk of epilepsy in general population 1.5%
Children with no risk factors have 2.5% chance of developing afebrile sz by 25yrs
Risk factors:
- Recurrent febrile seizures 4%
- Complex febrile sz (>15min or >2 in 24hrs) 6-8%
- Fever <1hr before sz 11%
- FHx of epilepsy 18%
- Complex febrile seizure (focality): 29%
- Neurodevelopmental abN prior to febrile sz 33%
- Complex febrile sz with all 3 features: 49%
Febrile convulsion and impact on intellect/behaviour
There is NO DIFFERENCE btwn children with febrile sz and their peers (in neurologically normal kids) in terms of:
- Academic progress
- Attention
- Intellect, neurocognitive function
- Behaviour
When do you do an EEG for a pt with febrile convulsions?
- If epileptic syndrome is highly suspected
- In febrile status epilepticus: focal slowing obtained within 72hrs of status has been shown to be highly associated with MRI evidence of acute hippocampal injury
- Nonepileptic twilight state: helpful to distinguish between ongoing sz activity and prolonged post-ictal period
EEG findings in simple febrile convulsions
- Spikes during drowsiness often seen in chlidren with febrile sz, esp >4yo - does NOT predict later epilepsy
- EEG performed within 2/52 of febrile sz will show nonspecific slowing posteriorly
- Not indicated if simple febrile sz and otherwise neurologically normal
Viruses implicated in febrile status epilepticus
HHV-6B and HHV-7 infections accounted for 1/3 of cases
Definition of status epilepticus
> 5min of continuous clinical and/or electrographic sz activity or recurrent sz activity without recovery (clusters)
Importance of T1 and T2 in status epilepticus
T1: time when the seizure is unlikely to abort spontaneously = 5min
- Abortive treatment should be introduced (e.g. midaz)
T2: time to neuronal injury = 30min
- Determines need to escalate to more aggressive therapy
Management of status epilepticus
- Seizure >5min: IV 0.1mg/kg midazolam OR buccal/IN 0.5mg/kg midazolam
- 10min after midaz: repeat dose if sz ongoing
- Optional step: PR paraldehyde whilst preparing PHT/PHB if required - 10min after second midaz: IV 20mg/kg phenytoin (if not on phenytoin) OR IV 20mg/kg phenobarbitone (if on phenytoin), both over 20min
- 20min after start of infusion: if still fitting, requires RSI with thiopentone
Genetic epilepsy with febrile seizures + spectrum: genetics
- ?AD, complex inheritance, penetrance 60%
- Genes involved: SCN1A, SCN1B, SCN2A, GABRG2 gene
- -> Encodes subunits of voltage gated Na channels and GABAa receptor subunit
- Mutation does not always predict phenotype, variable within families, modifier genes
Spectrum: febrile sz, GEFS+, Dravet Syndrome
Epileptiform pattern on EEG: Ohtahara syndrome
Burst suppression in both sleep and awake states (bursts of high amplitude spikes/sharp and slow waves, alternate with periods of flat/almost flat EEG)
Epileptiform pattern on EEG: West syndrome
Hypsarrhythmia (disorganised, multifocal sharp waves, high amplitude)
Epileptiform pattern on EEG: Lennox Gastaut Syndrome
Bianterior generalised slow (<2.5Hz) spike and waves with abnormal background
Epileptiform pattern on EEG: Absence epilepsy
Generalised 3Hz spike and wave (increases with photic stimuli and hyperventilation)
Epileptiform pattern on EEG: Childhood epilepsy with centro-temporal spikes
Centrotemporal spikes (unilateral or bilateral)
Epileptiform pattern on EEG: Temporal lobe epilepsy
Temporal sharp waves/multifocal spikes/slowing
Epileptiform pattern on EEG: Juvenile myoclonic epilepsy
Irregular bursts of polyspike-waves bursts (4-6Hz) - evoked by photic stimulation
Epileptiform pattern on EEG: GTCs
Generalised spike and wave (4Hz) on normal background
Epileptiform pattern on EEG: Landau-Kleffner Syndrome
Continuous temporal spike and waves
Epileptiform pattern on EEG: Dravet Syndrome
Similar progression to clinical state: normal (initially in 80%) to severely abnormal
- Background deteriorates with diffuse theta or delta waves
- Asymmetrical paroxysms of generalised polyspike and slow wave discharges
Which of these features are associated with NF1?
- Severe mental retardation
- Shortened life expectancy (50% of normal)
- Hypertrophy of 1 limb
- Precocious puberty
Hemihypertrophy
Precocious puberty
Porencephalic cyst
Cystic degeneration and encephalomalacia –> cystic structures within brain
Secondary to trauma, infection, antenatal haemorrhage or COL4A1 mutation leading to porencephaly
Rate of congenital malformations associated with Sodium Valproate
6-12%
