Download Spina Bifida

Spina Bifida
Biology of Neurodevelopmental
Disorders
January 24, 2008
Chris Chapleau
John Hammond
Spina Bifida
•What is it?
•What causes it?
•How can it be prevented?
•How can it be managed?
•Social impact
•Further information
Spina Bifida
•What is it?
•What causes it?
•How can it be prevented?
•How can it be managed?
•Social impact
•Further information
What is spina bifida?
“Split Spine” caused by incomplete
closure of the neural tube, usually in
the lumbar or sacral region
What is spina bifida?
-Worldwide incidence is 1-2 cases in 1000
births
-US incidence is 0.7 per 1000 live births
-East coast higher than West coast
-Slightly higher incidence in Caucasian
population
-Irish immigrants also have a higher risk
-Seen more in children born in late summer
and early fall
What is spina bifida?
Anatomy review
http://www.fpnotebook.com/LumbarSpineAnatomyVertebra.gif
http://thespine.net/articles/lumbardecompression_files/image001.gif
What is spina bifida?
Anatomy review
Meninges
Dorland’s Medical Dictionary
What is spina bifida?
Several classifications that vary in
severity depending on location and
extent of opening
Spina bifida occulta
Spina bifida cystica
meningocele
myelomenigocele
Spina bifida ventralis
What is spina bifida?
Spina bifida occulta – “hidden”
- The bony vertebra is open, but the spine is within the spinal canal
- The skin may have a lipoma (small benign fatty tumor), some
discoloration (birthmark), or a small tuft of hair overlying the spinal
defect
- Most patients with spina bifida occulta do not know they have it
- There may be tethering of the spinal cord
What is spina bifida?
Spina bifida occulta – tethered spinal cord
-Often occurs later in life
- Caused by limitations of movement of the spinal cord within the spinal
column
- Patients often have low back pain, weakness in the legs, and/or
incontinence depending on the site of tethering
http://www.uwhealth.org/images
/ewebeditpro2/upload/6144_Fig
ure_1.jpg
What is spina bifida?
Spina bifida cystica – meningocele
-The bony vertebra is open, part of the meninges is protruding out of
the spinal canal
- Since the spinal cord is not protruding, there is often normal function
- Some cases of tethering have been reported
What is spina bifida?
Spina bifida cystica – myelomeningocele
-The bony vertebra is open, part of the meninges and part or all of the
spinal cord is protruding out of the spinal canal
- Since the spinal cord is protruding, it is often not fully developed
- Involved nerve roots are often not developed resulting in weakness,
pain, and/or paralysis
What is spina bifida?
Spina bifida cystica – myelomeningocele
- Arnold Chiara malformation II is often associated with
myelomeningocele and occurs when the cerebellum is forced downward
- This can result in life-threatening situations because the build-up of
cerebrospinal fluid can cause pressure on the brain
- Patients with Arnold Chiari malformations often require placement of a
shunt to drain the excess fluid
http://www.thefetus.net/images/article-images/central_nervous_system/arnold_chiari_files/image001.jpg
What is spina bifida?
Spina bifida ventralis – anterior opening
- Much less common than other forms of spina bifida
- Meningeal sac will protrude into the retroperitoneal space and
impinge on retroperitoneal organs such as the duodenum,
ascending/descending colon, kidneys, adrenal glands, pancreas, aorta,
and inferior vena cava
http://myweb.lsbu.ac.uk/dirt/museum/margaret/871-3398-2082230.jpg
Spina Bifida
•What is it?
•What causes it?
•How can it be prevented?
•How can it be managed?
•Social impact
•Further information
What causes spina bifida?
- The exact cause of spina bifida is unknown
- All research to date has indicated both a
genetic and environmental influence
- The developmental process that results in
spina bifida is well studied
Genetic
Neuronal
Migration
White
Matter
Injury
Lin, J.-P. J Neurol Neurosurg Psychiatry 2003;74:23i-29i
Copyright ©2003 BMJ Publishing Group Ltd.
Cortical gray &
subcortical injury
What causes spina bifida?
Developmental Biology – 6th ed.
Stages in the closure of
a xenopus neural tube
Video Views and Reviews: Neurulation and the
Fashioning of the Vertebrate Central Nervous
System
Christopher Watters
What causes spina bifida?
What would prevent the neural tubes from
closing properly?
Folate seems to play a large role in the closing of the neural tube –
but it is unknown exactly how folate works in this process.
Folate influence was discovered by the increased incidence in spina
bifida seen in Irish babies born in late summer and early fall. The
lack of leafy green vegetables caused the mother to have low levels
of folate during conception.
Genetics also play a role in the development of spina bifida.
- Mothers with one child with spina bifida have an increased risk of
additional children having spina bifida
- Studies with folate-resistant mice
What causes spina bifida?
Valproic acid (Depakote)
-Oral medication used to treat
seizures/convulsions, migraines, and bipolar
disorder
- Mechanism of action – thought to increase
GABA levels in the brain
- Pregnant women taking Valproic acid have an
increased risk of having children with spina bifida
Spina Bifida
•What is it?
•What causes it?
•How can it be prevented?
•How can it be managed?
•Social impact
•Further information
How can spina bifida be
prevented?
Education
Folate intake
How can spina bifida be
prevented?
Education
-Neural tube begins to close at day 22 after
conception
- Neural tube is usually fully closed by day
28 after conception
How can spina bifida be
prevented?
How can spina bifida be
prevented?
Folate intake
-Recommended that women of child-bearing age
take 400 micrograms of folate per day
-Pregnant women should take 600 micrograms of
folate per day
-Women with a previous child with spina bifida
should take 4000 micrograms of folate per day
- Folate can decrease the risk of spina bifida by
up to 75%
How can spina bifida be
prevented?
Sources of folate
- Vegetables and grains
- Many foods are now enriched
with folate
- Most multi-vitamins contain
folate
- Some vitamins are specifically
formulated for women
Spina Bifida
•What is it?
•What causes it?
•How can it be prevented?
•How can it be managed?
•Social impact
•Further information
How can spina bifida be
managed?
Treatment for spina bifida depends on
the extent of spinal cord involvement
- Spina bifida occulta usually requires no treatment
unless pain from tethering develops
- Meningocele usually requires removal and early
management of the cyst
- Myelomeningocele usually requires the most
extensive treatment, but treatment is variable
How can spina bifida be
managed?
Lesion Level
Spinal-related disability
Above L3
Complete paraplegia and dermatomal paraanesthesia, Bladder incontinence, Nonambulatory
L4 and below
Same as for above L3 except preservation of hip
flexors, hip adductors, knee extensors; Ambulatory
with aids, bracing orthopedic surgery
S1 and below
Same as for L4 and below except preservation of feet
dorsiflexors, and partial preservation of hip extensors
and knee flexors; Ambulatory with minimal aids
S3 and below
Normal lower extremity motor function; Saddle
anesthesia; Variable bladder-rectal incontinence
How can spina bifida be
managed?
- Detection
- Antibiotics
- Surgery
- Careful observation
- Physical therapy
How can spina bifida be
managed?
-Detection
-Triple screening
-Maternal blood test for a-fetoprotein
-Ultrasound for bone defects
-Amniocentesis
- a-fetoprotein is elevated in 75-80% of
cases of spina bifida (myelomeningocele)
How can spina bifida be
managed?
Amniocentesis – using a needle to collect amniotic fluid
How can spina bifida be
managed?
-Antibiotics
- In some cases the spinal cord is
exposed to the environment
- Antibiotics are essential in preventing
infection of the CNS
How can spina bifida be
managed?
-Surgery
- In some cases the spinal cord is
exposed to the environment or tethered
- Surgery is performed in order to cover
the spinal cord with muscle and skin or
to untether the spinal cord
- in utero surgery has also become a
viable option for some cases
How can spina bifida be
managed?
- Careful Observation
- Children with myelomeningocele often have
hydrocephalus (blockage of CSF)
- Children may present with paralysis,
blindness, MR, inability to speak, convulsions
-Any changes in mental status or behavior
should be quickly brought to the attention of
the child’s physician(s)
How can spina bifida be
managed?
- Physical Therapy
- Spinal cord damage can cause muscle
weakening and wasting
- Speech therapy may also be useful for
some individuals
Spina Bifida
•What is it?
•What causes it?
•How can it be prevented?
•How can it be managed?
•Social impact
•Further information
Social impact
Prognosis and any deficits are dependent
upon level of involvement
- Estimates from 5-40 % of the world’s population
may have spina bifida occulta
- Meningocele is not very common and often has
minimal impact once the cyst is removed
- Myelomeningocele has the largest impact on
patients and their families
Social impact
Changes with time
- Before antibiotics most children with
myelomeningocele died because of infections in
the CNS; those that survived were unlikely to ever
walk
- During the 1990s, the discovery of the role of
folate in neural tube closure drastically decreased
the number of cases of myelomeningocele
- In the late 1990s, in utero surgery was attempted
to close neural tube defects
Social impact
Children born with spina bifida today require some special
treatment
- Multiple surgeries starting as early as 48 hours after birth
- Physical therapy
- Bowel and/or bladder surgery – helps prevent infection and social stigmatism
- Latex allergies are often present
In many cases, special centers are better equipped to treat
children with spina bifida and have a variety of specialists on
staff
Social impact
Most children that are treated early will have normal IQ and
be able to attend public schools
Mobility is the biggest concern for many patients with spina
bifida – lack of mobility can lead to obesity and scoliosis
With proper treatment, individuals will live well into
adulthood
Social impact
Notable people that have spina bifida
Hank Williams, Sr. (singer)
John Mellencamp (singer)
Buddy Winnett (horse jockey)
Bruce Payne (actor)
Jean Driscoll (Olympian)
Rene Kirby (actor)
Further information
Spina bifida association – www.sbaa.org
UAB Health systems - http://www.health.uab.edu/15521/
Local Clinic –
Children's Hospital
Spina Bifida Clinic #3
1600 7th Avenue S.,
Birmingham, AL 35233
Phone: 205-939-5281
Website: http://www.chsys.org/
Paper Segment
Spina Bifida
The Focus of the Papers
• What causes Spina Bifida?
– Genetic Mouse Models of Spina Bifida and Neural
Tube Disorders
• How can Spina Bifida be Repaired?
– In utero repair in humans
Curly Tail: Brief History
• Curly tail is a spontaneous mutation that
was first described in the UK (1950)
• The ct gene is incompletely penetrant:
Some individuals fail to express the trait,
even though they carry the allele.
• Not sure what is the main genetic defect
that leads to the curly tail phenotype
Curly Tail: The Phenotype
• Curly tail mouse can demonstrate 0-3 different
phenotypes:
–
–
–
–
Healthy
Curled tail
Lumbosacral spina bifida
Exencephaly: Brain located outside of skull
Curly Tail: Penetrance (Incomplete)
On average: 40-50% unaffected, 50-60% have some
neural tube defects or curled tail
Curly Tail: As a Model for Spina Bifida
Causative
• A mouse model of common
human NTDs would have to
contain the following:
– Have different degrees of
defect
– A degree of genetic
complexity
– Responsive to nutritional
supplementation (Inositol)
Mechanism
Cures
Curly tail: What gene are involved?
Inositol- and folate-resistant neural tube defects in mice lacking the epithelialspecific factor Grhl-3
Stephen B Ting, Tomasz Wilanowski, Alana Auden, Mark Hall, Anne K Voss,
Tim Thomas, Vishwas Parekh, John M Cunningham & Stephen M Jane
Ting et al. 2003
• Based on studies in the Drosphila, the gene
grainyhead (grhl) has been implicated in
patterning of the nervous system
• In addition mutations in the fly have shown that
defects exist in epithelial closures, (which neural
tube closure is)
• What role does mammalian grhl have in
neurulation? Are there any similarities between a
knockout of grhl and the curly tail mouse?
Grhl3 expression: Is grhl expressed in the developing mouse?
In situ hybridazation shows that grhl3 is expressed in non-neural
ectoderm that is adjacent to the neural tube.
Does grhl3 mutant mice have NTD?
• All embryos had spina bifida and
curled tails
• 2% had exencephaly
• Problems in the bone structure
•In the caudal region of the neural
tube, the neural folds never
occurred
The relationship between grhl and ct
Can Folate or Inositol rescue NTD in
grhl3 mutant mice
Gustavsson et al. 2007
• Further investigate if grhl3 is the gene that is defective in
the curly tail mutant mice
• Investigate expression of grhl3 in ct mice
• Can defects in the neural tube be rescued in curly tailed
mice
Grhl3 expression is reduced in curly tail
mice…
…but the expression is rescued
when grhl3 is overexpressed
Grhl3 mutation in the promoter region
exist in curly tail mice
Rescue by overexpression of grhl3
Conclusion
• Mutations in curly tail mice seem to correlate with
mutations in the promoter region of the grhl3
• Curly tail mice that overexpress grhl3 show no defects in
the neural tube
• The phenotype in grhl3 cannot be rescued by inositol
• Further research: Folate has reduced the risk of spina
bifida, can Inositol can be used in humans
• Further research: Do mutations of grhl3 exist in humans
that have spina bifida or other defects of the neural tube
Clinical Paper
• Can fetal surgery be used to correct or
reduce the risk of neurological defects that
are caused that exist in spina bifida?
• Looking at a group of papers from the
Children’s Hospital of Philadelphia
Why Fetal Surgery?
• Neurological defects in patients with spina bifida are
not necessarily caused by the defect in neurulation,
but caused by damage from injury or chemical induced
trauma when the fetal neural tissue is exposed and
unprotected
• Hypothesis is that surgically “covering up” the exposed
neural tissue would improve neurological outcome
• Fetal surgery has been used to improve neurological
function in a sheep model of spina bifida
First Evidence (1998)
• 27-year old woman, with a 23-week gestation fetus
• Lesion in the thoracolumbosacral (T11-S1 level) was
detected at 20 weeks, in addition α-fetoprotein was
raised. Arnold-Chiari II malformations were detected
• Good leg movements were detected in the fetus
• Surgery: A low transverse maternal laparotomy and
vertical hysterotomy were performed
• Cystic membrane of the spina bifida lesion was excised
and skin flaps were developed to close the defect and
protect the developing spinal cord
• Amniotic fluid was
replaced with Ringer’s
solution
• Uterine and laparotomy
wounds were closed
Birth
• At 30 weeks gestation a baby boy was born by caesarean
section
• Shunt tubing was removed
• Leg function was excellent, good knee and hip flexion
– Except for a absent plantar and a right club foot
• MRI confirmed that the lesion was repaired and the
Arnold-Chiari malformation was no longer present. No
hydrocephalus
• All developmental milestones were reached by 6 months
of age
Developmental milestones
Approx. age
Motor milestone
3 months
Holds head up
4-5 months
Rolls front to back, sits when
propped
7-9 months
Sits alone, crawls
2003 Protocol
• 1998-2002, 50 patients underwent in utero fetal
closure and were delivered
• To be consider for this study
– Pregnancy had to be between 20 weeks and 25
weeks and 6 days
– Demonstrate the presence of Arnold-Chiari
malformation (type II)
– Have a lesion at S1-level or higher
• S2 or lower lesions were excluded because outcome were
usually good
– Intact neurological function of lower extremities
• Absence of clubfoot
Surgical Procedure and Pregnancy Management
• Similar as before
• After the surgery, the mother
stayed in the hospital for 4-5
days
– Discharged to the Ronald McDonald
house and placed on bedrest with
minimal physical activity
• Delivery was performed at 3637 by cesarean section
– There was some births that occurred
before this day
• After delivery, the infant was
admitted to the NICU for
evaluation
3 deaths, both very premature
Surgery does not affect
gestational ages at birth
2003 outcomes
• Mean birth weight was within normal range
– 2354g (range 1100-3490kg)
• All the surviving fetuses had reversal of Arnold-Chiari
malformation (type II)
Leg Function
57% better than expected
17% worse than expected
2003 Conclusions
• Study suggests that fetal surgery to correct spina
bifida:
– Improves neurological leg function
– Rescues the Arnold-Chiari malformation
– Restores normal CSF hydrodynamics
• 2007 paper that followed up on 51 children that
went through the fetal surgery should no change
or improvement of cognitive function
– Shunt vs. No Shunt
• Can earlier surgical prevention further improve
function?