Personal Notes from ICNA 2006


Anti-epileptic drug and apoptosis in developing brain

Dr. Chrysanthy Ikonomidou


  • Apoptosis is normal in dev.
  • Alcohol and drugs affect this system
  • Studies done in rodents
  • Alcohol in 7d mouse, increased degeneration by apoptosis
  • Ethanol interferes with GLU and GABA to cause apoptosis
  • Anti-epileptic drugs affect GABA, GLU, and voltage gated channels, can cause massive apoptosis in rodents, but is this clinically relevant?
  • VPA-treated rats have smaller brains and less neurons on follow-up
  • Behavioral sequelae in rodents also – VPA causes poorer learning of Morris  water maze
  • Anaesthetic agents also cause widespread apoptosis and cognitive deficits
  • Phenobarbital for instance. Only levetiracetam and ACTH safe, and topiramate at low doses (dose dissociated)
  • AEDs impair intracellular signaling and neurotrophins
  • ?concurrent use of neuroprotection, e.g., estrogen compounds like 1-beta-estradiol
  • Of note in prems with sudden non-physiologic drop in estrogen at birth ???


Congenital muscular dystrophies

Dr. Haluk Topaloglu


CMD (congenital muscular dystrophy)

  • EMG is myopathic or normal, so muscle ultrasound is more useful
  • Deficient protein
    • Merosin deficiency
      • motor delay, peripheral neuropathy, non-ambulatory, contractures, wasting, and normal cognition. White matter changes on MRI.
      • Prenatal diagnosis possible @ 11 weeks (from 8-9 weeks)
    • Collagen VI
      • Bethlem myopathy (milder, in adults, decreased fetal movement, clubbed foot, finger contractures, normal CK)
      • Ullrich (proximal contractures, hyperlaxity, “dermatitis”)
      • Prenatal diagnosis possible by 8-9 weeks
      • Genotype/phenotype correlation
  • Deficient protein glycosylation
    • Remember eye abnormalities suggests brain abnormalities
    • Alpha-dystroglycan disorders
      • Fukuyama
      • MEB
      • LGMD2 1
      • MDC1C
      • WWS
      • LARGE (MDC1D)
  • Rigid spine syndrome
  • Marinesco-Seogren
  • merosin-positive CMD



Congenital myopathies

Dr. Monique Ryan


·         central core

o        autosomal dominant, variable expression

o        walk 3-4 years, kyphoscoliosis

o        atypical forms (limb-girdle, Autosomal resessive… )

o        >90% have mutated ryanodine receptor, malignant hyperthermia

·         nemaline myopathy

o        extraocular muscle and heart spared

o        nemaline bodies on Gomori trichrome

·         myotubular/centronuclear

o        X-linked myotubular myopathy

o        Dominant form – dynamin 2

o        Recessive form

·         Multiminicore myopathy

o        Ophthalmoplegic

o        Older onset

o        Ryanodine receptor or selenoprotein mutation

·         Congenital fiber-type disproportion

·         Myofibrillar myopathy

o        Distal weakness, dysphasia

o        Intermediate filaments, e.g., desmin

·         Selenoproteinopathies

o        Rigid spine, multiminicore, myofibrillar

o        Marfanoid habitus, tubular nose, midface hypoplasia, respiratory involvement



Congenital muscular dystrophies with structural brain involvement

Dr. Jiri Vajsar


  • Laminin alpha2 and alpha-dystroglycan deficiencies
  • Autosomal recessive, hypotonia, motor delay, high CK
  • Some have respiratory involvement
  • MDC1A – LAMA2 gene – seizures in 30%, normal internal capsule and corpus callosum





Classification of CNS malformations

H. Sarnat


It is not birth, nor marriage, nor death, but gastrulation that is truly the most important day of your life.


Vertical, longitudinal, and horizontal (medio-lateral or latero-medial) axes of the CNS. E.g. Emx2 gene expressed more rostrally.


Overexpression = hyperplasia/duplication

Underexprcssion = hypoplasia/dysplasia


E.g. diplomyelia is overexpression of Shh gene. Sacral agenesis from IDM (under expression). Rhombencephaloaynapsis (with septo-optic dysplasia) from under expression. Holoprosencephaly is underexpression.


Neural crest migrates in different streams.

  • Epidermal nevus syndrome – midline hyper or hypopigmentism
  • Holoprosencephaly
    • Or neural tube closes approx. 5 weeks
    • Depends on timing and location of mesencephalic neural crest migration disturbance


Intercanthal ligament from prosencephalic neural crest to cause forward facing eyes. Hypertelorisrn associated with agenesis of corpus callosum + procencephlic neural crest. Hypotelorism is from mesencephalic neural crest.


Face predicts the brain.


Neuroblast Migration



Ontogeny of 6-layer neocortex

  1. Neuronogenesis – 7 - 17 wks
  2. Migration of neuroblast – from 10 wks by the inside-out rule
  3. Differentiation Of neocortex – until postnatal period


·         Cajal-Retzius cells produce Relin to stop migration at the surface.

·         3 neuronal populations arise from 3 progenitor populations with 2 migration patterns.

·         Ventricular zone makes excitatory non-GABAergic  neurons

·         Radial migration

                                                               i.      Locomotion

                                                              ii.      Somal tronslocation

                                                            iii.      Multipolar migration

·         Tangential migration

                                                               i.      Interneurons - from medial/caudal ganglionic eminence

                                                              ii.      Cajal-Retzius cells – 3 origins migrating tangentially to cover brain surface (cortical hem)


Tuberous sclerosis complex

Paolo Curatolo


  • 1:6000 live births
  • TSC1 (9q34) Hamartin
  • TSC2 (16p13) Tuberin
  • Hamartin-tuberin complex is a tumor suppressor acting on mTor
  • Either one inherited and one acquired, or both acquired to cause hamartomas
  • More than 1000 mutations involved in tuberous sclerosis
  • TSC1 more common than TSC2
  • Epilepsy (focal – complex partial and drop – or infantile spasms), behavior, sleep disorders
  • TSC2 more severe tuber load, behavior, and seizures
  • Tubers, subependymal nodules, SEGA, agenesis of corpus callosum
  • Early onset seizures associated with more severe phenotype later on
  • Vigabatrin for infantile spasms in Tuberous Sclerosis
  • Vigabatrin retinal toxicity in 10% in early childhood, 30% in adults
  • Migration disorder
    • Abnormal cortical thickness – dyslamination
    • Tubers – focal cortical dysplasia
    • Arrested neuronoblast migration
    • Migration lines – related to tendency to generalized, intractible seizures
    • TSC1 mutation found in focal cortical dysplasia = “focal TSC1”
  • ? rapamycin can shrink cortical tubers – rapamycin works on mTor



L. Flores-Sarnat


  • Hamartomatous dysgenesis with overgrowth of one hemisphere
  • Unknown cause but easily confused with tumour
  • Pathogencsis
    • Cellular prolif
    • Neuroblast migration
    • Delayed maturation
    • Defective genetics
    • Mutated Symmetry genes
  • Forms of megalencephaly
    • Isolated
    • Associated – e.g. neurocutaneous, Aicardi, etc.
    • Total
  • Proteus Syndrome, hypermelanosis of Ito, hemilissencephaly, epidermal nevus syndrome, tuberous sclerosis

Molecular Genetics of CNS tumours

Peter Collins


Cancer treatment gets personal.


Common tumours

  • Pilocytic astrocytoma
  • Ependymoma
  • Medulloblastoma



  • Whole genome 1 MB array
  • Chromosome tile path array


Pilocytic astrocytoma

  • NF1 patients increased risk
  • Reports of 17q loss
  • Expression of NF1 in non-NF1 tumours
  • No clear pattern of loss – Single cases of tp53 and PTEN mutations
  • Microarray can be used to detect extra or missing copies of genes
  • Adult tumours have more trisomies, not in children



  • Grade II tumour
  • Common in NF2 – loss of chr 22q and NF2 mutations
  • E.g intracerebral ependymona – loss of chr 6 most common



  • Turcot syndrome type 2 – APC on 5q21
  • WNT pathway with mutations of beta-catenin most common
  • PTCH pathway with mutations in SMO and GLI1
  • Amplified chr 2 – MYCN, and other genes
  • Breakpoint on 17q
  • Atypical teratoid tumour – loss of 22q11.2, gene SMARCB1


Drugs targeting molecular abnormalities include Gleevec and Herceptin. Translate this to targeted therapy of pediatric tumours.


Epidemiology of CNS tumours

Sergio Rosemberg


Epidemiology difficult due to classification variations.




Genetic polymorphisms in preterm brain injury 

Walter Allan


  • Incidence of disability increasing in pretcrms, along with survival
  • For every 100 children 500-990g, 18 more survived, 11 handicapped
  • Incidence of PVL stable, grade 3-4 IVH climbing or not
  • Does gender/genomics play a role
  • Gender
    • IVH and DEHSI more common in males
    • Indomethacin prevents IVH and improves Peabody scores only in males
    • Sexually dimorphic gene expression precedes gonadal differentiation
    • XY cells more susceptible to toxicity and less oligo precursor development
  • Genetics
    • Concordance to IVH in twin pairs, but less than BPD (not NEC)
    • Col4a1 mutations segregate with porencephahy and IVH in family studies, and in mouse models (C-section prevented hemorrhage)


White matter injury in cardiac disease

Steven Miller


  • 6-8/1000 newborns have cardiac anomalies, 50% require surgery
  • Neurobehavioral anomalies in >50% pre-surgery
  • At school age, type of bypass did not affect performance
  • >33% had brain injuries prior to surgery for TGA, balloon atrial septostomy was highest risk factor
  • Brain lesions look like white matter injury in premature infants
  • Postoperatively, hypotension is highest risk factor for white matter injury
  • Stroke and white matter disease most common finding
  • Normal term injury patterns are watershed and basal nuclei, relative sparing of white matter
  • 3D MRS (NAA/choline, lactate/choline) and DTI (average diffusivity, fractional anisotropy)
  • Maturity increases NAA, decreases lactate, decreases relative diffusivity, increases fractional anisotropy
  • Diffusion tensor tractography increases over time, but increase in development of corticospinal tracts impaired by early injury


Short and long-term effects of early seizures

Yu-Ju Jiang


  • Recurrent seizures in neonatal rats causes long-term NMDA receptor subunit expression in vitro and in vivo
  • Changes in NMDA receptor may change Ca homeostasis


Early diagnosis of neonatal stroke

Linda deVries


  • Early neonatal stroke is DOL#1-3
  • Late neonatal stroke is within 1 month
  • AIS 70%, SVT 30% of neonatal stroke
  • SVT
    • sagittal, transverse, straight sinuses most commonly involved
    • Symptoms – seizures, bulging fontanelle, poor feeding, lethargy
    • Diagnosis by colour doppler ultrasound, CTV, or MRV
    • Term IVH can often be caused by SVT – look for it!
  •  AIS
    • MCA most common, and 70-80% L>R
    • Focal seizures are most common presenting symptom
    • Lipoprotein a, factor V leiden, MTHFR
    • Classic wedge shaped lesion on head ultrasound, but usually already MRl by time this can be seen
    • Cavitation by 3 months
    • In prems, left side also more common affected
    • Prem risks are CTG abnormalities, TTTS, hypoglycemia, low Apgars
    • MRS – high lactate, low NAA


Genetics Of Rett Syndrome

Alan Percy


  • Female predominance all over the world
  • Profound cog impairment, communication, stereotypies, growth failure
  • “normal” early development - quiet and hypotonic
  • Deceleration of growth, loss of purposeful hand movement
  • Evolve hypotonia to rigidity, loss of walking
  • Variable clinical expression
    • Phenotype
    • Seizures, behavioral patterns
    • Breathing irregularities (only during wakefulness)
    • GI difficulties (constipation, GERD)
    • nutrition requirement (more Calories and protein)
    • Scoliosis (surgery)
    • Ambulation
  • Significant longevity
  • Mutation in MECP2 – but can be without MECP2 and mutation can exist without Rett
  • Some males survive pregnancy, but are very ill from birth (fatal encephalopathy)
  • Imaging
    • Reduced brain weight, volume, melanin
    • Small neurons, simplified gyri
  • Genetics
    • MECP2 mutations – methyl-CpG-binding protein
    • Maintains maturation of neurons
    • Caudal-rostal expression
    • Usually new mutations, familial forms tend to be large deletions
    • Rett mutations increase mobility of protein binding
    • Mouse knock-out or knock.-in mutants 
    • Role in BDNF transcription


Organic acidurias

Bruce Korf


Glutaric aciduria type 1

  • Diagnosis by urine Glutaric acid
  • Dystonia, sudden acute attacks with neurological collapse like an encephalitic disorder, poor recovery to baseline, bright and anxious look, preserved visual function
  • Rapid increase in head circumference, macrocephaly
  • Prenatal diagnosis possible
  • Presentations
    • Acute 1 classic
    • Insidious/late
    • Asymptomatic
    • Macrocephalic variant
    • Congenital
    • Adult – with leukodystrophy
  • Management – low protein, no lysine, carnitine supplementation
  • Acute management – Avoid catabolism, IV calories and buffering
  • Diazepam helps for dystonia, as does intrathecal baclofen
  • Amish, Oji-Cree, Irish, Spanish, Nordic, and other multiethnic mutation
  • Glutaryl-CoA dehydrogenase (GCDH) in mitochondrial matrix
  • Acute striated necrosis symmetrically during metabolic crisis, neuronal loss in putamen in infancy, white matter in adults



Early cerebellar injury in premature infants

Catherine Limperopoulos


  • Germinal matrices are vulnerable to hemorrhage
  • Major events in cerebellar development are vulnerable to failure
  • Cerebellar migration from Germinal matrix
    • To deep nuclei
    • To Purkinje cell layer
    • To the secondary germinal matrix and the granular cell layer
  • Mastoid fontanelle ultrasound imaging to study posterior fossa in prems
  • Cerebellar hemorrhage significant in extreme low birthweight babies
  • Risk factors- emergency C-section, PDA, 5d acidotic pH
  • Unilateral hemorrhage most common, mostly associated with supratentorial  lesions
  • Inferomedial predilection for injury


Normal cerebellum with cerebral injury

  • Still has smaller cerebellum, perhaps from trophic withdrawal


Normal cerebellum and cerebrum on MRl

  • 3rd trimester is important for cerebellar growth
  • Prems at corrected term age have smaller cerebellum than normal babies born term


Outcome in cerebellar hemorrhage

  • Hypotonia
  • Gait problems
  • Extraocular abnormalities
  • Microcephaly
  • Expressive/receptive language
  • Visuo-motor deficit
  • Functional and behavioral/socialization deficits, autistic features


Developmental disorders of the cerebellum

Eugen Boltshauser


  • Cerebellar disorderd
    • Hypoplasia vs. Dysplasia
    • Focal vs. Generalized
  • Syndromes
    • Joubert syndrome (cerebello-ocular-renal syndromes)
      • Recessive inheritance
      • <50% have respiratory difficulties
      • Hypotonia, late ambulation
      • Oculomotor apraxia, retinitis pigmentosa
      • Low cognitive, and behavioral abnormalities
      • Molar tooth sign, not pathognomonic – other syndromes as well
    • Cerebellar hypoplasia