Surgical Treatment and Neurodevelopmental Outcome

1. Craniosynostosis
Surgical Treatment & Neurodevelopmental Outcome
Devon M. Fagel, J.D.
Clinical Neuroscience Clerkship
February 5, 2010

2. Learning Objectives
• Recognize the early presentation of skull deformities
• Describe the differential diagnosis of
craniosynostosis
• Review calvarial anatomy and suture
pathophysiology
• Interpret the epidemiology of nonsyndromic
synostosis
• Learn the surgical techniques for correcting
synostosis
• Review the complications and post-op management

3. • HPI: Full-term M infant presents for monitoring following
episode of hypoglycemia (stabilized to 58 w/o
intervention).
• PMH: No prenatal/birth complications.
• FH: No hx of craniofacial disorders.
• PE:
• Vitals: HR: 150 RR: 48 BP:75/38 SpO2: 100% Temp: 98.7
• Measure: Length: 48.9cm Weight: 3.1kg Head Circumference: 34cm
• CV: RRR, no m/r/g, 2+ pulses AFE, plethoric color
• GI/GU: Abd soft, no masses, + BS, urine/meconium not passed
• MS: Spine straight, upper/lower ext appear normal w full ROM
• Neuro: +Moro reflex, normal tone, spontaneous activity, strong cry
Case Presentation
Admission to NBSCU - Day 4

4. • PE:
• HEENT:
• Head: Symmetrical, central forehead angular vertical
prominence
• Fontanels: Normal, flat and soft
• Sutures: Normal, approximated
• Face: Symmetrical
• Eyes: Clear, +red reflex
• Ears: Normal shape and position
• Nose: Patent nares
• Mouth: Palate intact, normal tongue
• Neck: Normal, supple
Case Presentation
Admission to NBSCU - Day 4

5. Differential Diagnosis
Nonsyndromic Seconday Craniosynostosis
• Metabolic Disorders
• Rickets
• Hyperthyroidism
• Hematological Disorders
• Thalassemias
• Sickle cell anemia
• Polycythemia vera
• Lysosomal Storage
Disorders
• Sly Syndrome
• Hurler Syndrome
• Morquio Syndrome
• Teratogens
• Phenytoin
• Valproic Acid
• Retinoic Acid
• Aminopterin
• Malformations
• Microcephaly
• Encephalocele
• Shunted Hydrocephalus
• Positional Etiology
• Fetal Head Restraints
• Deformational
Plagiocephaly

6. Differential Diagnosis
Syndromic Primary Craniosynostosis
Syndrome Gene Additional Symptoms
Apert FGFR2 syndactyly, flat midface
Crouzon
FGFR2,
3
orbital hypertelorism, flat face
Muenke FGFR3
skeletal abnormalities hands/feet, hearing
loss
Pfeiffer
FGFR1,
2
syndactyly, short thumbs/big toes
Jackson-
Weiss
FGFR1,
2
enlarged, varus big toes

7. Calvarial Anatomy

8. Suture Pathophysiology
Sagittal Scaphocephaly 50-60%
Unilateral Coronal Frontal Plagiocephaly 20-30%
Bilateral Coronal Turribrachycephaly 10-15%
Metopic Trigonocephaly 5-10%
Unilateral
Lambdoid
Posterior
Plagiocephaly
2-4%

9. Suture Pathophysiology
• Skull begins developing between 23-26d gestation.
• Ossification begins, forming the cranial vault bones at 2m.
• Margins of these bones host osteoprogenitors with deposition
by osteoblasts and remodeling by osteoclasts to form sutures.
• Dura is essential for immature sutures to develop normally.
When neonatal rat dura was transplanted into subcutaneous
tissue, bone was formed. But when placed under sutures it
resisted ossification and formed cartilage.
• FGFRs play critical role in osteoblast proliferation (R2) and
differentiation (R1). FGFR2 is absent in the suture and dura
but highly expressed in bone fronts.

10. Epidemiology
• Incidence ranges from 3-10 per 10,000 live births.
• Of those, 2-8% have primary craniosynostosis.
• More than 90% of those occur spontaneously.
• 8-10% of coronal synostosis patients have +FH.
• 1-2% of sagital synostosis patients have +FH.
• Some patients misdiagnosed non-syndromic due
to extreme variability of some Mendelian
syndromes.
• Incidence of Apert syndrome 1 per 200,000
births.
• More than 98% of posterior plagiocephaly cases

11. Case Presentation
Workup for Craniosynostosis - Day 54

12. Case Presentation
Workup for Craniosynostosis - Day 54

13. Metopic Synostosis

14. Surgery Indications
• Signs of Elevated Intracranial Pressure
• 14% of single suture synostosis had elevated ICP
• 47% of multiple suture synostosis had elevated ICP
• Symptoms include HA, emesis, visual defects, AMS
• Most consistent finding is papilledema/optic nerve
atrophy
• Radiological signs are narrow ventricles, sulcal
effacement
• Ongiong debate about behavioral and cognitive deficits
• Cosmetic Considerations
• Calvarial deformity affects psychosocial development

15. Surgery Indications
• Cosmetic Considerations
• Deformities may also lead to proptosis and strabismus
• Calvarial deformity affects psychosocial development
• Untreated pts more likely to suffer personality
disorders

16. Correction of Metopic Synostosis
• Bifrontal craniotomy and bilateral
supraorbital rim osteotomy. Frontal
bone remolded to eliminate frontal
keel and triangular shape. Supra-
orbital rim also remodeled.
• Parallel osteotomies created in the
parietal region for lateral expansion.
• Supraorbital rim is advanced.
• Reshaped frontal bone attached to
the underlying dura and supraorbital
rim.

17. Case Presentation
Post-Op Imaging - 4 Months

18. Case Presentation
Post-Op Management
• HPI: s/p cranioplasty post-op day 0. Patient received 750cc
crystalloid and 300cc blood during procedure. Hct in OR
was 34, dropped to 31 on arrival to PICU.
• PE:
• Vitals: HR: 166 RR: 32 BP:82/69 SpO2: 95% Temp: 96.6
• HEENT: surgical incisions over parietal/occipital lobe c/d/i
• Lungs: CTAB, no tachypnea, no retractions
• CV: RRR, no m/r/g, pale, warm, cap refill <3s
• Neuro: Grasping dad’s hand, intermittently opens eyes, PERRLA

19. Neurodevelopment in SSC
• Assumption is that ICP increases with restricted cranial growth and
in turn adversely influences mental development, yet in SSC
patency of remaining sutures should allow for adequate
decompression.
• Though may expect decrease in intracranial volume, data suggests
that brain volume in SSC is normal or exceeds normal limits.
• Shape may also play critical role as changes in normal spacial
relations may affect neural organizational networks.
• Metopic synostosis patients have been found to exhibit corpus
callosum anomalies and abnormally small frontal lobes as well as
enlargement of the subarachnoid space in the areas of
compensatory bone expansion likely due to fluid shifts.
• Though linear distances between and among structures were altered
Effects on Brain Structure

20. Neurodevelopment in SSC
• A review of 17 studies between 1972-2003 found that the majority of
children demonstrated global development within normal range,
however 35-40% showed more subtle learning disability, language
impairment or “behavioral or cognitive abnormality.”
• Among several quasi-experimental studies of cranioplastic surgery
there is little evidence that intervention either prevented or reduced
risk of neurobehavioral impairment.
• Warschausky et al examined 22 infants with isolated metopic
synostosis before surgery using the Bayley scales of infant
development (problem-solving skills) and a psychomotor development
index. Scores were within normal range.
• Kapp-Simon et al recently reported data on first 100 patients in a
prospective longitudinal study with 24 metopic cases. Assessing
infants with BSID and PDI as well as preschool language scale-3,
study found that those with SSC had scores 1-2 standard deviations
below normal, regardless of subgroup.
Effects on Neurobehavioral Outcomes

21. Mechanism???
While it has been hypothesized that increasing ICP and
other structural changes caused by SSC are responsible for
neurodevelopmental deficits, we must consider the
possibility that SSC and the neuropsychological deficits
may both stem from a primary malformation of the brain.

22. FGF Pathway
• FGF induces
proliferation, migration,
differentiation leading to
neurogenesis and
angiogenesis.
• FGFs bind to activate
the Raf1-MEK-MAPK
and PI3K pathway for
proper mesoderm
development (bones and
cartilage).
• Mutations in genes
encoding FGFR1,2,3
cause both dwarfing
chondrodysplagia and
craniosynostosis

23. FGFR1 in Neurodevelopment

24. Increase in FGFR1 After Hypoxia

25. FGFR1 & Migration

26. FGFR1 & Differentiation

27. FGFR1 & Proliferation

28. Review
• Distinguish between primary vs secondary, syndromic vs
nonsyndromic and craniosynostosis vs positional DP.
• Sagital and unilateral coronal synostosis are the most common
deformities accounting for 80-90% of patients.
• Dura is essential for immature sutures to develop normally.
FGFRs play critical role in proliferation and differentiation.
• Indications for surgery include increased ICP (papilledema)
and cosmetic considerations (psychosocial development).
• Correction of metopic synostosis includes bifrontal
craniotomy and remodeling to eliminate triangular shape and
parietal barrel stave osteotomy to allow for lateral expansion.
• Suture fusion may lead to behavioral and cognitive deficits or
genetic mutations in growth factor genes may cause both
fused sutures and developmental disabilities in parallel.

29. References• Persing, JA, Jane, JA. Craniosynostosis. In: Youmans J. ed Neurological
Surgery. 4th ed. Philadelphia: WB Saunders; 1996: 995-1011.
• Ocal, E et al., Craniosynostosis. In: Albright, A. ed Principles and Practice
of Pediatric Neurosurgery. 2nd ed. New York: Thieme Medical Publishers;
2008: 265-288.
• Kimonis et al., Genetics of Craniosynostosis. Semin Pediatr Neurol 14:
150-61, 2007.
• Kapp-Simon et al., Neurodevelopment of Chilren with Single Suture
Craniosynostosis: A Review. Childs Nerv Syst 23: 269-281, 2007.
• Starr et al., Presurgical and Postsurgical Assessment of the
Neurodevelopment of Infants with Single-Suture Craniosynostosis:
Comparison with Controls. J Neurosurg 107: 103-110, 2007.
• Magge et al., Long-term Neuropsychological Effects of Sagittal Cranio-
synostosis on Child Development. J Craniofac Surg 13: 99-104, 2002.
• Fagel et al., Cortical Neurogenesis Enhanced by Chronic Perinatal
Hypoxia. Exp Neurol 199: 77-91, 2006
• Fagel et al., FGFR1 is Required for Cortical Regeneration and Repair After
Perinatal Hypoxia. J Neurosci 29: 1202-1211, 2009