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Paediatrics > Neurology > Flashcards

Neurology Flashcards

1
Q

Stages of neural development

A 
Dorsal induction
Ventral induction
Neuronal proliferation
Neuronal migration
Cortical organisation
Myelination
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2
Q

Myelination on MRI

A

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

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3
Q

Subdural haematoma

A

Tearing of bridging VEINS (venous bleeding) –> bleeding into potential space

  1. Crescentic
  2. Cross sutures
  3. Follows dural folds
  4. Outlines subarachnoid space
  5. Most consistent finding with abusive head injury
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4
Q

Epidural haematoma

A

Arterial bleed secondary to skull fracture

  1. Lens-shaped bleeding from stripping of dura from the skull
  2. Bound by sutures
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5
Q

Subarachnoid haemorrhage

A
  1. Extends into sulci and fissures

2. Best seen on T2* or FLAIR MRI

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6
Q

Holoprosencephaly

A

Failure of embryonic forebrain to separate –> fusion of e.g. frontal lobes

*Abnormality of ventral induction i.e. separation

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7
Q

Lissencephaly

with agyria/pachygyria complex

A

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

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8
Q

Polymicrogyria

A

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
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9
Q

Schizencephaly

A

Full-thickness cleft through hemisphere

  • Often lined by polymicrogyria
  • Open or closed lip

Causes:

  • Intrauterine neuro insult (~20wk): CMV infection, HIE
  • Genetic: COL4A1
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10
Q

Heterotopia

A

Abnormal position of grey matter

*Abnormality of neuronal migration

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11
Q

Focal cortical dysplasia

A

Subtle focal dysplastic cortex, can manifest as “blurring” of cortex (subtle finding)

*Accelerated myelination

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12
Q

EEG: normal background activity

A
  1. Alpha rhythm:
    - 8-12Hz - usually gradually increases with age; infancy 6-8Hz, 3yrs >8Hz
    - Prominent posteriorly on eye closure
  2. Theta waves:
    - 4-8Hz
    - Normal in children up to 13yrs and in drowsiness/sleep
  3. Delta waves:
    - <4Hz
    - Normal in deep sleep (stage 2 and 3)
    - Focal finding: can be assoc with structural pathology
    - Generalised finding: diffuse encephalopathy
  4. Beta waves:
    - >13Hz
    - Often prominent in presence of drugs (barbituates, BZD)
    - Commonly seen in frontal region
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13
Q

EEG: epileptiform discharges

A
  1. Sharply contoured discharges
    - Sharp waves <200ms
    - Spikes <70ms
    - No difference in biological significance between 2 forms
  2. Multiple phases
  3. Clearly disrupts background activity
  4. After-coming slow wave
  5. Sensible electrical field distribution
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14
Q

Genes associated with Charcot-Marie-Tooth Disease Type 1

A 
Autosomal dominant inheritance: 
CMT1A - PMP22 (17p11)
CMT1B - Po (1q22)
CMT1C - LITAF (16p13)
CMT1D - EGR2 (10q21)
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15
Q

Genes associated with Charcot-Marie-Tooth Disease Type 2 and Type 3

A

CMT2 - MFN2 (autosomal dominant)

CMT3 - PMP22 (point mutations) - 8q23, 17p11, 10q21

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16
Q

Risk factors for CP

A

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

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17
Q

Strongest predictor of mortality in CP

A

Profound intellectual disability

  • 22% die by 5yrs
  • 50% die by 18yrs
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18
Q

GMFCS Level 1

A
  • Can walk independently on all surfaces
  • Can run and jump, but speed, co-ordination and balance are reduced
  • 35% of CPs
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19
Q

GMFCS Level 2

A

Walks independently, but:

  • Difficulty walking on uneven surfaces, inclines, crowded places
  • 24% of CPs
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20
Q

GMFCS Level 3

A
  • Requires assistive mobility devices, orthoses for walking
  • Wheelchair required for long distances
  • Sits independently, has independent floor mobility
  • 12% of CPs
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21
Q

GMFCS Level 4

A
  • Uses power mobility outdoors and in community
  • Supported sitting function
  • Requires assistance with standing transfers
  • Mobility is limited
  • 13% of CPs
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22
Q

GMFCS Level 5

A
  • No independent mobility
  • Poor antigravity head and trunk postures
  • Require tilt in space and seating systems
  • 15% of CPs
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23
Q

Selective dorsal rhizotomy

A

Laminectomy L1-S1 –> dorsal nerve root transection
- 20-30% sensory nerve rootlets from L2-S1
To reduce lower limb spasticity
Irreversible

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24
Q

Indications for selective dorsal rhizotomy

A

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

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25
Q

Intrathecal baclofen

A

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.

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26
Q

Advantage of IT baclofen c.f. PO

A

Delivered directly around spinal cord, overcomes side effects secondary to large oral doses

  • 1/100th of oral dose
  • Small amount crosses BBB
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27
Q

Side effects and withdrawal effects of IT baclofen

A

Overdosing:

  • Sedation
  • Light-headedness
  • Respiratory depression
  • Seizures
  • LOC/Coma

Withdrawl: life-threatening

  • Hyperthermia
  • Rhabdomyolysis
  • Seizures, coma
  • Multiple organ system failure
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28
Q

Indications for Botulinum Toxin A

A

Indications:
- Spasticity and dystonia - specific muscle groups
- Interferes with function or cares
- Severe drooling - can inject into salivary glands
Aim: delay surgery

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29
Q

Side effects of BTA

A

Fibrosis

LRTI/URTI in those with pre-existing dysphagia and GMFCS V

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30
Q

Indication for deep brain stimulation in CP

A

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

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31
Q

CP Prevention

A
  • 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
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32
Q

Causes of hemiplegic CP

A
  • 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
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33
Q

Clinical criteria for neurofibromatosis type 1:

2 or more of…

A
  • 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
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34
Q

Features of NF1 more common in <5yo

A
  • 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)
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35
Q

Genetics of NF1

A

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)

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36
Q

Clinical criteria for neurofibromatosis type 2:

1 of…

A
  1. Bilateral vestibular schwannomas
  2. First degree relative with NF2 AND
    - Unilateral schwanomma OR
    - 2 or more of: meningioma, schwannoma, glioma, neurofibroma or posterior subcapsular lens opacity
  3. Multiple meningiomas (2 or more) AND
    - Unilateral schwannoma OR
    - 2 or more of: meningioma, schwannoma, glioma, neurofibroma or posterior subcapsular lens opacity
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37
Q

Genetics of NF2

A 
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
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38
Q

Management and prognosis of NF2

A

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)
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39
Q

Diagnostic criteria for tuberous sclerosis:

- 2 major criteria or 1 major and 2 minor criteria

A

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
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40
Q

Respiratory manifestations of tuberous sclerosis

A

LAM - lymphangioleioangiomyomatosis

  • Proliferation interstitium and dilated lymphatics –> obstruction and subsequent cystic lung changes
  • Presents with PTX and dyspnoea
  • F»M, poor prognosis
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41
Q

CNS manifestations of tuberous sclerosis

A

85% of TS have CNS Cx!!!

  1. Seizures (most significant cause of morbidity - 75%)
    - Infantile spasms (20%) - hard to treat
    - Myoclonic, focal, GTCS
    - Can be refractory to treatment
  2. Intellectual disability (50%)
    - 30% are profound
  3. Behavioural issues
    - ADHD, autism, sleeping problems, aggression, psychiatric disorders
  4. CNS changes/tumours (>75%)
    - Subependymal nodules, giant cell astrocytoma (teens), cortical tubers, white matter radial migration
    - Obstructive hydrocephalus
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42
Q

mTOR inhibitors for tuberous sclerosis

A
  • 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
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43
Q

Genetics of tuberous sclerosis

A

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)
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44
Q

Anencephaly

A

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

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45
Q

Dandy-Walker Malformation

A

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
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46
Q

DDx for acute hemiplegia

A
  1. 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
  2. Complex migraine: usually assoc. with a significant headache with focal deficits lasting hours, positive FHx!, MRI shows no acute infarct
  3. 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.
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47
Q

AEDs:

Greatest risk of Stevens-Johnson Syndrome

A

Lamotrigine: 1/100

Others: CBZ, PHT, OXC - 1-6/10000

Avoid by starting low and going slow

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48
Q

Which AED is associated with SJS in Han Chinese population?

A

Carbemazepine

CBZ-SJS strongly associated with HLA-B*1502: Han Chinese, Hong Kong Chinese, Thai

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49
Q

Foetal valproate syndrome

A

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

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50
Q

Which AED is associated with the development of neural tube defects?

A

VPA 1-5%

CBZ 0.5-1%

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51
Q

AEDs:

The greatest risk factor for teratogenicity/malformations…

A

Polytherapy, high drug levels in 1st trimester

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52
Q

Teratogenic effects of topiramate

A

CHDs, orofacial clefts, hypospadias

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53
Q

Major cognitive side effects of AEDs

A

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

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54
Q

Inducers of CYP450 system

A

PHT, PHB, CBZ

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55
Q

AEDs that are renally excreted

A

GBP, VGB, TPM, LVT, ZNS

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56
Q

AEDs that undergo hepatic clearance

A

PHT, PHB (75%), CBZ, OXC, VPA, LTG, BZ (diazepam)

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57
Q

Phenytoin: MOA, Adv, Disadv, SE

A
  • 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)
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58
Q

Carbamazepine: MOA, Ind, Adv, Disadv, SE

- Dose: 5mg/kg/day –> 15-20mg/kg/day

A
  • 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
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59
Q

Valproate: MOA, Ind, Adv, Disadv, SE

- Dose: 10mg/kg/day –> 20-30mg/kg/day

A
  • 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)
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60
Q

Ethosuximide: MOA, Ind, Adv, Disadv, SE

A
  • 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
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61
Q

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
A
  • 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
62
Q

Topiramate: MOA, Ind, Adv, Disadv, SE

- Dose: 1mg/kg/day –> 5-10mg/kg/day

A
  • 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
63
Q

Vigabatrin: MOA, Ind, Adv, Disadv, SE

- Dose: 50-150mg/kg/day

A
  • 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
64
Q

BZDs: MOA, Ind, Adv, Disadv, SE

A
  • 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
65
Q

Specific BZDs: clonazepam

A

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
66
Q

Specific BZDs: clobazam

A

Long-acting BZD

  • Half life of 18hrs
  • Less sedation, active metabolite
  • Potent and effective
67
Q

Gabapentin: MOA, Adv, Disadv, SE

A
  • 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
68
Q

Levetiracetam: MOA, Ind, Adv, SE

- Dose: 10mg/kg/day –> 25-50mg/kg/day

A
  • 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
69
Q

Phenobarbitone: MOA, Ind, Disadv, SE

- Dose: load with 20mg/kg, maintenance 5mg/kg/day

A
  • 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
70
Q

Oxcarbazepine: MOA, Ind, Adv, Disadv, SE

- Dose: 5mg/kg/day –> 15-25mg/kg/day

A
  • 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
71
Q

Zonisamide: MOA, Ind Adv, Disadv, SE

- Dose: 2-4mg/kg/day –> 4-8mg/kg/day

A
  • 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)
72
Q

Rufinamide: MOA, Ind, Disadv, SE

A
  • MOA: prolongs inactivation of Na channels
  • Ind: LGS
  • Disadv: extensive interactions
  • SE: hypersesitivity, headaches, nausea, somnolence, dizziness, ataxia
73
Q

Cannabidiol in Dravet syndrome

A
  • 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
74
Q

Ketogenic diet

A
  • 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
75
Q

AEDs for focal epilepsies

A

CBZ, OXC, GBP, PHT, PHB, VGA
CBZ - frontal and temporal lobe epilepsies
LVT or PHB - symptomatic focal epilepsies in infants

76
Q

AEDs for generalised (and focal epilepsies)

A

VPA - if >3yrs
LTG, CLZ, LEV, TPA
- If <3yo: LEV, LTG, CLZ
Note: CBZ aggravates most generalised epileptic syndromes

77
Q

AED for absence epilepsy

A

Ethosuximide

78
Q

For CBZ failure in symptomatic/structural focal epilepsy

A
  1. Trial increasing dose of CBZ
    - Check levels, SEs
  2. Swap to OXC - similar drug with better SE profile if some benefit from CBZ
  3. Add: LVT or TPA depending on pt factors/urgency
79
Q

For CBZ failure in idiopathic focal epilepsy (e.g. benign occipital, significant rolandic e.g. language delay apparent)

A
  1. Do not increase dose - can worsen seizures, stop CBZ
  2. Change to VPA
  3. If sz ongoing, EEG very active, language delay - consider combination of VPA and CLZ
80
Q

For VPA failure in idiopathic generalised epilepsy

A
  1. Increase dose
  2. 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
81
Q

For VPA failure in symptomatic generalised epilepsy

A
  1. Consider addition of LTG, TPA, CLZ, PHT
82
Q

CNS side effects for Na channel blockers

A
  • 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

83
Q

CNS side effects for GABAergic AEDs

A
  • 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

84
Q

AEDs that cause weight gain

A

VPA - major issue due to compliance

CBZ, LTG, GBP, VGB

85
Q

AEDs that cause weight loss

A

TPA, Zonisamide

86
Q

AEDs implicated in rickets, osteomalacia and osteoporosis

A

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

87
Q

AEDs to avoid in renal failure

A

GBP, LEV, VGB, TPM, ZNS

88
Q

AEDs to avoid in hepatic failure

A

CBZ, OXC, PHT, PHB, VPA, LTG, BZ, ESM

89
Q

AEDs to avoid with behavioural problems

A

LEV, BZ, PB, TPM
Psychosis: LEV, VGB

VPA and LTG are good mood stabilisers

90
Q

AED titration rates: rapid titration

A

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)
91
Q

AED titration rates: slow titration

A

CBZ (wks), OXC (wks), LTG (mths), TPA (mths)

  • Rash is a major problem if starting too quickly
  • LTG and TPA are difficult to tolerate
92
Q

Predictors of seizure recurrence (6)

A
  1. Intellectual disability (esp severe mental retardation - IQ <50)
  2. Abnormal neurological examinatinon - underlying brain abnormality/symptomatic aetiology
  3. Abnormal EEG before or during withdrawal
  4. Strong family history of epilepsy
  5. Certain recognised epilepsy syndromes
    - Juvenile myoclonic epilepsy, photosensitive epilepsies, idiopathic generalised epilepsies, temporal/frontal lobe epilepsies
  6. Recurrence after previous attempts to withdraw AEDs
93
Q

Predictors of good outcome for seizure remission (4)

- NOVA SCOTIA Camfield et al

A
  1. Age of onset <12yrs
  2. Normal intelligence
  3. Lack of preceding neonatal seizures
  4. <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%

94
Q

Best predictors of outcome for seizure remission (4)

  • Sillanpaa and colleagues
  • 64% had 5yr terminal remission
A
  1. Cause of seizures
  2. Initial response to medication
    - 75-100% reduction in seizure frequency by 3mth of Tx
    - Best predictor
  3. Initial seizure frequency
  4. Seizure type (remote symptomatic vs idiopathic)
95
Q

Approach to an AED resistant epilepsy

A
  1. Review diagnosis - seizure and syndrome
  2. Identify and remove triggers, modify lifestyle
  3. Check pt compliance
  4. Check AED - is it the best medication for the sz type/syndrome?
  5. Trial maximum tolerated dose (depending on medication)
  6. Consider medication combinations
  7. Is it a surgically remediable epilepsy syndrome?
  8. Consider alternative therapies e.g. ketogenic diet
96
Q

Focal lesional epilepsies

A
  • 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
97
Q

Indications for vagal nerve stimulator

A
  1. Intractible epilepsy
    - E.g. tonic drop attacks in LGS, recurrent status/clustering, frequent epileptic crises
  2. Not surgical candidate for resection
  3. Consideration of callosotomy
  4. May benefit from seizure termination
  5. Fail appropriate AEDs
98
Q

Efficacy of vagal nerve stimulator

A
  • 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
99
Q

Indications and CI for ketogenic diet

A

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

100
Q

Reasons to avoid VPA in <2yo (2)

A
  1. Hepatic failure (esp multiple AEDs, ID)
  2. If undiagnosed metabolic condition can unmask mitochondrial disorders
    - VPA is a mitochondrial toxin
101
Q

West Syndrome - associated gene mutations

A

ARX, CDKL5, SPTAN1, STXBP1

102
Q

Good prognostic indicators for West Syndrome (4)

A
  1. Normal development prior to/at the onset of spasms with preservation of visual function
  2. No symptomatic aetiology - normal neuroimaging
  3. 4-8mths of age
  4. Symmetrical epileptic spasms and symmetrical EEG hypsarrhythmia
103
Q

Landau-Kleffner Syndrome - clinical manifestations

A
  1. 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
  2. Cognitive and behavioural abN: ADHD very common, severe disinhibition, psychosis
  3. Seizures: nocturnal sz that are heterogeneous e.g. GTCs, focal, atypical absence, atonic, automatisms etc
104
Q

Landau-Kleffner Syndrome - EEG

A

Continuous bitemporal spike wave activity

Continuous status epilepticus of sleep

105
Q

Landau-Kleffner Syndrome - prognosis

A

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

106
Q

Gelastic seizures

A
  • 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
107
Q

Pathognomonic seizure for Dravet Syndrome

A

Hemiclonic seizures

108
Q

Most effective AED in Dravet Syndrome

A

Stiripentol

  • Increases GABAergic activity
  • Inhibits LDH
  • Interferes with reuptake and metabolism of GABA
109
Q

Features suggestive of Dravet Syndrome

A

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

110
Q

AEDs to avoid in Dravet Syndrome

A

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

111
Q

Management:

Generalised epilepsy

A 
GTC: 
- >3yo: VPA
- <3yo: LTG, LEV, CLZ
Absence:
- Ethosuximide
Myoclonic:
- VPA, CLZ
112
Q

Management:

Focal epilepsy

A

CBZ or LTG

Avoid CBZ in HLA-B*1502 pos pts

113
Q

Management:

Child absence epilepsy

A

First line: ethosuximide
Second line: VPA, LTG
Third line: LEV, CLZ, acetazolamide
Refractory: ketogenic diet, steroids

114
Q

Management:

Juvenile myoclonic epilepsy

A

First line: VPA

Second line: LTG, LEV, TPM

115
Q

Management:

Benign Rolandic Epilepsy

A

First line: CBZ (low dose), LTG

Second line: VPA, LEV

116
Q

Management:

West Syndrome

A

First line: high dose prednisolone/ACTH, then taper
Second line: VGB, ketogenic diet
If TS, first line: VGB
If lesion: surgery

117
Q

Management:

Dravet Syndrome

A

First line: VPA, CLZ
Second line: TPM, LEV, stiripentol (most effective)
Refractory: VNS, ketogenic diet

118
Q

Management:

Lennox-Gastaut Syndrome

A

First line: VPA, CLZ
Second line: rufinamide, LTG, TPM, felbamate, ketogenic diet
Refractory: surgery/callosotomy, VNS

119
Q

Management:

Doose Syndrome

A

First line: steroids, ketogenic diet

120
Q

Management:

Landau-Kleffner Syndrome

A

First line: high dose VPA +/- CLZ +/- LEV
Second line: steroids
Refractory: IVIG, surgery

121
Q

Management:

Symptomatic Focal Epilepsies (temporal, frontal)

A

First line: CBZ, PHT (temporal lobe epilepsy)

Second line: VNS, surgery

122
Q

Interictal EEG patterns seen in neonates

A
  1. Electrocerebral inactivity of a flat or almost flat EEG of severe brain damage
  2. Burst suppression pattern of neonatal epileptic encephalopathies (Ohtahara, early myoclonic enceph), certain drugs or ischaemic encephalopathy (transient)
  3. Persistently focal sharp or slow waves in localised lesions
  4. Quasi-periodic focal or multifocal pattern in neonatal herpes simplex encephalitis
  5. Periodic complexes in glycine encephalopathy
123
Q

Ohtahara Syndrome

A
  • 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
124
Q

Features suggestive of GEFS+ (5)

A
  1. Early onset (<6mo) of febrile convulsions
  2. Persistence of febrile convulsions beyond 6yrs (can be both febrile and afebrile sz)
  3. Association with afebrile sz e.g. GTCs, absence, myoclonic, myoclonic atonic sz, focal sz (frontal or temporal)
  4. FHx
  5. Multiple episodes of febrile convulsions
125
Q

Febrile convulsions

A

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

126
Q

Febrile convulsion: recurrence risk

A
  • 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%
127
Q

Significance of family history and febrile convulsions

A

FHx of febrile convulsions are associated with 25% increments in absolute risk of recurrent febrile seizure

128
Q

Febrile convulsion: RF for first febrile seizure

A

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
129
Q

Risk factors for development of epilepsy after febrile convulsions

A

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%
130
Q

Febrile convulsion and impact on intellect/behaviour

A

There is NO DIFFERENCE btwn children with febrile sz and their peers (in neurologically normal kids) in terms of:

  1. Academic progress
  2. Attention
  3. Intellect, neurocognitive function
  4. Behaviour
131
Q

When do you do an EEG for a pt with febrile convulsions?

A
  1. If epileptic syndrome is highly suspected
  2. 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
  3. Nonepileptic twilight state: helpful to distinguish between ongoing sz activity and prolonged post-ictal period
132
Q

EEG findings in simple febrile convulsions

A
  • 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
133
Q

Viruses implicated in febrile status epilepticus

A

HHV-6B and HHV-7 infections accounted for 1/3 of cases

134
Q

Definition of status epilepticus

A

> 5min of continuous clinical and/or electrographic sz activity or recurrent sz activity without recovery (clusters)

135
Q

Importance of T1 and T2 in status epilepticus

A

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

136
Q

Management of status epilepticus

A
  1. Seizure >5min: IV 0.1mg/kg midazolam OR buccal/IN 0.5mg/kg midazolam
  2. 10min after midaz: repeat dose if sz ongoing
    - Optional step: PR paraldehyde whilst preparing PHT/PHB if required
  3. 10min after second midaz: IV 20mg/kg phenytoin (if not on phenytoin) OR IV 20mg/kg phenobarbitone (if on phenytoin), both over 20min
  4. 20min after start of infusion: if still fitting, requires RSI with thiopentone
137
Q

Genetic epilepsy with febrile seizures + spectrum: genetics

A
  • ?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

138
Q

Epileptiform pattern on EEG: Ohtahara syndrome

A

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)

139
Q

Epileptiform pattern on EEG: West syndrome

A

Hypsarrhythmia (disorganised, multifocal sharp waves, high amplitude)

140
Q

Epileptiform pattern on EEG: Lennox Gastaut Syndrome

A

Bianterior generalised slow (<2.5Hz) spike and waves with abnormal background

141
Q

Epileptiform pattern on EEG: Absence epilepsy

A

Generalised 3Hz spike and wave (increases with photic stimuli and hyperventilation)

142
Q

Epileptiform pattern on EEG: Childhood epilepsy with centro-temporal spikes

A

Centrotemporal spikes (unilateral or bilateral)

143
Q

Epileptiform pattern on EEG: Temporal lobe epilepsy

A

Temporal sharp waves/multifocal spikes/slowing

144
Q

Epileptiform pattern on EEG: Juvenile myoclonic epilepsy

A

Irregular bursts of polyspike-waves bursts (4-6Hz) - evoked by photic stimulation

145
Q

Epileptiform pattern on EEG: GTCs

A

Generalised spike and wave (4Hz) on normal background

146
Q

Epileptiform pattern on EEG: Landau-Kleffner Syndrome

A

Continuous temporal spike and waves

147
Q

Epileptiform pattern on EEG: Dravet Syndrome

A

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
148
Q

Which of these features are associated with NF1?

  • Severe mental retardation
  • Shortened life expectancy (50% of normal)
  • Hypertrophy of 1 limb
  • Precocious puberty
A

Hemihypertrophy

Precocious puberty

149
Q

Porencephalic cyst

A

Cystic degeneration and encephalomalacia –> cystic structures within brain
Secondary to trauma, infection, antenatal haemorrhage or COL4A1 mutation leading to porencephaly

150
Q

Rate of congenital malformations associated with Sodium Valproate

Paediatrics (16 decks)

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