CASE 1 - spina bifida Flashcards
how does the neural tube develop?
neurulation
describe neurulation
- notochord forms in the middle of the mesoderm — under where the primitive streak was , mesoderm cells differentiate into the notochord
- notochord sends inductive signals to the overlying ectoderm to form a thickening in the ectoderm = neural plate
- neural plate is widest at cranial end
- laterally the edges thicken to form the neural folds
- neural folds develop towards each other to eventually form the neural groove, ultimately fusing as the neural tube
- the brain develops at the cranial end and the remainder gives rise to the spinal cord
- at the end of the tube are the anterior + posterior neurospores which close in the middle and end of the 4th week respectively (25th and 27th day)
what is vital for the closing of the anterior and posterior neurospores?
folic acid
failure of closure of anterior neurospore = ____?
anencephaly — brainstem forms but the upper part of the brain doesn’t develop — not compatible with extra-uterine survival
failure of closure of posterior neurospore = ______?
spina bifida
after closure of the anterior neurospore, what does the head end of the neural tube form?
3 primary vesicles:
1) prosencephalon (forebrain)
2) mesencephalon (midbrain)
3) rhombencephalon (hindbrain)
due to insufficient space, the tube in the cranial end is forced to bend, forming what?
cervical and cephalic flexures
what do the 3 primary vesicles become by the 5th week?
5 secondary vesicles
- telencephalon
- diencephalon
- mesencephalon
- metencephalon
- myelencephalon
what does the lumen of the neural tube become?
the central canal of the spinal cord and the ventricular system
what are 2 NTDs of the brain?
- anencephaly = the total or partial absence of the upper part of the brain, the bones make up the top of the skull, and the skin that would cover these parts. very severe (death). failure of closure of anterior neuropore
- encephalocele = an opening in the skull bones that exposes part of the brain or the tissues that covers it
name a NTD of the spinal cord
spina bifida = failure of closure of posterior neurospore
what are the types of SB?
> OPEN — neural tissue exposed (not covered by skin)
- spina bifida occulta
- meningocele
- myelomeningocele
> CLOSED — neural tissue not exposed
what is a NTD of both the brain and spinal cord?
craniorachischisis — incompatible with life, entire brain and spina cord are exposed
folic acid roles
= a B vitamin
- essential for a wide range of normal bodily functions including DNA synthesis/repair, cell division and neurodevelopment
where is folate supply from at the start of embryogenesis?
yolk sac
what are the international recommendations of folic acid in terms of pregnancy?
400ug/day 3 months before pregnancy and 3 months into pregnancy
folic acid supplements can prevent up to what % of NTDs?
70%
what is an indicator of a serious loss of folate availability to the brain?
fluid accumulation due to drainage insufficiency
when does the neural tube normally close?
28th day
SB = 1/____ globally?
1/500
describe spina bifida occulta
- occulta means hidden
- mildest and most common type
- there is a small gap in one or more bones in the spine — many people don’t even know they have it
- tuft of hair
what does a tuft of hair indicate?
that CSF is leaking from the neural tube and stimulating hair follicles to form hairs — tells us exactly where the tube defect is
describe myelomeningocele
- open spina bifida
- most severe type
- spinal canal is open along several vertebrae in the lower or middle back
- the membranes and spinal nerves push through this opening at birth, forming a sac on the baby’s back — typically exposes tissue and nerves
- makes baby prone to life-threatening infections and may also cause paralysis and bladder and bowel dysfunction (because the nerves that supply the bowel and bladder come from the lowest level of the spinal cord)
describe meningocele
- rare type
- characterised by a sac of CSF bulging throguh an opening in the spine
- no nerves affected
- spinal cord not in fluid sac
- babies born with it have some minor problems functioning, including those affecting the bladder and bowels
what happens do the ventricles in SB?
ventriculomegaly as the CSF is formed
why does CSF go into the opening in the spine in SB?
due to the opening in the neural tube, there is not enough pressure for the CSF to leave the 4th ventricle so it goes down the spinal canal and protrudes out into the opening
what are risk factors for NTD?
- nutritional status
- obesity and diabetes
- no folic acid supplementation and/or fortification during and before pregnancy
- environmental toxicants
- genetic predisposition among ethnic groups
- some medications such as anti-seizure meds (eg. valproic acid) when taken during pregnancy — interfere with body’s ability to use folate and folic acid
complications of spinal bifida
- walking and mobility problems — the nerves that control the leg muscles dont work properly below the area of the defect
- bowel and bladder problems
- hydrocephalus (myelomeningocele) — 50%
- shunt malfunction — shunts put in brain to treat hydrocephalus
what is chiari malformation type II?
- problem in myelomeningocele
- cerebellum and brainstem tissue extend into the foramen magnum
what is the lemon sign?
- noted on antenatal imaging
- indentation of frontal bone
- classically seen as a sign of chiari II malformation
- can only be seen before 24 weeks
- due to decrease in intrapspinal pressure
spina bifida treatment?
- most serious types of SB cannot be cured
- some may require catheterisation and help training to learn to manage bladder and bowel functions
- surgery to repair spine postnatally (cannot repair nerve damage)
- shunt to treat hydrocephalus
- open lesion — antibiotics to treat infection
- decompression surgery — help remove pressure on brain
- post natal surgery within 48 hours
- surgery in utero (weeks 23-27) = high risk, only done in 3 places in UK
what is between the dura mater and arachnoid mater?
sub dural space
what is between arachnoid mater and pia mater?
subarachnoid space
what is in the subarachnoid space?
- CSF
- all cerebral arteries and veins
what is meningitis?
infection of meninges
what is between the periosteum and meningeal layers of the dura mater?
dural venous sinuses — venous drainage, drain into IJV
vascular supply of dura mater?
has its own vascular supply from middle meningeal artery and vein
what do dural reflections do?
- compartmentalise the cranial cavity
- hold brain in place
what dural reflection houses:
a) superior and inferior sagittal sinuses
b) occipital sinus
c) anterior and posterior intercavernous sinuses
a) falx cerebri
b) falx cerebelli
c) diaphragma selllae
vascular supply of arachnoid mater?
avascular
what is the relationship between arachnoid mater and sulci + gyri?
does not extend into sulci — brides over one gyrus to the next
innervation of arachnoid mater?
no innervation
what do arachnoid granulations do?
CSF diffuses through the lining of arachnoid granulations into the dural venous issues — their function is to enable the continuous drainage of the CSF from the subarachnoid into the vascular system
what is the function of pia mater?
to physically separate the neural tissue from the blood vessels in the subarachnoid space
what does each vessel that enters the brain carry with it?
a sleeve of pia mater — pia mater fairly adheres to the surface of the brain and spinal cord, each sulcus contains blood vessels which lie just outside the pia
what is pia mater made of?
connective tissue and has many tiny blood vessels
what is breech position?
positioned feet or bottom first in the uterus
when do most babies turn to the head first position?
week 36
why are babies with spina bifida more likely to be in breech position?
reduced leg movements — legs not strong enough to move around into correct position
risk factors for breech position
- prematurity
- uterine abnormalities
- maternal smoking
- maternal diabetes
- too much or too little amniotic fluid
- multiple pregnancy
- foetal malformation (eg. hydrocephalus)
many babies with myelomeningocele (severe type of SB) tend to be breech
what is depakote?
- anti-seizure medication in epileptic people >10y
- also used in adults to prevent migraines or to treat manic episodes related to bipolar disorder
how does depakote work?
- works by increasing the amount of gamma-aminobutyric acid (GABA) in the brain
- GABA is a chemical neurotransmitter naturally produced by the body
- GABA is an inhibitory neurotransmitter — it attaches to a GABA receptor and decreases activity in the nervous system
- hence by increasing this pathway, there is a calming effect, helping with feelings of anxiety, stress and fear
it is also a FOLATE ANTAGONIST
GABA levels in people with seizure disorders, movement disorders (eg. Parkinson’s), ADHD, anxiety, panic and mood disorders?
levels may be lower
how does sodium valproate interfere with folate?
- it is a folate antagonist
- it interferes with folate transport and metabolism by inhibiting glutamate formyl transferase, an enzyme mediating the pathway that produces folinic acid
side effects of depakote?
- upset stomach
- headache
- sleepiness/drowsiness
- muscle weakness
- causes suicidal thoughts in a small % of people
- tremors
depakote and pregnancy?
- must not be on depakote while pregnant
- must be on effective brith control while using depakote
- it makes SB 30x more likely
- impaired folate metabolism contributes to congenital risks, including NTDs
Valproate should not be used in female children and women of childbearing potential unless other treatments are ineffective or not tolerated — valproic pregnancy prevention program
what is gillick competence?
> established in 1983
allows a child, if they past the gillick test, to medical treatment without their parents knowing or given permission
gillick test : in order to assess an under 16’s capacity to provide informed consent, they must pass this test. to pass, they must demonstrate sufficient understanding and knowledge of the treatment and the processes it involves, awareness of the benefits and risks, as well as the alternative options
if not found competent, then parental permission must be obtained
what are the fraser guidelines?
> guidelines build on the gillick competency test
guidelines relate specifically to the issue of contraceptive advice for under 16s
they state a doctor can give contraceptive advice and treatment without parental consent, provided the doctor is satisfied:
1That the young person will understand the professional’s advice
2The young person cannot be persuaded to inform their parents
3The young person is likely to begin, or to continue having, sexual intercourse with or without contraceptive treatment
4That unless the young person receives contraceptive treatment, their physical or mental health (or both) are likely to suffer
5That the young person’s best interests require them to receive contraceptive advice or treatment with or without parental consent
> the guidelines have been applied more broadly to include other related treatments, including abortion
at what age are you legally assumed capacity?
16
what is bipolar disorder?
used to be known as manic-depression
- a severe and enduring mental disorder in which sufferers usually experience recurrent periods of sustained depressed mood and hopelessness (major depressive episodes) and periods of abnormally elated mood with increased energy (known as manic episodes, or – when less severe – hypomanic episodes)
what do each of the 5 secondary vesicles become?
telencephalon — cerebral cortex and basal nuclei (and caudate and putamen)
diencephalon — retina of the eye, thalamus, hypothalamus (and subthalamic nucleus and globus pallidus)
mesencephalon — midbrain, sup + inf colliculus (and substantia nigra)
metencephalon — pons, cerebellum
myelencephalon — medulla
what produces all the peripheral NS?
neural crest cells
what does sunken eyes indicate?
pressure on the oculomotor nerve
why does hydrocephalus accompany nearly 50% of SB cases?
due to chiari malformation blocking CSF exit from the ventricles
what are 4 obvious distinctions between brainstem-spinal cord development and cerebral cortex development?
- notochord does not control cerebral development
- genetics
- Hox genes for brain and spinal cord
- Emx and Otx genes for prosencephalon - timing
- fluid system changes
what stimulates cells to migrate?
CSF
what are some causes of neurodevelopment defects?
- genetic
- metabolic/immune disorders (phenylketonuria etc)
- environment (alcohol, tobacco, nutritional deficiencies)
- accidents - complications of an infection
what leads to formation of the neural plate?
gastrulation
what is spina bifida detected by?
ultrasound
what are essential for the patterning of the dorsoventral and anteroposterior axes?
- secreted molecules called morphogens (such as Shh or BMP)
- hemeotic genes are also required for the setting up of the AP axis
prenatal diagnosis of NTDs?
- foetal liver is the main source of a-fetoprotein (AFP) which leaks through the open neural tube defects into the amniotic fluid and then into the maternal blood
- this abnormal increase in maternal serum AFP is best detected at weeks 16-18
- maternal serum screening does not detect closed defects and is less sensitive in women taking sodium valproate
- ultrasound recommended to at risk women and those with a +ve serum AFP screening
- lemon sign
- amniocentesis
when can anencephaly and SB be detected?
- anencephaly — from 12th week
- SB — from 16-20 weeks
what is a posterior fossa decompression surgery?
performed on adults with type 1 and 2 chiari malformations to create more space for the cerebellum and to relieve pressure on the spinal column
what is the only type of chiari malformation that can be acquired?
type 1
what are glia?
= the connective tissue of the nervous system, consisting of several different types of cell associated with neurons
- glia are more numerous than neurons in the brain (3:1)
- glia do not participate directly in synaptic interactions and electrical signalling
what are some roles of glial cells in the nervous system?
what are 3 types of glial cells in the mature CNS?
- astrocytes
- oligodendrocytes
- microglial cells
describe astrocytes
- physical support, repair, K+ metabolism, removal of excess neurotransmitter, maintenance of blood-brain barrier
- star-like appearance
describe oligodendroglia
- myelinate CNS axons
- these cells are destroyed in MS
- predominant type of glial cells in white matter
descirbe microglia
- CNS phagocytes
- mesodermal origin
what does a mutation in Shh cause?
holoprosencephaly
what is holoprosencephaly?
- a disorder caused by the failure of the prosencephalon (embryonic forebrain) to sufficiently divide into the double lobes of the cerebral hemispheres
what can cause microcephaly?
zika virus
what is lissencephaly?
- smooth brain (absence of the normal convulsions and microcephaly)
- failure in cells migrating
what do the alar and basal plates in the spinal cord give rise to?
alar plate — dorsal horn (sensory)
basal plate — ventral horn (motor)
what is received by neurons as a signal for migration through the disabled-1 signalling pathway?
reelin
what secretes reelin?
CR cells in marginal zone
what stops reelin output from CR cells?
BDNF
The needle in a lumbar puncture is usually inserted between the L3 and L4 (or L4 and L5) vertebrae. The spinous process of L4 is determined by a plane that transects the highest points of the iliac crests.
what is the name of this plane?
supracristal plane
the ectoderm sends and receives signals of what?
BMP4
what is the neural plate derived from?
ectoderm
what is the notochord derived from?
mesoderm
what direction does the neural tube fuse in?
centrally, spreading outward
on what date does the anterior neurospore close?
25
what are the alar and basal plate separated by?
sulcus limtians
during apical constriction, the neural plate cells change shape into what?
pyramidal
what patterns the ventral neural tube?
Shh
what does Shh bind to? this binding results in the activation of what? which rests in the Gli complex releasing what?
- binds to patched
- results in activation of smoothened
- results in the Gli complex releasing Gli activator
the highest levels of Shh cause what?
floor plate differentiation
what is the name given to the condition in whcih the cerebral hemispheres are missing and instead filled with sacs of CSF?
hydrancephaly
what is folate aka?
vitamin B9
which type of chairi malformation involves the extension of the cerebellar tonsils into the foramen magnum, without involving the brain stem?
type 1
which type of chiari malformation involves the herniation of the cerebellum and brain stem through the foramen magnum and into the spinal cord?
type 3
which type of chiari malformation involves an incomplete or underdeveloped cerebellum?
type 4
which type of chiari malformation involves the extension of both cerebellar and brainstem tissue into the foramen magnum?
type 2
whcih type of chairi malformatuon is known as “classic CM”?
type 2
